Category: Hem/Onc Updates

Late Breaking Abstract – ESMO 2022: PADCEV® plus KEYTRUDA® in Previously Untreated Cisplatin-Ineligible Patients with Locally Advanced or Metastatic Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in the United States for 2022, about 81,180 new cases of bladder cancer will be diagnosed and approximately 17,100 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. Approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic Urothelial Carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is an Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, Monomethyl auristatin E, which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-103 is a clinical trial conducted to examine the safety and efficacy of Enfortumab vedotin given as monotherapy, and in combination with other anticancer therapies, as first line and second line treatment, for patients with urothelial cancer. This study was conducted in multiple parts for both locally advanced or metastatic urothelial cancer and muscle invasive bladder cancer.

EV-103/KEYNOTE-869 Cohort K is a randomized cohort investigating Enfortumab vedotin alone or in combination with Pembrolizumab as first line treatment in patients with unresectable locally advanced or metastatic urothelial cancer, who are ineligible to receive Cisplatin-based chemotherapy. In this Phase Ib/II randomized study, 149 eligible patients (N=149) were randomly assigned to receive a combination of Enfortumab vedotin 1.25 mg/kg given intravenously on days 1 and 8, and Pembrolizumab 200 mg given intravenously on day 1, every 21 days (N=76) or Enfortumab vedotin monotherapy given on the same schedule (N=73). Ineligibility for Cisplatin-based chemotherapy could be due to at least one of the following: Glomerular filtration rate (GFR) less than 60 mL/min, ECOG Performance Status of 2, Grade 2 or more hearing loss, or New York Heart Association Class III heart failure. No prior systemic treatment for locally advanced or metastatic disease, and adjuvant/neoadjuvant Platinum-based therapy within 12 months prior to randomization, were allowed. The Primary endpoint was confirmed Objective Response Rate (ORR) by BICR (Blinded Independent Central Review). Secondary endpoints included Duration of Response (DOR), Safety, Progression Free Survival (PFS) and Overall Survival (OS).

At a median follow up of 14.2 months, the confirmed Objective Response Rate was 64.5% with the Enfortumab vedotin and Pembrolizumab combination, with 10.5% of patients experiencing a Complete Response and 53.9% of patients experiencing a Partial Response. The median Duration of Response was not reached. The most common Treatment-Related Adverse Events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%).

It was concluded that in Cisplatin-ineligible patients with unresectable locally advanced or metastatic urothelial cancer, treatment with Enfortumab vedotin and Pembrolizumab combination in chemo naïve patients, resulted in high Overall Response Rate, along with a safety profile that was tolerable. The authors added that Antibody-Drug Conjugates have the potential to make a greater impact in treating bladder cancer, especially in combination with checkpoint inhibitors, as shown in this trial and these data support ongoing investigations of first line Enfortumab vedotin and Pembrolizumab in patients with locally advanced or metastatic urothelial cancer.

Study EV-103 Cohort K: Antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). Rosenberg JE, Milowsky M, Ramamurthy C, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA73

Late Breaking Abstract – ESMO 2022: Neoadjuvant KEYTRUDA® with Chemoradiation in Locally Advanced Head and Neck Squamous Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that in the US for 2022, about 54,000 new cases of oral cavity or oropharyngeal cancer will be diagnosed and about 11,230 patients will die of the disease. Patients with Squamous Cell Carcinoma of the head and neck, frequently present with locoregionally advanced disease.

The treatment paradigm for Head and Neck cancer has been rapidly evolving with the recognition and better understanding of immune evasion and the role of immune checkpoints or gate keepers in suppressing antitumor immunity. Blocking the immune checkpoints unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. Checkpoint inhibitors administered in a neoadjuvant setting activates both the priming phase of immunity within tumor tissue, and the effector phase within the tumor microenvironment. It has been shown that neoadjuvant immunotherapy expands more T-cell clones than adjuvant treatment. Preclinical models have also demonstrated that both radiation therapy and Cisplatin chemotherapy increase the PD-L1 expression on the tumor, suggesting that combining radiotherapy with anti-PD-1 therapy could improve the outcomes.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. Pembrolizumab has been shown to improve Overall Survival in patients with Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma

KEYNOTE-412 is a randomized, double-blind, Phase III trial, conducted to evaluate the efficacy and safety of Pembrolizumab in combination with chemoradiation versus placebo in combination with chemoradiation, in treatment naïve patients with locally advanced Head and Neck Squamous Cell carcinoma. In this study, 804 patients were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV every 3 weeks plus chemoradiation (70Gy in 35 fractions along with Cisplatin 100 mg/m2 IV every 3 weeks) followed by Pembrolizumab (N=402), or placebo every 3 weeks plus chemoradiation, followed by placebo (N=402). Patients received Pembrolizumab /placebo priming dose 1 week before chemoradiation, followed by 2 doses during chemoradiation and 14 doses of maintenance therapy after chemoradiation, for a total of 17 doses. Enrolled patients had newly diagnosed, pathologically proven, treatment naive locally advanced Head and Neck Squamous Cell carcinoma (T3-T4, N0-N3 or any N2a-3, T1-T4 larynx/hypopharynx/oral cavity/p16-negative oropharynx cancers, or T4 or N3 p16-positive oropharynx cancer). Both treatment groups were well balanced. The Primary endpoint was Event Free Survival (EFS). Secondary endpoints included Overall Survival (OS), and Safety.

At the time of data cutoff, with a median follow up of 47.7 months, there was a favorable trend toward improved Event Free Survival (EFS) with the addition of Pembrolizumab vs placebo to chemoradiation (HR 0.83, P=0.04), but the difference did not achieve statistical significance. The 2-year EFS was 63.2% in the Pembrolizumab group and 56.2% in the placebo group. In an exploratory analysis however, the 2-year EFS among patients with high expression of PD-L1 (CPS 20 or higher) was 71% in the Pembrolizumab group and 62% in the placebo group. A favorable of Overall Survival benefit was also observed among these patients, with a 3-year OS of 79% in Pembrolizumab group and 73% in the placebo group.

It was concluded that Pembrolizumab in combination with chemoradiation was associated with a favorable trend toward improved Event Free Survival, compared with placebo plus chemoradiation, in patients with locally advanced Head and Neck Squamous Cell carcinoma, but the difference did not reach statistical significance. The researchers added that perhaps patients with high CPS score on the tumor could benefit with this treatment approach.

Primary results of the phase III KEYNOTE-412 study: Pembrolizumab (pembro) with chemoradiation therapy (CRT) vs placebo plus CRT for locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). Machiels J, Tao Y, Burtness B, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA5

Late Breaking Abstract – ESMO 2022: Abemaciclib plus Transtuzumab versus Chemotherapy in HR-positive, HER2-positive Advanced Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 290,560 new cases of breast cancer will be diagnosed in 2022 and about 43,780 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is a heterogeneous disease and approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. Human Epidermal growth factor Receptor 2 (HER2) overexpression is reported in about 15%-20% of primary breast carcinomas and is associated with poor prognosis, and nearly half of HER2-positive breast cancers are also HR-positive. Patients with HER2-positive breast cancers are generally treated with HER2-targeted therapy combined with chemotherapy. Patients with HER2-positive and HR-positive breast cancer are additionally treated with long-term hormone therapy.

Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. VERZENIO® (Abemaciclib) is an oral, selective inhibitor of CDK4 and CDK6 kinase activity, and prevents the phosphorylation and subsequent inactivation of the Rb tumor suppressor protein, thereby inducing G1 cell cycle arrest and inhibition of cell proliferation. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2 oncogene. FASLODEX® (Fulvestrant) is a parenteral, Selective Estrogen Receptor Degrader (SERD) and is approved for the treatment of postmenopausal women with HR-positive metastatic breast cancer.

monarcHER (NCT02675231) is an International, randomized, multicenter, open-label, three-group, Phase 2 trial, conducted to compare the efficacy of Abemaciclib plus Trastuzumab with or without Fulvestrant, with standard-of-care chemotherapy of physician’s choice plus trastuzumab, in women with advanced breast cancer. In this study, 237 patients were enrolled. Eligible patients had Hormone Receptor (HR)-positive, HER2-positive advanced breast cancer, with unresectable, locally advanced, recurrent, or metastatic disease, and had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to Group A (Abemaciclib, Trastuzumab, and Fulvestrant) N=79, Group B (Abemaciclib and Trastuzumab) N=79, or Group C (standard-of-care chemotherapy and trastuzumab) N=79. Treatment consisted of Abemaciclib 150 mg orally twice daily on days 1-21 of a 21-day cycle, Trastuzumab 8 mg/kg IV on cycle 1, day 1, followed by 6 mg/kg IV on day 1 of each subsequent 21-day cycle, and Fulvestrant 500 mg IM on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Patients were stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. An exploratory biomarker analysis of breast cancer molecular subtypes was conducted by RNA sequencing. The Primary endpoint was investigator-assessed Progression Free Survival (PFS), first testing Group A versus Group C, and if this result was significant, then Group B versus Group C. Secondary end points included Overall Survival (OS), Overall Response Rate, Patient Reported Outcomes, and pharmacokinetics. Safety was assessed in all patients who had received at least one dose of study treatment.

Previous analyses from this trial revealed that after a median follow up of 19.0 months, the Primary endpoint was met, with significantly superior PFS in Group A compared to Group C (8.3 months versus 5.7 months, respectively, HR=0.67; P=0.051), with a reduction in the risk for disease progression or death of 33%. (Lancet Oncol. 2020;21:763–775). The researchers herein reported the results, after a median follow up of 52.9 months.

The median Overall Survival was 31.1 months in Group A, 29.2 months in Group B and 20.7 months in Group C. When Group A was compared with Group C, the triplet regimen with Abemaciclib, Trastuzumab, and Fulvestrant (Group A) induced a statistically significant improvement in Overall Survival, compared with Trastuzumab plus chemotherapy (Group C). There was a numerically improved Overall Survival benefit with Abemaciclib, in combination with HER2-targeted therapy (Trastuzumab) with or without hormonal therapy (Fulvestrant), compared with chemotherapy plus Trastuzumab, and there was a consistent benefit observed with the addition of Abemaciclib across all pre-specified subgroups. Updated Progression Free Survival and safety findings were consistent with the primary analysis. An exploratory biomarker analysis by RNA sequencing suggested that Luminal subtypes were associated with longer Progression Free Survival (8.6 versus 5.4 months, HR=0.54) and Overall Survival (31.7 versus 19.7 months, HR=0.68), compared to non-Luminal subtypes. The most common serious adverse events in Group A were pyrexia, diarrhea, urinary tract infection, and acute kidney injury (3% each); in Group B were diarrhea and pneumonitis (3% each); and in Group C were neutropenia (6%) and pleural effusion (3%).

The authors concluded that based on this final analysis, a triple-agent, chemotherapy-free treatment regimen consisting of Abemaciclib plus Trastuzumab, with or without Fulvestrant, numerically improved Overall Survival in women with Hormone Receptor-positive, HER2-positive, advanced breast cancer, compared to chemotherapy plus Trastuzumab.

Final overall survival (OS) for abemaciclib plus trastuzumab +/- fulvestrant versus trastuzumab plus chemotherapy in patients with HR+, HER2+ advanced breast cancer (monarcHER): A randomized, open-label, phase II trial. Andre F, Nadal JC, Denys H, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA18

Late Breaking Abstract – ESMO 2022: CABOMETYX®, OPDIVO® and YERVOY® in Previously Untreated Advanced Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 79,000 new cases of kidney cancers will be diagnosed in the United States in 2022 and about 13,920 people will die from this disease. Clear Cell Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer in adults. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five-year survival of patients with advanced RCC is about 14% and there is a significant unmet need for improved therapies for this disease.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, whereas YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152). Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation, and a therapeutic response. The FDA in 2018, granted approvals to OPDIVO® and YERVOY® in combination, for the treatment of Intermediate or Poor-risk, previously untreated advanced Renal Cell Carcinoma.

CABOMETYX® (Cabozantinib) is an oral, small-molecule Tyrosine Kinase Inhibitor (TKI), which targets Vascular Endothelial Growth Factor Receptors (VEGFR), as well as tyrosine kinases MET and AXL. Both MET and AXL are upregulated in Renal Cell Carcinoma as a consequence of VHL inactivation, and increased expression of MET and AXL is associated with tumor progression and development of resistance to VEGFR inhibitors. Further, CABOMETYX® promotes an immune-permissive environment, which may enhance response to checkpoint inhibitors. CABOMETYX® was approved by the FDA in 2016 for the treatment of advanced Renal Cell Carcinoma.

COSMIC-313 is a global, multicenter, randomized, double-blinded, controlled, ongoing Phase III pivotal trial, conducted to evaluate the triplet combination of Cabozantinib, Nivolumab and Ipilimumab versus the doublet combination of Nivolumab and Ipilimumab, in patients with previously untreated advanced Intermediate or Poor-risk Renal Cell Carcinoma. COSMIC-313 was designed to answer whether adding Cabozantinib to dual checkpoint inhibition can improve outcomes among patients with Intermediate and Poor-risk advanced Renal Cell Carcinoma.

In this trial, 855 treatment naïve, advanced clear cell Renal Cell Carcinoma patients of IMDC (International Metastatic RCC Database Consortium) Intermediate or Poor risk were randomized 1:1 to receive Cabozantinib plus Nivolumab and Ipilimumab (N=428) or placebo plus Nivolumab and Ipilimumab (N=427). Patients in the study group received Cabozantinib 40 mg, orally once daily in combination with Nivolumab 3 mg/kg IV and Ipilimumab 1 mg/kg IV once every 3 weeks for 4 doses total followed by Cabozantinib 40 mg orally once daily and Nivolumab 480 mg/kg flat dose IV, once every 4 weeks for up to 2 years. Patients in the control group received the same regimen, but instead of Cabozantinib, received a matched placebo. Both treatment groups were well balanced. The median patient age was 60 years, 75% were men, 63% had PD-L1 expression of less than 1%, 75% had Intermediate-risk disease, 25% were Poor risk, and 65% had prior nephrectomy. The Primary endpoint was Progression Free Survival (PFS), as assessed by Blinded Independent Radiology Committee (BIRC). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety. The median follow up was 20.2 months.

The study met the Primary endpoint and the median PFS was not reached in the Cabozantinib group and was 11.3 months in the placebo group (HR=0.73; P=0.013). Patients treated with the Cabozantinib three-drug combination had a 27% lower risk of disease progression or death compared to those on the two drug immunotherapy combination. This PFS benefit was predominantly noted in the Intermediate-risk group. The Objective Response Rate was 43% with the Cabozantinib combination versus 36% in the placebo plus dual immunotherapy group, with 3% of patients achieving a Complete Response in both treatment groups. The Disease Control Rate was 86% and 72%, respectively. The median Duration of Response was not reached in either treatment group. Grade 3/4 adverse events occurred in 73% of patients treated with the combination of Cabozantinib, Nivolumab and Ipilimumab, and in 41% of patients treated with the Nivolumab and Ipilimumab combination. Discontinuation of all treatment agents due to adverse events occurred in 12% and 5% of patients, respectively.

The authors concluded that this is the first study to show that a TKI added to dual checkpoint inhibition significantly improved Progression Free Survival, in patients with untreated, Intermediate or Poor risk advanced kidney cancer, compared to doublet immunotherapy. Follow-up for Overall Survival is ongoing.

Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Choueiri TK, Powles TB, Albiges L, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089. LBA8

Late Breaking Abstract – ESMO 2022: Apalutamide Plus Androgen Deprivation Therapy in Biochemically Relapsed Prostate Cancer

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SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 9 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 268,490 new cases of prostate cancer will be diagnosed in 2022, and 34,500 men will die of the disease. The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer and is the first treatment intervention.

The major source of PSA (Prostate Specific Antigen) is the prostate gland, and the PSA levels are therefore undetectable within 6 weeks after Radical Prostatectomy. Similarly, following Radiation Therapy there is a gradual decline in PSA, before reaching a post treatment nadir. A detectable PSA level after Radical Prostatectomy, or a rising PSA level following Radiation Therapy, is considered PSA failure or biochemical recurrence. Approximately 35% of the patients with prostate cancer will experience PSA only relapse within 10 years of their primary treatment and a third of these patients will develop documented metastatic disease within 8 years following PSA only relapse. Rising PSA is therefore a sign of recurrent disease. Patient’s with biochemically relapsed prostate cancer following local therapy, and a short PSA doubling time, are at risk for distant metastases.

ERLEADA® (Apalutamide) is an orally administered Androgen Receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Apalutamide inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. Apalutamide is presently approved for the treatment of patients with metastatic Castration Sensitive Prostate Cancer and non-metastatic Castration Resistant Prostate Cancer. ZYTIGA® (Abiraterone) is a selective, irreversible inhibitor of CYP 17A1 enzyme and decreases androgen biosynthesis in the testes, adrenal glands, and prostate-tumor tissue. Both Apalutamide and Abiraterone plus prednisone have been shown to prolong Overall Survival in the metastatic prostate cancer.

The purpose of this study was to evaluate if intensification of Androgen Deprivation Therapy (ADT) prolongs biochemical Progression Free Survival (PFS), in patients with biochemically relapsed prostate cancer. PRESTO is a randomized, open-label Phase III trial, in which 504 prostate cancer patients who had radical prostatectomy were included. Study patients had biochemical recurrence (PSA more than 0.05 ng/mL), a PSA doubling time of 9 months or less, and without distant metastases on conventional imaging (CT and Bone scan). Patients were randomized 1:1:1 to receive a finite 52-week treatment course with ADT alone (N=167), ADT plus Apalutamide (N=168), or ADT plus Apalutamide plus Abiraterone/Prednisone (N=169). Patients were stratified by PSA doubling time (less than 3 months versus 3-9 months) and patients were followed up following treatment completion with mostly lab assessment until PSA progression, at which point, treatment was per investigator discretion. Patient and disease characteristics at baseline were well balanced among the 3 study groups. The median age was 67 years and 84% of patients were white. The median PSA at baseline was 1.77 ng/mL. The PSA doubling time was less than 3 months for 26% of patients and between 3 and 9 months for 74% of patients. The median time between radical prostatectomy and baseline was 4.4 years. Overall, 85% of patients had prior radiation and 42% of patients had prior ADT. The Primary endpoint of the study was to compare biochemical Progression Free Survival (defined as increase in serum PSA of more than 0.2 ng/mL following treatment) in each experimental group with ADT alone. Secondary endpoints included safety, patient-reported Quality of Life (QOL), time to testosterone recovery (more than 50 ng/dL following treatment completion), Metastasis-Free Survival, and time to castration resistance.

The first planned interim analysis at a median follow-up of 21.5 months showed that both study groups significantly prolonged biochemical PFS compared to the control group. The median biochemical (PSA) PFS was 24.9 months with Apalutamide plus ADT versus 20.3 months with ADT alone (HR=0.52; P=0.00047). The median biochemical PFS was 26.0 months with ADT plus Apalutamide plus Abiraterone/Prednisone versus 20.0 months with ADT alone (HR=0.48; P=0.00008). A preplanned subgroup analysis based on stratification by PSA doubling time showed a consistent benefit in both study groups, compared to the control group, regardless of the length of PSA doubling time. The median time to testosterone recovery following treatment completion was 3.9 months with ADT alone, 3.8 months with Apalutamide plus ADT and 4.7 months with ADT plus Apalutamide plus Abiraterone/Prednisone. There was an increase in the incidence of adverse events with the addition of Abiraterone.

It was concluded that intensifying Androgen Receptor blockade with Apalutamide plus Androgen Deprivation Therapy prolongs biochemical PFS with a manageable safety profile and without impacting time to testosterone recovery, following a finite duration of treatment. The authors added that intensification of Androgen Receptor blockade should be considered in high-risk biochemically relapsed prostate cancer.

LBA63 – PRESTO: A phase III, open-label study of androgen annihilation in patients (pts) with high-risk biochemically relapsed prostate cancer (AFT-19). Aggarwal R, Heller G, Hillman D, et al. Annals of Oncology (2022) 33 (suppl_7): S808-S869. 10.1016/annonc/annonc1089

FDA Grants Regular Approval to TABRECTA® for Metastatic Non-Small Cell Lung Cancer

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SUMMARY: The FDA on August 10, 2022, granted regular approval to TABRECTA® (Capmatinib), for adult patients with metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have a mutation leading to Mesenchymal-Epithelial Transition (MET) exon 14 skipping, as detected by an FDA-approved test. The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

MET is a widely expressed Receptor Tyrosine Kinase and plays a pivotal role in cell growth, proliferation, and survival. The MET gene encodes for a protein known as the Hepatocyte Growth Factor (HGF) Receptor. Upon binding by Hepatocyte Growth Factor (HGF), the HGF Receptor is activated, with resulting activation of the downstream RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby serving different important biological functions. Alterations in the MET gene leading to abnormal MET signaling, has been identified in different types of cancers including thyroid, lung, breast, liver, colon, kidney, ovary, and gastric carcinoma.

Two key MET alterations include MET exon 14 skipping mutations and MET amplification. MET exon 14 skipping mutations occur in approximately 5% of NSCLC patients with enrichment in sarcomatoid lung cancers (22%). MET exon 14 skipping mutation is a recognized oncogenic driver and is a molecular genetic abnormality indicating the presence of a splice site mutation that results in a loss of transcription of exon 14 of the MET gene. Most exon 14 mutations occur in never-smokers and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping generally have very high response rates to MET inhibitors and molecular testing for MET exon 14 skipping should therefore be performed on all lung cancers, because this is a targetable alteration. MET amplification has been more commonly seen in smokers, and responses in patients with MET-amplified tumors might be more variable and dependent on level of amplification, with higher responses noted in tumors with more than 5-6- fold amplification. Tumors with MET exon 14 skipping mutations usually do not harbor activating mutations in EGFR, KRAS, or BRAF or concurrent ALK, ROS1 or RET translocations. However, it appears that cMET exon 14 skipping is not mutually exclusive with cMET amplification.

TABRECTA® is a highly potent and selective, reversible inhibitor of MET tyrosine kinase. The FDA in May 2020 granted accelerated approval for the same indication based on the primary findings from the GEOMETRY mono-1 trial, which is a non-randomized, open-label, multi-cohort, Phase II study, conducted to evaluate the efficacy and safety of single-agent TABRECTA® in adult patients with EGFR wild-type, ALK-negative, metastatic NSCLC, whose tumors have a mutation that leads to MET exon 14 skipping (METex14), as detected by an RNA-based RT-PCR. The conversion to regular approval was based on data from an additional 63 patients (Total N=160), as well as an additional 22 months of follow- up time, to assess durability of response and verify clinical benefit.

In this updated analysis, a total of 160 patients (N=160) with metastatic NSCLC and confirmed MET exon 14 skipping mutations were included, of whom 60 patients were treatment naïve and 100 patients were previously treated. The patients received TABRECTA® at 400 mg orally twice daily until disease progression or unacceptable toxicity. The median patient age was 71 years and all NSCLC histologies including sarcomatoid/carcinosarcoma were included. Majority of the patients (77%) were white and 23% were Asian, 61% never smoked, 83% had adenocarcinoma, and 16% had CNS metastases. Among previously treated patients, 81% received one, 16% received two, and 3% received three prior lines of systemic therapy. Amongst previously treated patients, 86% received prior platinum-based chemotherapy. The Primary efficacy outcome was Overall Response Rate (ORR), and additional efficacy outcomes included Duration of Response, Time to Response, Disease Control Rate, Progression Free Survival (PFS) and Safety, as determined by a Blinded Independent Review Committee (BIRC).

Among the treatment-naïve patients (N=60), the ORR was 68% with a median Duration of Response of 12.6 months. Among the previously treated patients (N=100), the ORR was 44%, with a median Duration of Response of 9.7 months. The most common adverse events (occurring in at least 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. TABRECTA® can also cause Interstitial Lung Disease, hepatotoxicity and photosensitivity.

It was concluded that TABRECTA® is a new treatment option for patients with MET exon 14 skipping- mutated advanced NSCLC, regardless of the line of therapy, with deep and durable responses, and with manageable toxicity profile.

Capmatinib in MET exon 14-mutated, advanced NSCLC: Updated results from the GEOMETRY mono-1 study. Wolf J, Garon EB, Groen HJM, et al. DOI: 10.1200/JCO.2021.39.15_suppl.9020 Journal of Clinical Oncology – published online before print May 28, 2021.

FDA Approves IMFINZI® in Combination with Chemotherapy for Advanced Biliary Tract Cancer

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SUMMARY: The FDA on September 2, 2022, approved IMFINZI® (Durvalumab) in combination with Gemcitabine and Cisplatin for adult patients with locally advanced or metastatic Biliary Tract cancer. Bile Tract cancer (Cholangiocarcinoma) is a rare, heterogenous cancer, and comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. The 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival, has been increasingly explored.

IMFINZI® (Durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics and unleashes the T cells. IMFINZI® in combination with Gemcitabine and Cisplatin showed encouraging antitumor activity in a Phase II study, among patients with advanced Biliary Tract cancers.

TOPAZ-1 is a double-blind, multicenter, global, Phase III trial conducted to evaluate the efficacy of first line immunotherapy given along with Gemcitabine and Cisplatin in patients with advanced metastatic Biliary Tract cancer. In this study, a total of 685 previously untreated patients with unresectable, locally advanced, recurrent or metastatic Biliary Tract cancer were randomized 1:1 to receive IMFINZI® (Durvalumab) 1500 mg IV every 3 weeks (N=341) or placebo (N=344), along with Gemcitabine 1000 mg/m2 IV and Cisplatin 25 mg/m2 IV given on Days 1 and 8, every 3 weeks for up to 8 cycles, followed by IMFINZI® 1500 mg IV every 4 weeks or placebo, until disease progression or unacceptable toxicity. Patients with recurrent disease more than 6 months following curative surgery or adjuvant therapy were also included. The median patient age was 64 years and approximately 50% of patients had an ECOG Performance Status of 0. Randomization was stratified by disease status (initially unresectable, recurrent) and primary tumor location (intrahepatic cholangiocarcinoma versus extrahepatic cholangiocarcinoma versus gallbladder cancer). Approximately 56% had intrahepatic cholangiocarcinoma, followed by gallbladder cancer (25%) and extrahepatic cholangiocarcinoma (19%). Tumor assessments were conducted every 6 weeks for the first 24 weeks, and then every 8 weeks until confirmed objective disease progression. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), and Safety.

IMFINZI® plus Gemcitabine and Cisplatin significantly improved Overall Survival compared with placebo plus chemotherapy, with a 20% reduction in the risk of death. The median OS was 12.8 months and 11.5 months in the IMFINZI® and placebo groups, respectively (HR=0.80; P=0.021). The median PFS was 7.2 months and 5.7 months in the IMFINZI® and placebo arms, respectively (HR=0.75; P=0.001). The Objective Response Rate was 26.7% in the IMFINZI® plus chemotherapy group and 18.7% in the placebo plus chemotherapy group. Grade 3 or 4 treatment-related adverse events were almost similar in both treatment groups (62.7% versus 64.9%), and treatment discontinuation due to adverse events was 8.9% in the IMFINZI® plus chemotherapy group and 11.4% in the placebo plus chemotherapy group.

It was concluded that in patients with advanced Biliary Tract cancers, IMFINZI® in combination with Gemcitabine and Cisplatin significantly improved Overall Survival and Progression Free Survival with manageable safety, when compared to chemotherapy alone, and should therefore be considered first line standard-of- care for this patient group.

A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (gemcis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. Oh D-Y, He AR, Qin S, et al. J Clin Oncol. 2022;40(suppl 4):378. DOI:10.1200/JCO.2022.40.4_suppl.378.

Neoadjuvant Chemotherapy and Organ Preservation in Rectal Cancer

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SUMMARY: The American Cancer Society estimates that 44,850 new cases of rectal cancer will be diagnosed in the US in 2022. Based on the information from the SEER database, the 5-year relative survival rates for rectal cancer, all SEER stages combined is 67%.
Patients with high-risk clinical T1 and T2N0 rectal tumors undergo surgical resection along with total mesorectal excision, combined with preoperative chemoradiation for patients with T3 or N1 tumors. Even though locoregional relapse rates with neoadjuvant therapy are low with excellent survival rates, total mesorectal excision can result in bowel and sexual function issues, as well as bowel incontinence. Up to 60% of patients can experience these symptoms with the addition of perioperative radiation.

Transanal excision surgery is increasingly used for treatment of select T1N0 or T2N0 rectal tumors. There is however an increased rate of local relapse with local excision compared with surgical resection, as a significant proportion of clinical T1-2N0 tumors are pathologically node-positive. Pelvic chemoradiation followed by transanal excision surgery in patients with clinical T1-3 rectal cancer is associated with an organ preservation rate of 50%-68%. However, preoperative radiation can significantly effect wound-healing and adversely affect sphincter and sexual function. Neoadjuvant chemotherapy followed by surgical excision can potentially reduce locoregional recurrence as well as distal relapse in Stage II/III rectal cancer. There are no prospective studies with regards to neoadjuvant chemotherapy and transanal excision surgery for Stage I rectal tumors.

The Canadian Cancer Trials Group (CCTG) CO.28 NEO is a Phase II trial, designed to determine the outcomes and organ preservation rate among patients with early stage rectal tumors treated with neoadjuvant chemotherapy followed by transanal excision surgery, and to further explore the prognostic value of tumor biomarkers for the outcomes. A total of 58 eligible patients were enrolled in Canada and the United States. Enrolled patients had clinical T1-T3ab, N0 (node negative) low or mid-rectal invasive, well/moderately differentiated adenocarcinoma, deemed eligible for endoscopic resection by the study surgeon. All patients were required to have a pelvic MRI and CT scan of the chest, abdomen, and pelvis. Neoadjuvant chemotherapy could be either six cycles of mFOLFOX6 or four cycles of CAPOX, at the discretion of the investigator. mFOLFOX6 consisted of Leucovorin 400 mg/m2 and Oxaliplatin 85 mg/m2 in one 2-hour IV infusion, Fluorouracil 400 mg/m2 IV bolus on day 1, and 46-hour IV infusion of Fluorouracil 2400 mg/m2, given every 14 days. CAPOX consisted of Capecitabine 1000 mg/m2 orally twice daily for 14 days, and Oxaliplatin 130 mg/m2 IV on day 1, given every 21 days. Patients with a history of external-beam pelvic radiation, prior therapy for rectal cancer, or metastatic disease were excluded. The median age was 67 years, 95% had preserved mismatch repair status and in 5% was unknown, two thirds of the patients had clinical T2 lesion by MRI, median tumor distance from the anal verge was 6 cm, and 60% of the tumors were RAS mutated.

Following neoadjuvant chemotherapy, patients underwent pelvic MRI imaging and proctoscopy, 2-3 weeks after the last dose of chemotherapy. Tumors with protocol-defined evidence of response proceeded to have transanal excision surgery and those with progression or no response to chemotherapy were recommended total mesorectal excision surgery and preoperative pelvic radiation if the MRI revealed clinical T3ab disease, Node positive or involved or threatened circumferential radial margin. Transanal excision surgery was performed between 2-6 weeks after the last cycle of chemotherapy. Tumor excision included a minimum of 1 cm gross margin. Patients with yp Stage T0/N0 or T1N0 with no poor prognostic features were recommended observation, whereas ypT1 tumors with poor prognostic features, ypT2/3, or any N+ were recommended radical total mesorectal excision surgery. Poor prognostic features included poorly differentiated histology, lymphovascular invasion, and/or positive margin less than 1 mm. Patients assigned to observation were followed for 36 months from the time of transanal excision surgery, with proctoscopy every 6 months, pelvic MRI every 6 months or pelvic CT at months 12, 24, and 36, CEA every 6 months, and annual contrast CT of the chest, abdomen, and pelvis for 3 years. The Primary end point was organ preservation rate, defined as the proportion of patients with tumor downstaging to ypT0/T1 N0/X, and who avoided radical surgery.

Neoadjuvant induction chemotherapy followed by transanal excision surgery was well tolerated and resulted in downstaging to ypT0/T1 clinical N0 tumors in 57% of the enrolled patients and the protocol-specified organ preservation rate was 79%. The median follow up was 15.4 months. The 1-year and 2-year locoregional Relapse Free Survival was 98% and 90% respectively, and there were no distant recurrences or deaths. There was no significant change noted in Quality of Life and rectal function scores, compared to baseline scores.

It was concluded that three months of neoadjuvant induction chemotherapy may successfully downstage a significant proportion of patients with early stage rectal cancer, allowing a much-desired organ-sparing surgical treatment option.

Kennecke HF, O’Callaghan CJ, Loree JM, et al. DOI: 10.1200/JCO.22.00184 Journal of Clinical Oncology. Published online August 18, 2022.

Opdualag™ (nivolumab and relatlimab-rmbw): A New Dual I-O Option in the 1L Treatment of Metastatic Melanoma

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Written By: Leonel Fernando Hernandez Aya, MD. Division of Medical Oncology, Department of Medicine, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center

Content Sponsored by: Bristol Myers Squibb
Dr Hernandez Aya is a paid consultant for BMS and was compensated for his contribution in drafting this content.

See additional definitions of abbreviations used throughout the article at the bottom of this page.

Overview of Metastatic Melanoma
Since the approval of anti–CTLA-4 in 2011 for metastatic melanoma, immuno-oncology(I-O) has transformed treatment outcomes.1 There are now several approved I-O options, and of those approved for the treatment of metastatic melanoma, dual immunotherapy in particular has had long-term success.2 The first dual immunotherapy, approved in 2015, consisted of PD-1 and CTLA-4 checkpoint inhibitors for the 1L treatment of unresectable or metastatic melanoma, regardless of BRAF mutation status.1,3,4 This anti–PD-1 and anti–CTLA-4 combination showed benefit in overall survival (OS) compared with anti–CTLA-4 alone.5 In general, the safety profile was consistent with previous experience with anti–PD-1 or anti–CTLA-4 alone.4 Until March 2022, this dual anti–PD-1 and anti–CTLA-4 immunotherapy was the only option indicated for the 1L treatment of unresectable or metastatic melanoma.3,6 Opdualag, the second approved dual immunotherapy, has provided an additional treatment option for nivolumab-monotherapy–appropriate patients with unresectable or metastatic melanoma.6-8

Opdualag
Opdualag is a dual immunotherapy option combining an anti–PD-1, nivolumab, with the first-in-class anti–LAG-3, relatlimab, in a fixed-dose formulation.7,8 PD-1 and LAG-3 are two distinct inhibitory immune checkpoints.7 Combined PD-1 and LAG-3 inhibition results in increased T-cell activation compared to the activity of either antibody alone. This initiates an improved anti-tumor immune response.8

Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.8 The approval is based on RELATIVITY-047, a phase 3, randomized, double-blind, global study of Opdualag versus nivolumab monotherapy.7 Patients were stratified by AJCC v8 M stage, BRAF, PD-L1, and LAG-3 status.7 Key exclusion criteria include patients with active or untreated brain or leptomeningeal metastases, uveal melanoma, active autoimmune disease, or medical conditions requiring systemic treatment with moderate- or high-dose corticosteroids or immunosuppressive medications.8

RELATIVITY-047 enrolled 714 patients who were randomized 1:1 to receive Opdualag (480 mg nivolumab/160 mg relatlimab as a fixed-dose combination[FDC]) every 4 weeks (n=355) or nivolumab 480 mg every 4 weeks (n=359).8 The primary endpoint was progression-free survival(PFS), and secondary endpoints were OS and overall response rate(ORR). PFS was determined by BICR using RECIST v1.1. Baseline characteristics were balanced across both treatment arms.7

Study design8

Median duration of treatment for Opdualag at the 19.3-month median follow-up was 8.3 months.7,9 Treat until disease progression or unacceptable toxicity.8

*Patients were allowed to have received prior adjuvant and neoadjuvant melanoma therapy. Anti–PD-1, anti–CTLA-4, or BRAF-MEK therapy was allowed as long as there was at least 6 months between the last dose of therapy and date of recurrence; interferon therapy was allowed as long as the last dose was at least 6 weeks prior to randomization.8† PD-L1 expression (≥1% vs <1%) using PD-L1 IHC 28-8 pharmDx test.8‡ LAG-3 expression (≥1% vs <1%) using a clinical trial assay.8§ The final analysis of OS was not statistically significant.8

Opdualag is associated with the following Warnings and Precautions: severe and fatal immune-mediated adverse reactions (IMARs) including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, dermatologic adverse reactions, myocarditis, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation (HSCT); and embryo-fetal toxicity.

Opdualag demonstrated superior PFS compared to nivolumab at the primary analysis(median of 13.2 months) with curve separation as early as 3 months and sustained over time.7,8 Median PFS (mPFS)was 10.1 months with Opdualag versus 4.6 months with nivolumab (HR=0.75; 95% CI: 0.62–0.92; P=0.0055).8 Similarly, patients who received Opdualag had longer PFS regardless of key prognostic indicators, such as the AJCC metastasis stage of the tumor, LDH level, and tumor burden.7

At the follow-up analysis (median of 19.3 months), mPFS was 10.22 months with Opdualag and 4.63 months with nivolumab (HR=0.78; 95% CI: 0.64-0.94).10 OS and ORR were also evaluated.8 The final analysis for the secondary endpoint of OS was not statistically significant (threshold for significance was P<0.04302), and median OS (mOS)was not reached with Opdualag compared with nivolumab, which resulted in a mOS of 34.1 months (HR=0.80; 95% CI: 0.64–1.01; P=0.0593). Additionally, the ORR was higher with Opdualag (43%) versus nivolumab (33%), with the median DOR not yet reached for both treatment arms.8,10 ORR was not formally tested based on the testing hierarchy.8

Progression-free survival at the 19.3-month median follow-up10*†‡

Symbols represent censored observations.
*Assessed by BICR.8† Final PFS analysis.8‡ Kaplan-Meier estimate.8§ Based on stratified Cox proportional hazard model.8II Based on stratified log-rank test.8

Overall survival10*

*At the time of the final OS analysis, which was event-driven and occurred after the final PFS analysis.8† Based on stratified Cox proportional hazard model.8‡ Based on stratified log-rank test.8§ Not significant at alpha level 0.04302.8

In RELATIVITY-047, Opdualag had no additional safety events and similar most common Grade 3/4 AEs versus nivolumab monotherapy.7,8 Adverse reactions occurring in ≥15% of patients receiving Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), diarrhea (24%), nausea (17%), headache (18%), hypothyroidism (17%), decreased appetite (15%), and cough (15%).8

Toxicity was graded per NCI CTCAE v5.
*Clinically relevant adverse reactions in <15% of patients who received Opdualag included vitiligo, adrenal insufficiency, myocarditis, and hepatitis.8† Includes multiple terms.8

Opdualag is a FDC administered as a 30-minute intravenous infusion every 4 weeks.8 A FDC is the co-formulation of 2 active ingredients in a single vial administered as a single infusion, which may help reduce preparation and infusion times and could help minimize potential risk of administration errors.7,8,11 Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.8

Summary/conclusions
Dual immunotherapy has changed the metastatic melanoma treatment landscape.2 Currently there are 2 dual immunotherapy options available for 1L treatment of adult patients with unresectable or metastatic melanoma.3,8 As the newest dual immunotherapy, Opdualag more than doubled mPFS with a similar safety profile compared with nivolumab.8 Opdualag can be used for the treatment of all nivolumab monotherapy-appropriate patients, providing the opportunity for more patients with unresectable or metastatic melanoma to receive a dual immunotherapy.8 From my clinical experience, “it is great to have another treatment option for patients with metastatic melanoma.”

Indication for Opdualag
Opdualag is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

Important Safety Information for Opdualag
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis
Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis
Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies
Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction
Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions
Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis
Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions
The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdualag or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: Cardiac/Vascular: pericarditis, vasculitis; Nervous System: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Harada–like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica; Endocrine: hypoparathyroidism; Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions
Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation
There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions
In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in ≥1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities
The most common adverse reactions reported in ≥20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in ≥20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see US Full Prescribing Information for Opdualag.

Indication for OPDIVO® (nivolumab) + YERVOY® (ipilimumab)
OPDIVO, in combination with YERVOY, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

Important Safety Information
Severe and Fatal Immune-Mediated Adverse Reactions
Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis
OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%).

Immune-Mediated Colitis
OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%).

Immune-Mediated Hepatitis and Hepatotoxicity
OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3 (1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2 (1.8%).

Immune-Mediated Endocrinopathies
OPDIVO and YERVOY can cause primary or secondary adrenal insufficiency, immune-mediated hypophysitis, immune-mediated thyroid disorders, and Type 1 diabetes mellitus, which can present with diabetic ketoacidosis. Withhold OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated.

In patients receiving OPDIVO monotherapy, adrenal insufficiency occurred in 1% (20/1994), including Grade 3 (0.4%) and Grade 2 (0.6%).In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 8% (35/456), including Grade 4 (0.2%), Grade 3 (2.4%), and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypophysitis occurred in 0.6% (12/1994) of patients, including Grade 3 (0.2%) and Grade 2 (0.3%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (42/456), including Grade 3 (2.4%) and Grade 2 (6%).

In patients receiving OPDIVO monotherapy, thyroiditis occurred in 0.6% (12/1994) of patients, including Grade 2 (0.2%).

In patients receiving OPDIVO monotherapy, hyperthyroidism occurred in 2.7% (54/1994) of patients, including Grade 3 (<0.1%) and Grade 2 (1.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hyperthyroidism occurred in 9% (42/456) of patients, including Grade 3 (0.9%) and Grade 2 (4.2%).

In patients receiving OPDIVO monotherapy, hypothyroidism occurred in 8% (163/1994) of patients, including Grade 3 (0.2%) and Grade 2 (4.8%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, hypothyroidism occurred in 20% (91/456) of patients, including Grade 3 (0.4%) and Grade 2 (11%).

In patients receiving OPDIVO monotherapy, diabetes occurred in 0.9% (17/1994) of patients, including Grade 3 (0.4%) and Grade 2 (0.3%), and 2 cases of diabetic ketoacidosis.

Immune-Mediated Nephritis with Renal Dysfunction
OPDIVO and YERVOY can cause immune-mediated nephritis. In patients receiving OPDIVO monotherapy, immune-mediated nephritis and renal dysfunction occurred in 1.2% (23/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.5%), and Grade 2 (0.6%).

Immune-Mediated Dermatologic Adverse Reactions
OPDIVO can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug rash with eosinophilia and systemic symptoms (DRESS) has occurred with PD-1/PD-L1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes.

YERVOY can cause immune-mediated rash or dermatitis, including bullous and exfoliative dermatitis, SJS, TEN, and DRESS. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-bullous/exfoliative rashes.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

In patients receiving OPDIVO monotherapy, immune-mediated rash occurred in 9% (171/1994) of patients, including Grade 3 (1.1%) and Grade 2 (2.2%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated rash occurred in 28% (127/456) of patients, including Grade 3 (4.8%) and Grade 2 (10%).

Other Immune-Mediated Adverse Reactions
The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received OPDIVO monotherapy or OPDIVO in combination with YERVOY or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: cardiac/vascular: myocarditis, pericarditis, vasculitis; nervous system: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune neuropathy; ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur; gastrointestinal: pancreatitis to include increases in serum amylase and lipase levels, gastritis, duodenitis; musculoskeletal and connective tissue: myositis/polymyositis, rhabdomyolysis, and associated sequelae including renal failure, arthritis, polymyalgia rheumatica; endocrine: hypoparathyroidism; other (hematologic/immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis (HLH), systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

In addition to the immune-mediated adverse reactions listed above, across clinical trials of YERVOY monotherapy or in combination with OPDIVO, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in <1% of patients unless otherwise specified: nervous system: autoimmune neuropathy (2%), myasthenic syndrome/myasthenia gravis, motor dysfunction; cardiovascular: angiopathy, temporal arteritis; ocular: blepharitis, episcleritis, orbital myositis, scleritis; gastrointestinal: pancreatitis (1.3%); other (hematologic/immune): conjunctivitis, cytopenias (2.5%), eosinophilia (2.1%), erythema multiforme, hypersensitivity vasculitis, neurosensory hypoacusis, psoriasis.

Some ocular IMAR cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada–like syndrome, which has been observed in patients receiving OPDIVO and YERVOY, as this may require treatment with systemic corticosteroids to reduce the risk of permanent vision loss.

Infusion-Related Reactions
OPDIVO and YERVOY can cause severe infusion-related reactions. Discontinue OPDIVO and YERVOY in patients with severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild (Grade 1) or moderate (Grade 2) infusion-related reactions. In patients receiving OPDIVO monotherapy as a 60-minute infusion, infusion-related reactions occurred in 6.4% (127/1994) of patients. In a separate trial in which patients received OPDIVO monotherapy as a 60-minute infusion or a 30-minute infusion, infusion-related reactions occurred in 2.2% (8/368) and 2.7% (10/369) of patients, respectively. Additionally, 0.5% (2/368) and 1.4% (5/369) of patients, respectively, experienced adverse reactions within 48 hours of infusion that led to dose delay, permanent discontinuation or withholding of OPDIVO. In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation
Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with OPDIVO or YERVOY. Transplant-related complications include hyperacute graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease (VOD) after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between OPDIVO or YERVOY and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with OPDIVO and YERVOY prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal studies, OPDIVO and YERVOY can cause fetal harm when administered to a pregnant woman. The effects of YERVOY are likely to be greater during the second and third trimesters of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with OPDIVO and YERVOY and for at least 5 months after the last dose.

Increased Mortality in Patients with Multiple Myeloma when OPDIVO is Added to a Thalidomide Analogue and Dexamethasone
In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of patients with multiple myeloma with a PD-1 or PD-L1 blocking antibody in combination with a thalidomide analogue plus dexamethasone is not recommended outside of controlled clinical trials.

Lactation
There are no data on the presence of OPDIVO or YERVOY in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment and for 5 months after the last dose.

Serious Adverse Reactions
In Checkmate 067, serious adverse reactions (74% and 44%), adverse reactions leading to permanent discontinuation (47% and 18%) or to dosing delays (58% and 36%), and Grade 3 or 4 adverse reactions (72% and 51%) all occurred more frequently in the OPDIVO plus YERVOY arm (n=313) relative to the OPDIVO arm (n=313). The most frequent (≥10%) serious adverse reactions in the OPDIVO plus YERVOY arm and the OPDIVO arm, respectively, were diarrhea (13% and 2.2%), colitis (10% and 1.9%), and pyrexia (10% and 1.0%).

Common Adverse Reactions
In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO plus YERVOY arm (n=313) were fatigue (62%), diarrhea (54%), rash (53%), nausea (44%), pyrexia (40%), pruritus (39%), musculoskeletal pain (32%), vomiting (31%), decreased appetite (29%), cough (27%), headache (26%), dyspnea (24%), upper respiratory tract infection (23%), arthralgia (21%), and increased transaminases (25%). In Checkmate 067, the most common (≥20%) adverse reactions in the OPDIVO arm (n=313) were fatigue (59%), rash (40%), musculoskeletal pain (42%), diarrhea (36%), nausea (30%), cough (28%), pruritus (27%), upper respiratory tract infection (22%), decreased appetite (22%), headache (22%), constipation (21%), arthralgia (21%), and vomiting (20%).

Please see US Full Prescribing Information for OPDIVO and YERVOY.

References
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2. Curti BD, Faries MB. Recent advances in the treatment of melanoma. N Engl J Med. 2021;384(23):2229-2240.
3. OPDIVO [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1):23-34.
5. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546.
6. Cancer Research Institute. FDA Approval Timeline of Active Immunotherapies. Updated June 27, 2022. Accessed July 11, 2022. https://www.cancerresearch.org/en-us/scientists/immuno-oncology-landscape/fda-approval-timeline-of-active-immunotherapies.
7. Tawbi HA, Schadendorf D, Lipson EJ, et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N Engl J Med. 2022;386(1):24-34.
8. Opdualag [package insert]. Princeton, NJ: Bristol-Myers Squibb Company.
9. PubD 00058298. Princeton, NJ: Bristol-Myers Squibb Company; 2022.
10. Long GV, Hodi FS, Lipson EJ, et al. Relatlimab and nivolumab vs nivolumab in previously untreated metastatic or unresectable melanoma: overall survival and response rates from RELATIVITY-047 (CA224-047). Oral presentation at ASCO Plenary Series 2022. Presentation number 9505.
11. US Food and Drug Administration. CFR–Code of Federal Regulations Title 21. Updated March 29, 2022. Accessed July 1, 2022.https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=300.50.

© 2022 Bristol-Myers Squibb Company. OPDIVO®, YERVOY®, Opdualag™, and the related logos are trademarks of Bristol-Myers Squibb Company.
7356-US-2200441 8/22

Additional Definitions
AJCC=American Joint Committee on Cancer; BICR=blinded independent central review; CI=confidence interval;CTLA-4=cytotoxic T-lymphocyte antigen 4; DOR=duration of response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; HR=hazard ratio;IHC=immunohistochemistry; IV=intravenous;LAG-3=lymphocyte-activation gene 3; LDH=lactate dehydrogenase; M stage=metastasis stage; mo=month; no=number; NS=not significant; PD-1=programmed death receptor-1; PD-L1=programmed death ligand 1; q4w=every 4 weeks; RECIST=Response Evaluation Criteria In Solid Tumors.

FDA Grants Accelerated Approval to ENHERTU® for HER2-Mutant Non Small Cell Lung Cancer

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SUMMARY: The FDA on August 11, 2022, granted accelerated approval to ENHERTU® (fam-trastuzumab deruxtecan-nxki), for adult patients with unresectable or metastatic Non-Small Cell Lung Cancer (NSCLC) whose tumors have activating human Epidermal Growth Factor Receptor 2 or HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. This is the first drug approved for HER2-mutant NSCLC. FDA also approved Oncomine™ Dx Target Test (tissue) and Guardant360® CDx (plasma) as companion diagnostics for ENHERTU®. If no mutation is detected in a plasma specimen, the tumor tissue should be tested.

The American Cancer Society estimates that for 2022, about 236,740 new cases of lung cancer will be diagnosed and 135,360 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. HER2 is a Tyrosine Kinase Receptor expressed on the surface of several tumor types including Breast, Gastric, Lung and Colorectal cancers. It is a growth-promoting protein, and HER2 overexpression/HER2 gene amplification is often associated with aggressive disease and poor prognosis in certain tumor types. However, HER2 overexpression and gene amplification are associated with distinct molecular entities and have limited therapeutic value in lung cancer.

HER2 mutations unlike HER2 overexpression and gene amplification are oncogenic drivers and are detected in 2 to 4% of NSCLCs. They are more often detected in younger, female and never-smokers, and almost exclusively in Adenocarcinomas. Next-generation sequencing is used to identify HER2 mutations. Majority of HER2 mutations (80-90%) occur in exon 20, as either a duplication or an insertion of 12 nucleotides, resulting in the addition of four amino acids (YVMA) at codon 775 in the kinase domain. This distinct molecular entity is characterized by specific pathological and clinical behavior. These acquired HER2 gene mutations have been independently associated with cancer cell growth, aggressive form of disease and poor prognosis, and with an increased incidence of brain metastases. There are currently no therapies approved specifically for the treatment HER2 mutant NSCLC and is therefore an unmet need.

ENHERTU® (Trastuzumab Deruxtecan) is an Antibody-Drug Conjugate (ADC) composed of a humanized monoclonal antibody specifically targeting HER2, with the amino acid sequence similar to HERCEPTIN® (Trastuzumab), attached to a potent cytotoxic Topoisomerase I inhibitor payload by a cleavable tetrapeptide-based linker. ENHERTU® has a favorable pharmacokinetic profile and the tetrapeptide-based linker is stable in the plasma and is selectively cleaved by cathepsins that are up-regulated in tumor cells. Unlike KADCYLA® (ado-Trastuzumab emtansine), which is also an Antibody-Drug Conjugate, ENHERTU® has a higher drug-to-antibody ratio (8 versus 4), the released payload easily crosses the cell membrane with resulting potent cytotoxic effect on neighboring tumor cells regardless of target expression, and the released cytotoxic agent (payload) has a short half-life, minimizing systemic exposure. ENHERTU® is approved in the US for the treatment of adult patients with unresectable or metastatic HER2-positive or HER2-Low breast cancer and locally advanced or metastatic HER2-positive Gastric or GastroEsophageal Junction adenocarcinoma who have received a prior Trastuzumab based regimen. Translational research demonstrated that HER2-mutant NSCLC may preferentially internalize the HER2 receptor Antibody-Drug Conjugate complex regardless of HER2 protein expression and overcome resistance to other HER2-targeted agents.

In the DESTINY-Lung01 Phase II, open-label, two-cohort trial of heavily pretreated population of patients with HER2-mutated advanced NSCLC, treatment with ENHERTU® 6.4 mg/kg given by IV infusion every 3 weeks resulted in an Objective Response Rate (ORR) of 55%, with a median Duration of Response was 9.3 months. Responses were observed across different HER2 mutation subtypes. The median PFS was 8.2 months, and the median OS was 17.8 months (NEJM 2022;386:241-251).

The present FDA approval was based on DESTINY-Lung02, which is a global, multicenter, multi-cohort, randomized, blinded, dose-optimization, Phase II trial, in which the safety and efficacy of two doses ENHERTU® (5.4mg/kg or 6.4mg/kg) was evaluated, in patients with HER2 mutated metastatic NSCLC, with disease recurrence or progression during or after at least one regimen of prior anticancer therapy that must have contained a platinum-based chemotherapy. This study enrolled 152 patients (N=152) and patients were selected for treatment with ENHERTU® based on the presence of activating HER2 (ERBB2) mutations in a tumor specimen. Patients were randomized to receive ENHERTU® 6.4 mg/kg or 5.4 mg/kg by IV infusion every 3 weeks, until unacceptable toxicity or disease progression. The Primary endpoint of the trial was Objective Response Rate (ORR) as assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Disease Control Rate (DCR), Duration of Response (DoR), Progression Free Survival (PFS), Overall Survival (OS) and Safety. The primary/interim efficacy analysis included a pre-specified cohort of 52 patients (N=52). The median age in this cohort was 58 years, 69% were female; 79% were Asian, 12% were White, and 10% were of other races.

ENHERTU® 5.4mg/kg IV demonstrated a confirmed Objective Response Rate of 57.7%, with a Complete Response Rate of 1.9%, Partial Response Rate of 55.8%, and median Duration of Response of 8.7 months. The most common adverse effects included nausea, alopecia, increased AST and ALT, cytopenias, and was consistent with previous clinical trials, with no new safety concerns identified.

It was concluded that ENHERTU® is the first HER2-directed treatment option for patients with HER2 mutated NSCLC, and fulfills an unmet medical need in this patient population.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-her2-mutant-non-small-cell-lung