Category: Hem/Onc Updates

FDA Approves TRODELVY® for HR-Positive Breast Cancer

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SUMMARY: The FDA on February 3, 2023, approved TRODELVY® (Sacituzumab govitecan-hziy) for patients with unresectable, locally advanced or metastatic Hormone Receptor (HR)-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer, who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting.

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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
Approximately 70% of breast tumors in patients with metastatic disease are Estrogen Receptor (ER) and/or Progesterone Receptor (PR) positive and HER2-negative. These patients are often treated with single agent endocrine therapy, endocrine therapy in combination with CDK4/6 inhibitor, or single agent chemotherapy. Resistance to hormonal therapy occurs in a majority of the patients and there is therefore an unmet need for agents with novel mechanisms of action.

TRODELVY® (Sacituzumab govitecan) is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells, as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38. TRODELVY® was approved by the FDA in 2021 for patients with unresectable, locally advanced or metastatic Triple Negative Breast Cancer, who have received two or more prior systemic therapies, at least one of them for metastatic disease.

In the IMMU-132 Phase I/II TRODELVY® study, the Hormone Receptor positive (HR+)/HER2-negative cohort of patients with metastatic breast cancer patients had an Objective Response Rate (ORR) of 31.5%, median Progression Free Survival (PFS) of 5.5 months and median Overall Survival (OS) of 12 months, with manageable toxicities.

The present new FDA approval is based on TROPiCS-02, a global, open-label, randomized, Phase III study, conducted to confirm the benefit of TRODELVY® in HR+/HER2- negative advanced breast cancer. In this study, 543 patients with HR+/HER2-negative, unresectable, locally advanced or metastatic breast cancer, were randomly assigned 1:1 to receive TRODELVY® 10 mg/kg IV on D1 and 8, every 21 days (N=272), or treatment of physician’s choice, which included single agent treatment with either Capecitabine, Eribulin, Vinorelbine, or Gemcitabine (N=271). Treatment was continued until disease progression or unacceptable toxicity. Both treatment groups were well balanced. Eligible patients had 3 median prior chemotherapy regimens for metastatic breast cancer, and one prior therapy for metastatic breast cancer was allowed if disease progressed in 12 months or less after neoadjuvant chemotherapy. Patients were required to have received endocrine therapy, a CDK4/6 inhibitor and at least one prior therapy with a Taxane in any setting. Majority of patients had visceral metastases (95%), 86% had prior endocrine therapy for metastatic breast cancer for at least 6 months, and 60% and 38% received prior CDK4/6 inhibitors for 12 months or less, and for more than 12 months, respectively. The Primary endpoint was Progression Free Survival (PFS) by Blinded Independent Central Review and key Secondary endpoint was Overall Survival (OS).

The median Progression Free Survival was 5.5 months with TRODELVY® versus 4 months with standard chemotherapy (HR=0.66; P=0.0003), representing a 34% improvement in PFS with TRODELVY®. This benefit was seen across all treatment subgroups including those who were 65 years or older, those who were heavily pretreated, as well as those with visceral metastases. The authors reported the planned TROPiCS-02 Overall Survival data at the 2nd interim analysis.

At a median follow up of 12.5 months, TRODELVY® significantly improved median Overall Survival compared to standard chemotherapy (14.4 months versus 11.2 months; HR=0.79; P=0.02). The Objective Response Rate (ORR) was 21% with TRODELVY® versus 14% with standard chemotherapy, and the median Duration of Response was 8.1 months versus 5.6 months, respectively. Treatment with TRODELVY® also resulted in an overall Health-Related Quality of Life benefit over chemotherapy, with delayed deterioration in fatigue and global health score/ Quality of Life. Grade 3 or more adverse events were observed in 74% of patients receiving TRODELVY® and in 60% of those receiving chemotherapy, and the most common toxicities associated with TRODELVY® were diarrhea neutropenia, nausea, alopecia and fatigue.

It was concluded from this landmark analysis that treatment with TRODELVY® resulted in a statistically significant and clinically meaningful improvement in Progression Free Survival, Overall Survival, Objective Response Rate and Quality of Life, compared to standard chemotherapy, in heavily pre-treated patients with HR+/HER2-negative, endocrine-resistant, unresectable, locally advanced or metastatic breast cancer. TRODELVY® should therefore be considered as a new treatment option for this patient population.

Overall survival results from the phase III TROPiCS-02 study of sacituzumab govitecan vs treatment of physician’s choice in patients with HR+/HER2– metastatic breast cancer. Rugo HS, Bardia A, Marmé F, et al: ESMO Congress 2022. Abstract LBA76. Presented September 9, 2022.

FDA Approves Enfortumab vedotin with Pembrolizumab for Advanced Urothelial Carcinoma

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SUMMARY: The FDA on April 3, 2023, granted accelerated approval to Enfortumab vedotin-ejfv (PADCEV®) with Pembrolizumab (KEYTRUDA®) for patients with locally advanced or metastatic urothelial carcinoma who are ineligible for Cisplatin-containing chemotherapy. The American Cancer Society estimates that in the United States for 2023, about 82,290 new cases of bladder cancer will be diagnosed and approximately 16,710 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

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. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. 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 a first-in-class 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 (MMAE), 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 an ongoing multi-cohort, open-label, global, multicenter Phase Ib/II study, investigating Enfortumab vedotin alone or in combination with Pembrolizumab and/or chemotherapy in first or second line settings, in patients with locally advanced or metastatic urothelial cancer, and in patients with muscle-invasive bladder cancer. The present FDA approval was based on Objective Response Rates (ORR) and median Duration of Response (DOR) in combined Dose Escalation/Cohort A and Cohort K of this study, also known as KEYNOTE-869 trial. The Dose Escalation Cohort and Cohort A were single-arm cohorts treating patients with Enfortumab vedotin plus Pembrolizumab, whereas patients in Cohort K were randomized to either Enfortumab vedotin monotherapy or Enfortumab vedotin in combination with Pembrolizumab. Patients had not received prior systemic therapy for locally advanced or metastatic urothelial cancer and were ineligible for Cisplatin-containing chemotherapy. 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. In this analysis, a total of 121 patients (N=121) received Enfortumab vedotin plus Pembrolizumab. Patients received Enfortumab vedotin 1.25 mg/kg IV (up to a maximum of 125 mg for patients 100 kg or more) on days 1 and 8 and Pembrolizumab 200 mg IV on day 1, every 3 weeks. Treatment was continued until disease progression or unacceptable toxicity. The major efficacy outcome measures were Objective Response Rate (ORR) and Duration of Response (DOR) determined by Blinded Independent Central Review.

Patients treated with a combination of Enfortumab vedotin and Pembrolizumab had an Objective Response Rate of 68%, with 12% of patients experiencing a Complete Response. The median Duration of Response for the Dose Escalation cohort plus Cohort A was 22 months and for Cohort K was Not Reached. The most common Treatment Related Adverse Events (TRAE) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Two thirds of patients had Grade 3 TRAEs, and the most common toxicities were increased lipase, maculopapular rash, and fatigue.

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.

Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. Hoimes CJ, Flaig TW, Milowsky M, et al. DOI: 10.1200/JCO.22.01643 Journal of Clinical Oncology 41, no. 1 (January 01, 2023) 22-31.

Tremelimumab in Combination with Durvalumab and Chemotherapy in Metastatic Non Small Cell Lung Cancer: The Phase III POSEIDON Study

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the T cells of the immune system. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response.

IMFINZI® (Durvalumab) is a human immunoglobulin G1 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. IMJUDO® (Tremelimumab) is a human immunoglobulin G2 monoclonal antibody that targets and blocks the activity of CTLA-4, enhancing binding of CD80 and CD86 to CD28. This complimentary mechanisms of action broadens clinical activity, potentially overcoming primary resistance to PD-(L)1 blockade by enabling novel T-cell responses. The concurrent addition of chemotherapy to checkpoint inhibitors causes tumor cell death and release of neoantigens, which increases immune priming, important for early disease control.

POSEIDON is a global, randomized, open-label, three-arm, Phase III study, which evaluated the efficacy of Tremelimumab plus Durvalumab along with chemotherapy, and Durvalumab along with chemotherapy, compared to chemotherapy alone, in first-line treatment of metastatic NSCLC. In this trial, 1013 patients (N=1013) with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to receive either Tremelimumab 75 mg IV plus Durvalumab 1,500 mg IV along with chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, with one additional Tremelimumab dose after chemotherapy at week 16 (fifth dose), Durvalumab 1500 mg IV plus chemotherapy for up to four 21-day cycles, followed by Durvalumab 1500 mg IV once every 4 weeks until disease progression, or chemotherapy alone for up to six 21-day cycles. Chemotherapy options for treatment groups included Carboplatin plus nab-Paclitaxel regardless of histology, Cisplatin or Carboplatin plus Gemcitabine for patients with squamous histology, and Cisplatin or Carboplatin plus Pemetrexed for patients with nonsquamous histology. Patients with nonsquamous histology who received Pemetrexed-Platinum doublet could receive Pemetrexed maintenance therapy if eligible. Patients continued treatment until progressive disease or unacceptable toxicity. Patients were stratified by PD-L1 expression (50% or more versus less than 50%), disease Stage (IVA versus IVB), and histology (squamous versus nonsquamous). The median age was 64 yrs, 63% had nonsquamous histology, and approximately a third of the patients had PD-L1 expression less than 1%. The treatment groups were well balanced. The Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) for the Durvalumab plus chemotherapy group, compared to the chemotherapy alone group. Key Secondary end points were PFS and OS for Tremelimumab plus Durvalumab along with chemotherapy, compared to chemotherapy alone.

The coPrimary end point of PFS benefit with Durvalumab plus chemotherapy compared to chemotherapy alone was met (HR=0.74; P=0.0009), and the median PFS was 5.5 versus 4.8 months respectively and the 12-month PFS rates were 24.4% versus 13.1%. However, OS did not reach statistical significance (HR=0.86; P=0.075). When Secondary end points were formally evaluated, Tremelimumab plus Durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to chemotherapy alone (HR=0.77; P=0.003). The median OS was 14 months versus 11.7 months respectively and 2 year OS was 32.9% versus 22.1% respectively. The median PFS was 6.2 months and 4.8 months in the treatment arms, respectively (HR=0.72; P=0.0003) and the 1-year PFS rate was 26.6% and 13.1% respectively. Treatment benefit was seen across all PD-L1 subgroups, particularly in tumors with PD-L1 expression of 50% or more. Patients with tumor PD-L1 expression less than 1% appeared to gain improved survival benefit from the addition of Tremelimumab to Durvalumab and chemotherapy.

Based on this study, the FDA approved Tremelimumab in combination with Durvalumab and platinum-based chemotherapy for adult patients with metastatic NSCLC, with no sensitizing EGFR mutation or ALK genomic tumor aberrations.

It was concluded that Durvalumab plus chemotherapy significantly improved Progression Free Survival when compared to chemotherapy alone. A limited course of Tremelimumab added to Durvalumab and chemotherapy significantly improved Overall Survival and Progression Free Survival when compared to chemotherapy, and the clinical benefit extended to patients who had tumor PD-L1 expression less than 1%.

Durvalumab With or Without Tremelimumab in Combination With Chemotherapy as First-Line Therapy for Metastatic Non–Small-Cell Lung Cancer: The Phase III POSEIDON Study. Johnson ML, Cho BC, Luft A, et al. DOI: 10.1200/JCO.22.01737 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1176-1179.

Real World Experience of Anti-BCMA CAR T-Cell Therapy in Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730 new cases will be diagnosed in 2023 and 12,590 patients will die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD 38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed/Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR) by transducing with a gene encoding the engineered CAR via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

ABECMA® (Idecabtagene vicleucel) is the first FDA approved cell-based gene therapy for multiple myeloma and was based on results from the pivotal, open-label, single-arm, multicenter, multinational, Phase II study (KarMMa trial), in which the efficacy and safety of ABECMA® was evaluated in adults with Relapsed and Refractory multiple myeloma. The KarMMa trial however had stringent eligibility criteria, which was likely not representative of real-world population.

The researchers conducted this study to evaluate safety and efficacy of Standard of Care ABECMA® for the treatment of Relapsed and Refractory multiple myeloma in a real-world population. This retrospective, multicenter, observational study included 196 patients planned for Standard of Care ABECMA® for Relapsed and Refractory multiple myeloma from 11 US medical centers. Unlike the KarMMa trial which had stringent eligibility criteria, not representative of real-world patient population, the present study included patients with comorbidities that would have made them ineligible for the KarMMa trial. A total of 159 patients successfully received ABECMA®. The median age was 64 years, and 35% of patients had high-risk cytogenetics (del(17p), t(4;14) and t(14;16), the median number of prior lines of therapy was seven and 44% of patients had penta-refractory disease. In this real-world experience study, 21% had prior anti-BCMA therapy, 84% had prior Autologous Stem Cell Transplant and 6% had Allogeneic Stem Cell Transplant. Approximately 75% of patients in this study would not have met KarMMa eligibility criteria. Further, relative to KarMMa trial, this real-world cohort had more patients with extramedullary and penta-refractory disease.

The median time from leukapheresis to ABECMA® infusion was 47 days. The CAR T-cells manufacturing failure rate in real-world patients was higher than that seen in KarMMa trial and this was attributed to poor bone marrow reserve among patients in this study, probably related to prior treatment, including alkylators, which can result in T-cell depletion. Nonetheless, 90% of eligible patients were administered ABECMA®, which is comparable with 91% in the KarMMa trial. The median follow up from infusion was 6.1 months.

Overall, the efficacy of ABECMA® in the real-world population was comparable with that in the KarMMa trial group of patients. The Overall Response and Complete Response rates with Standard of Care ABECMA® were 84% and 42%, which are comparable with 73% and 33% noted in the KarMMa trial. The median DOR was 8.6 months in the present study versus 10.7 months in the KarMMa trial and the median time to response was 1 month. The median PFS in this study was 8.5 months, similar to that observed in the KarMMa trial and the median Overall Survival was 12.5 months. In a multivariable analysis of this study, prior use of BCMA targeted therapy, high-risk cytogenetics, ECOG PS 2 or more, lymphodepletion, and younger age were independent predictors of inferior Progression Free Survival. Any grade and Grade 3 or more Cytokine Release Syndrome and neurotoxicity occurred in 82%/3% and 18%/6%, respectively.

It was concluded from this trial that safety and efficacy of ABECMA® in patients with Relapsed and Refractory multiple myeloma in the Standard of Care setting were comparable with those in the Phase II pivotal KarMMa trial, even though majority of patients in this study did not meet KarMMa trial eligibility criteria. This real-world population study also suggested that if BCMA chimeric antigen receptor-T-cell treatment is planned, prior exposure to BCMA-targeted therapy should be avoided.

Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium. Hansen DK, Sidana S, Peres LC, et al. DOI: 10.1200/JCO.22.01365 Journal of Clinical Oncology. Published online January 09, 2023.

Zolbetuximab Plus Chemotherapy Improves Survival in CLDN18.2 Positive Metastatic Gastric and Gastroesophageal Junction Cancer

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SUMMARY: The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.
Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. The five-year relative survival rate for patients at the metastatic stage is approximately 6%.

These patients frequently are treated with platinum containing chemotherapy along with a Fluoropyrimidine such as modified FOLFOX6. Patients with HER2-positive disease are usually treated with chemotherapy plus trastuzumab, and for those patients with HER2-negative disease, patients receive chemotherapy along with a checkpoint inhibitor or checkpoint inhibitor alone if the tumors express PD-L1.

Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2, a transmembrane protein. CLDN18.2 protein found in normal gastric cells, and is a major component of epithelial and endothelial tight junctions controlling the flow of molecules between cells. Pre-clinical studies have shown that CLDN18.2 expression which can also be present in gastric tumors, increases as cancer progresses, and may become more exposed and accessible to targeted therapies with antibodies as gastric tumors develop. The binding interaction of Zolbetuximab to CLDN18.2 activates Antibody-Dependent Cellular Cytotoxicity (ADCC) and Complement Dependent Cytotoxicity (CDC) resulting in cancer cell death. About 30-40% of patients with gastric cancer have CLDN18.2 expression.

SPOTLIGHT trial is a Phase III, global, multi-center, double-blind, randomized study, in which the efficacy and safety of Zolbetuximab plus mFOLFOX6 was compared with placebo plus mFOLFOX6, as first-line treatment of patients with CLDN18.2-positive, HER2- negative, locally advanced unresectable or metastatic Gastric or GastroEsophageal Junction cancer. In this study, 565 enrolled patients were randomly assigned 1:1 to receive the combination of Zolbetuximab and mFOLFOX6 (N=283) or placebo and mFOLFOX6 (N=282). Zolbetuximab was given at 800 mg/m2 IV on day 1 of cycle 1 followed by 600 mg/m2 on day 22 of cycle 1, and days 1 and 22 of subsequent cycles, every 3 weeks. mFOLFOX6 (Oxaliplatin, 5-Fluorouracil and Leucovorin) was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, Zolbetuximab was given at the same dosing schedule in combination with 5-Fluorouracil and Leucovorin IV every 2 weeks. Those in the placebo arm were given placebo at the every 3-week schedule and chemotherapy was administered at the same dosing schedule. Treatment was continued until disease progression or discontinuation criteria were met. Enrolled patients had moderate-to-strong CLDN18 staining intensity in at least 75% of tumor cells based on a validated ImmunoHistoChemistry assay, had HER2-negative disease, and an ECOG performance status of 0 or 1. Patients were stratified by region (Asian versus non-Asian), number of organs with metastases (0-2 versus 3 or more), and prior gastrectomy. The median age was 61 years and 31.4% of patients were from Asia. Majority of patients had 0-2 organs with metastases, 30% had prior gastrectomy. Approximately 13% of patients had tumors with a PD-L1 CPS of at least 5. The primary disease site was stomach in 76% of patients and was GastroEsophageal Junction in 24%. The Primary endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), and Safety.

This study met the Primary endpoint and the median PFS was 10.61 months with the Zolbetuximab plus mFOLFOX6 combination versus 8.67 months with placebo plus mFOLFOX6 (HR=0.75; P=0.0066) and this was statistically significant. The OS was also significantly improved (18.23 versus 15.54 months, HR=0.750; P=0.0053), making this one of the longest durations of median OS seen in Phase III trials for this patient population. The most common Adverse Events with Zolbetuximab plus mFOLFOX6 were nausea, vomiting and decreased appetite. The incidences of serious Adverse Events were similar between the two treatment groups.

The authors concluded that Zolbetuximab plus mFOLFOX6 is a new potential Standard-of-Care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic Gastric/GE Junction adenocarcinoma. It is unclear if this regimen is superior to chemotherapy plus a checkpoint inhibitor in patients with PD-L1–positive and CLDN18.2-positive disease.

Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. Shitara K, Lordick F, Bang Y-J, et al. J Clin Oncol. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

Avoiding Radiotherapy in Bulky Early Stage Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2023, about 8830 new cases of Hodgkin Lymphoma will be diagnosed and about 900 patients will die of the disease. Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted, subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin lymphoma histology, accounts for approximately 80% of Hodgkin Lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin and giant multinucleated Reed-Sternberg (RS) cells collectively known as Hodgkin and Reed-Sternberg cells (HRS).

Patients with Stage I/II classical Hodgkin Lymphoma (cHL) with bulky disease (mass more than 10 cm or 1/3 the maximum intrathoracic diameter on chest x-ray), are typically treated with chemotherapy followed by radiation. However radiotherapy to the chest can result in late complications which include risk of secondary malignancies, particularly breast cancer in women treated under the age of 30 years, cardiovascular disease, as well as the possibility of radiation-associated pneumonitis and fibrosis. Given the prognostic impact of interim PET scans after two cycles of chemotherapy (PET2) on Progression Free Survival, several trials evaluated response-adapted therapy, with de-escalation of treatment in patients with negative PET2, and intensifying therapy in patients with PET2-positive findings.

CALGB 50801 is a single-arm, Phase II trial with response-adapted therapy on the basis of centrally reviewed interim PET, and is the first study focusing exclusively on patients with bulky Stage I and II disease. The researchers hypothesized that a PET-adapted strategy would be effective and limit the use of mediastinal radiotherapy and prevent late complications in this high-risk group of patients. This study included 94 eligible and evaluable patients with bulky disease, for the safety and efficacy analyses. Patients were treated with two cycles of full-dose ABVD (Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine) without delay, regardless of neutrophil count, followed by interim FDG PET (PET2). Patients with a negative PET2 defined as 1-3 on the Deauville 5 point scale received four additional cycles of ABVD. Patients with a positive interim PET2 defined as 4 and 5 on the Deauville 5 point scale were treated with escalated BEACOPP (Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone) for four cycles, followed by 30 Gy involved-field radiotherapy. Median age of patients was 30 years, 22% were PET2 positive and 78% were PET2 negative after two cycles of ABVD.

The Primary objectives of this study were to use a PET-adapted approach to maintain Progression Free Survival (PFS) in patients with negative PET2 without the use of radiotherapy, and to improve outcomes in PET2 positive patients by intensifying therapy. The researchers assessed whether PFS for PET2 positive patients receiving escalated BEACOPP was not inferior to that of PET2 negative patients receiving ABVD, compared with historical differences in PFS between PET2 positive patients and PET2 negative patients receiving ABVD.

This PET-adapted study met the primary objective of maintaining ongoing remissions in PET2 negative patients treated with chemotherapy only, without the addition of radiation therapy. The Primary end point of 3-year Progression Free Survival was 93.1% in PET2 negative patients and 89.7% in PET2 positive patients. The 3 year Overall Survival was 98.6% and 94.4%, respectively. Outcomes were similar with intensified chemotherapy followed by radiation for the 22% of PET2 positive patients. The predominant toxicity was neutropenia, with 9% of patients developing febrile neutropenia. The majority of PET2 positive patients remained disease free without the need for high-dose chemotherapy with Autologous Stem Cell Transplant. The researchers pointed out that this study was initiated before the publication of RATHL study, and consistent with current practice, recommended eliminating Bleomycin from cycles 3-6 in PET2 negative patients.

It was concluded from this study that PET-adapted therapy in bulky Stage I/II classical Hodgkin Lymphoma met its primary goal and was associated with an excellent 3-year Progression Free Survival in all patients, with the majority being spared radiotherapy and exposure to intensified chemotherapy.

Positron Emission Tomography–Adapted Therapy in Bulky Stage I/II Classic Hodgkin Lymphoma: CALGB 50801 (Alliance). LaCasce AS, Dockter T, Ruppert AS, et al. J Clin Oncol 2023; 41:1023-1034.

Capivasertib Plus Fulvestrant Improves Progression Free Survival in Advanced Hormone Receptor Positive 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. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.

About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and Hormone Receptor-positive (HR-positive), HER2-negative breast cancer is the most frequently diagnosed molecular subtype. The most common subtype of metastatic breast cancer is 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. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of HR+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression due to resistance to endocrine therapy. Therapies overcoming this resistance is an area of active research in the breast cancer space.

Capivasertib is a novel pyrrolopyrimidine derivative, and is first-in-class orally available inhibitor of the serine/threonine protein kinase AKT (protein kinase B), with potential antineoplastic activity. It is a potent, selective ATP-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Inhibition of AKT prevents the phosphorylation of AKT substrates that mediate cellular processes, such as cell division, apoptosis, and glucose and fatty acid metabolism. A wide range of solid and hematological malignancies show dysregulated PI3K/AKT/mTOR/PTEN signaling due to mutations in the genes involved. By targeting AKT, the key node in the PIK3/AKT signaling network, Capivasertib potentially may be used as monotherapy or combination therapy for a variety of human cancers. The researchers conducted the CAPItello-291 trial to determine whether the addition of Capivasertib to Fulvestrant would improve outcomes in patients with HR-positive breast cancer whose tumors had developed resistance to an Aromatase Inhibitor.

CAPItello-291 is a randomized, double-blind Phase III trial in which 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer, whose disease has recurred or progressed during or after Aromatase Inhibitor therapy, with or without a CDK4/6 inhibitor, were enrolled. Patients were randomly assigned 1:1 to receive either the Capivasertib plus Fulvestrant (N=355) arm or the placebo plus Fulvestrant arm (N=353). Patients in the study group received Capivasertib 400 mg orally twice daily for 4 days on and 3 days off along with Fulvestrant 500 mg IM on days 1 and 15 during cycle 1, then every 4 weeks thereafter. The present dosing of Capivasertib was chosen based on tolerability and the degree of target inhibition in early phase trials. The control group received matched placebo along with Fulvestrant. In this trial, patients could have received up to one line of chemotherapy for advanced disease and approximately 40% of tumors had PI3K/AKT/PTEN alterations. Both treatment groups were well balanced. Stratification factors included liver metastases and prior CDK 4/6 inhibitor. The dual Primary endpoints were Progression Free Survival (PFS) in the overall patient population and in a subgroup of patients whose tumors have qualifying alterations in the PIK3CA, AKT1 or PTEN genes. Secondary endpoints included Overall Survival (OS) and Objective Response Rate (ORR).

The trial met both Primary endpoints, improving PFS in the overall patient population and in a prespecified biomarker subgroup of patients whose tumors had qualifying alterations in the AKT pathway genes. In the overall trial population, patients treated with Capivasertib plus Fulvestrant had a median PFS of 7.2 months, compared to 3.6 months in patients treated with placebo plus Fulvestrant (HR=0.60; P<0.001). This amounted to a 40% lower risk of disease progression among patients who received Capivasertib plus Fulvestrant.

Among patients with AKT pathway mutations treated with Capivasertib plus Fulvestrant, the median PFS was 7.3 months versus 3.1 months in the placebo group (HR=0.50; P<0.001), reducing the risk of disease progression or death by 50%, versus placebo plus Fulvestrant. In the group without qualifying alterations in the AKT pathway genes, the PFS was 7.2 months in the Capivasertib group versus 3.7 months in the placebo group (HR=0.70). The benefit from Capivasertib was consistent across key clinically relevant subgroups, including patients previously treated with CDK4/6 inhibitor and patients with liver metastases.

The Objective Response Rate in the overall trial population was 22.9% among patients treated with Capivasertib plus Fulvestrant compared with 12.2% for patients treated with placebo plus Fulvestrant and was 28.8% and 9.7% respectively in the biomarker altered population. Although the Overall Survival data were immature at the time of the analysis, early data are encouraging and follow up is ongoing.

The most frequent Grade 3 or higher toxicities occurring in 5% or more of patients were diarrhea (9.3%) and rash (12.1%). Treatment discontinuation due to adverse events was 13% among patients who received Capivasertib plus Fulvestrant versus 2.3% among patients who received placebo plus Fulvestrant.

It was concluded that a combination of Capivasertib plus Fulvestrant is a new treatment option with significantly improved Progression Free Survival, in patients who have Hormone Receptor–positive/HER2-negative advanced breast cancer, who had progressed on, or become resistant to, endocrine therapies and CDK4/6 inhibitors.

Capivasertib and fulvestrant for patients with aromatase inhibitor-resistant hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: results from the Phase III CAPItello-291 trial. Turner N, Oliveria M, Howell SJ, et al. Presented at the 2022 San Antonio Breast Cancer Symposium: December 6-10, 2022; San Antonio, TX. Abstract GS3-04.

BRUKINSA® Superior to IMBRUVICA® in Relapsed/Refractory CLL/SLL

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SUMMARY: The American Cancer Society estimates that for 2022, about 20,160 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4410 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. IMBRUVICA® demonstrated survival benefits, when compared to chemoimmunotherapy, both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to IMBRUVICA® discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.

Zanubrutinib (BRUKINSA®) is an irreversible, potent, next-generation, small molecule inhibitor of Bruton’s Tyrosine Kinase, designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity, while minimizing off-target inhibition of TEC- and EGFR-family kinases. It has been hypothesized that the increased selectivity of BRUKINSA® may minimize toxicities, (such as those often associated with IMBRUVICA®) and improve efficacy outcomes. BRUKINSA® demonstrated promising efficacy among patients with CLL/SLL (Small Lymphocytic Lymphoma), in early phase trials.

ALPINE study is a randomized, global, Phase III trial in which BRUKINSA® was compared with IMBRUVICA® in previously treated patients with relapsed or refractory CLL or SLL. In this trial, a total of 652 patients were randomly assigned 1:1 to receive either BRUKINSA® 160 mg orally twice daily or IMBRUVICA® 420 mg orally once daily, until disease progression or unacceptable toxicity. Enrolled patients had at least one prior systemic therapy and were required to have measurable lymphadenopathy by CT scan or MRI. Exclusion criteria included current or past Richter’s transformation and prior treatment with BTK inhibitors. The median age was 67 years, 45% of the patients had bulky disease with a tumor that was 5 cm or more in the greatest dimension, 73% had unmutated IGHV status, and 23% had a chromosome 17p deletion, TP53 mutation, or both and fewer than 15% of patients were on anticoagulants. The median number of previous lines of therapy was 1 and a total of 80% of the patients in the BRUKINSA® group and 76% of those in the IMBRUVICA® group had previously received chemoimmunotherapy. The Primary end point of the trial was Overall Response Rate (ORR) assessed by investigator and Independent Review Committee (IRC), and Secondary end points included Progression Free Survival (PFS), event rate of Atrial Fibrillation or Flutter, Duration of Response, Time to Treatment Failure, Overall Survival (OS), Patient-Reported Outcomes, and Safety.

A prespecified interim analysis showed that BRUKINSA® was superior to IMBRUVICA®, with respect to Overall Response Rate. The authors in this final analysis reported the clinical outcomes of Progression Free Survival, a key Secondary endpoint. Progression Free Survival was assessed with the use of a hierarchical testing strategy to determine whether BRUKINSA® was noninferior to IMBRUVICA®. If noninferiority was established, the superiority of BRUKINSA® was assessed and claimed if the two-sided P value was less than 0.05.

At a median follow up of 29.6 months, BRUKINSA® was found to be superior to IMBRUVICA® with respect to Progression Free Survival, as assessed by the investigators and Independent Review Committee (HR=0.65; P=0.002). The PFS at 24 months was 78.4% in the BRUKINSA® group and 65.9% in the IMBRUVICA® group. Median PFS was not reached in the BRUKINSA® group and was 34.2 months in the IMBRUVICA® group.

Among patients with a 17p deletion, a TP53 mutation, or both, those who received BRUKINSA® had longer PFS than those who received IMBRUVICA® (HR=0.53). The percentage of patients who were alive without disease progression at 24 months in this high-risk population was 72.6% in the BRUKINSA® group, and 54.6% in the IMBRUVICA® group. The PFS benefit was in favor of BRUKINSA® across major prespecified subgroups, including age, previous lines of therapy, disease stage, and IGHV mutational status.

Consistent with the findings at the interim analysis, the Overall Response Rate was higher in the BRUKINSA® group than in the IMBRUVICA® group, and were 86.2% and 75.7%, respectively, as assessed by the Independent Review Committee.

BRUKINSA® had a more favorable safety profile, with a lower incidence of cardiac disorders (21.3%), than in the IMBRUVICA® group (29.6%). Cardiac events leading to treatment discontinuation occurred in 0.3% of patients in the BRUKINSA® group and in 4.3% of patients in the IMBRUVICA® group. The incidence of Atrial fibrillation or flutter of any grade, a key Secondary endpoint, was lower in the BRUKINSA® group than in the IMBRUVICA® group (5.2% versus 13.3%).

It was concluded that in patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma, treatment with BRUKINSA® resulted in a significantly longer Progression Free Survival, compared to those patients who received IMBRUVICA®, and BRUKINSA® was associated with fewer cardiac adverse events.

Zanubrutinib or Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Brown JR, Eichhorst B, Hillmen P, et al. N Engl J Med 2023; 388:319-332.

NALIRIFOX Improves Overall Survival in Patients with Metastatic Pancreatic Cancer

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SUMMARY: The American Cancer Society estimates that in 2022, about 62,210 people will be diagnosed with pancreatic cancer and 49,830 people will die of the disease. Pancreatic cancer is the fourth most common cause of cancer-related deaths in the United States and Western Europe. Unfortunately, unlike other malignancies, very little progress has been made and outcome for patients with advanced pancreatic cancer has been dismal, with a 5-year survival rate for metastatic pancreatic cancer of approximately 10%. Pancreatic cancer has surpassed breast cancer as the third leading cause of cancer death in the United States and is on track to surpass colorectal cancer, to move to the second leading cause of cancer related deaths in the United States. Majority of patients with pancreatic cancer (80% of cases) are diagnosed at an advanced stage, and are not amenable to curative surgical resection, at the time of diagnosis. The current treatment regimens for advanced disease have proved ineffective, conferring a median Overall Survival (OS) of 6-8 months.

ONIVYDE® is a novel nanoliposomal encapsulation of Irinotecan, a topoisomerase 1 inhibitor. It is designed to optimize the delivery of Irinotecan, by extending the duration of circulation of the drug in the body and preferentially activating the drug within the tumor tissues, to achieve higher levels of the active cytotoxic drug metabolite, SN-38. This approach reduces the toxicity of Irinotecan to normal tissues while maintaining or increasing its anti-tumor efficacy.

In the NAPOLI-1 open-label Phase III study, a combination of ONIVYDE®, 5-FU and Leucovorin improved Overall Survival, Progression Free Survival, CA19-9 response and Disease Control Rate following Gemcitabine-based therapy, in patients with metastatic Pancreatic adenocarcinoma. ONIVYDE® in combination with Fluorouracil (5-FU) and Leucovorin was approved for this indication in 2015. In a Phase I/II study, ONIVYDE® in combination with 5-FU, Leucovorin and Oxaliplatin (NALIRIFOX) demonstrated promising anti-tumor activity in patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI 3 is a global, randomized, open-label Phase III trial which tested the safety and efficacy of NALIRIFOX regimen in treatment naïve patients with metastatic pancreatic ductal adenocarcinoma. In this study, 770 patients with histopathologically/cytologically confirmed untreated metastatic pancreatic ductal adenocarcinoma were randomized in a 1:1 ratio to receive NALIRIFOX (N=383) or Gemcitabine plus nab-Paclitaxel (N=387). The NALIRIFOX regimen consisted of ONIVYDE® 50 mg/m2 IV, given along with 5-FU 2400 mg/m2 IV, Leucovorin 400 mg/m2 IV and Oxaliplatin 60 mg/m2 IV on days 1 and 15 of a 28-day cycle. Patients in the Gemcitabine/nab-Paclitaxel group received Gemcitabine 1000 mg/m2 IV along with nab-Paclitaxel 125 mg/m2 IV, on days 1, 8 and 15 of a 28-day cycle. Both treatment groups were well balanced with similar baseline characteristics, including median age of 64.5 years and number of metastatic sites (three or greater in 37% of patients). Patients were stratified by ECOG performance status, geographic region, and presence or absence of liver metastases. The Primary endpoint was Overall Survival (OS) and Secondary endpoints included were Progression Free Survival (PFS), Overall Response Rate (ORR) and Safety.

At a median follow-up of 16.1 months, the median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gemcitabine plus nab-Paclitaxel arm (HR=0.84; P=0.04). There was also a significant improvement in the PFS at 7.4 months versus 5.6 months respectively (HR=0.70; P=0.0001). This OS and PFS benefit was observed across subgroups. The NALIRIFOX group also had a higher Objective Response Rate at 41.8% versus 36.2% for patients treated with Gemcitabine and nab-Paclitaxel group, and a lower percentage of patients who received NALIRIFOX went on to receive subsequent anticancer therapy (50.5% versus 54.4%). Treatment related toxicities associated with NALIRIFOX regimen were manageable and consistent with the drug profiles in this regimen.

It was concluded that first line treatment with NALIRIFOX regimen demonstrated clinically meaningful and statistically significant improvement in Overall Survival and Progression Free Survival, compared with Gemcitabine and nab-Paclitaxel, in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma.

NAPOLI-3: A randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Wainberg ZA, Melisi D, Macarulla T, et al. Presented at: ASCO Gastrointestinal Cancers Symposium; Jan. 19-21, 2023; San Francisco. Abstract LBA661.

Biomarkers May Predict Response to Enfortumab Vedotin in Advanced Urothelial Cancer

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SUMMARY: The American Cancer Society estimates that in 2023, approximately 82,290 new cases of Bladder Cancer will be diagnosed and 16,710 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. Treatment options for patients who progress after first and second line therapies are limited, with poor outcomes. The response rates with standard chemotherapy in this patient population, is about 10%. 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. However there are limited data available on biomarkers predictive of outcomes when treated with Enfortumab vedotin.

The researchers in this study investigated potential biomarkers of response to Enfortumab vedotin by analyzing data from the UNITE (Urothelial Cancer Network to Investigate Therapeutic Experiences) database. This analysis include 170 patients from 16 different sites, with available Next Generation Sequencing using institutional or commercial platforms, treated with Enfortumab vedotin alone, outside of a clinical trial setting, for whom outcomes were available. The median age was 70 years, 78% were men, 65% had pure urothelial histology, 69% had primary bladder tumor, and 68% had 2 or more lines of therapy before Enfortumab vedotin.

The following molecular biomarkers were assessed: Tumor Mutation Burden (TMB), PD-L1 status, presence of 1 or more DNA damage response mutations such as BRCA1, BRCA2, PALB2, ATM, CHEK2, CDK12, BARD1, PPP2R2A, or RAD51B, and somatic alterations such as TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1, in 10% or more of patients. Investigators determined observed response to Enfortumab vedotin in patients with scans after one or more doses of the therapy.

For all patients included in this analysis, the Observed Response Rate was 47%, median Progression Free Survival was 6 months and median Overall Survival was 12 months. The Observed Response Rates were higher in patients with ERBB2 and TSC1 alterations versus wild-type (67% versus 44%; P=0.05 and 68% versus 25%; P=0.04, respectively). Shorter median Progression Free Survival was noted in patients with CDKN2A, CDKN2B, and MTAP alterations, whereas patients with high Tumor Mutation Burden (10 or more Mut/Mb) had longer median Overall Survival.

It was concluded that analysis of this large, multicenter, retrospective cohort of patients with advanced urothelial carcinoma, identified several potential biomarkers associated with differential outcomes to Enfortumab vedotin, and these findings may help inform clinical decision making and potential therapy sequencing.

Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study. Jindal T, Kilari D, Alhalabi O, et al.DOI: 10.1200/JCO.2023.41.6_suppl.450 Journal of Clinical Oncology.