Category: Hem/Onc Updates

Late Breaking Abstract – ASCO 2023: Toripalimab Plus Chemotherapy Improves Progression Free Survival in Metastatic Triple Negative 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.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC. Toripalimab, a checkpoint inhibitor, is a humanized IgG4K monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response, and unleashes the tumor-specific effector T cells. Toripalimab provided significant clinical activity with a favorable safety profile in several solid tumors.

The purpose of this study is to compare the efficacy and safety of Toripalimab versus placebo, in combination with nab-Paclitaxel for metastatic or recurrent TNBC. The rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as Toripalimab when given along with chemotherapy can enhance endogenous anticancer immunity.

TORCHLIGHT is a randomized, double-blind, placebo-controlled, multi-center, Phase III trial, in which the safety and efficacy of Toripalimab plus nab-Paclitaxel was compared with placebo plus nab-Paclitaxel in patients with Stage IV or recurrent/metastatic TNBC. In this study, 531 (N=531) eligible patients were randomly assigned 2:1 to receive Toripalimab 240mg IV on Day 1 every 3 weeks (N=353) or placebo (N=178), along with nab-Paclitaxel given at 125 mg/m2 on days 1 and 8 of each cycle. Treatment was continued until disease progression or intolerable toxicity. Patients could not have received more than one line of chemotherapy in the metastatic setting and had to be eligible for taxane monotherapy. Baseline characteristics were well balanced between the treatment groups and patients were stratified based on PD-L1 expression, Paclitaxel therapy history and line of prior therapy at enrollment. In the Toripalimab group, 200 patients had PD-L1 positive disease, whereas 100 patients in the placebo group had PD-L1-positive disease. The Primary endpoint was Progression Free Survival (PFS) assessed by a Blinded Independent Central Review (BICR), first in the PD-L1-positive population and then in the Intent-To-Treat (ITT) population. Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR), Duration of Response (DoR), Disease Control Rate and Safety.

At interim analysis, with the median follow up of 14 months, a statistically significant improvement in PFS was demonstrated with Toripalimab in the PD-L1 positive subgroup. The median PFS was 8.4 months versus 5.6 months respectively (HR=0.65; P=0.01). The PFS in the overall population showed a similar trend and was 8.4 months in the Toripalimab group and 6.9 months in the placebo group (HR=0.77; P=0.04). A descriptive Overall Survival analysis showed a trend towards improved OS with Toripalimab in the PD-L1 positive group (median OS 32.8 versus 19.5 months; HR=0.61; P=0.01). In the overall population, the median OS was 33.1 versus 23.5 months (HR=0.69, P=0.01). No new safety signals were identified.

The authors concluded that, for PD-L1 positive metastatic or recurrent Triple Negative Breast Cancer patients receiving first-line treatment, the addition of Toripalimab to nab-Paclitaxel resulted in a significant improvement in Progression Free Survival with an acceptable safety profile. Patients are being followed for the final PFS and OS analysis.

TORCHLIGHT: A randomized, double-blind, phase III trial of toripalimab versus placebo, in combination with nab-paclitaxel(nab-P) for patients with metastatic or recurrent triple-negative breast cancer (TNBC). Jiang Z, Ouyang Q, Sun T, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA1013)

Late Breaking Abstract- ASCO 2023: BCMA-directed CAR T-cell therapy Cilta-cel in Lenalidomide Refractory 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, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to 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 CD38 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. 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.

With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed or 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.

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.

Ciltacabtagene autoleucel (Cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with Relapsed or Refractory multiple myeloma and was approved by the FDA in February 2022 for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including a Proteasome Inhibitor (PI), an Immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. The researchers in this study investigated the efficacy of cilta-cel in earlier treatment lines among patients with Lenalidomide-refractory disease.

CARTITUDE-4 is an open-label, multicenter, randomized Phase III trial conducted to compare cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

Treatment with cilta-cel resulted in a significantly lower risk of disease progression or death than standard-of-care (HR=0.26; P<0.001). The median PFS was not reached in the cilta-cel group and was 11.8 months in the standard-of-care group. Progression-free survival at 12 months was 75.9% in the cilta-cel group and 48.6% in the standard-of-care group. The ORR was 84.6% in the cilta-cel group and 67.3% in the standard-of-care group (P<0.001), the CR rate or better was 73.1% versus 21.8% (P<0.001), and MRD negativity was 60.6% versus 15.6% (P<0.001), respectively. Among the patients who had a response, an estimated 84.7% in the cilta-cel group as compared with 63.0% in the standard-of-care group continued to have a response for at least 12 months.

The most common Grade 3 or 4 adverse events in both groups were hematologic and most high-grade cytopenias in patients who received cilta-cel recovered to Grade 2 or less by day 60. Serious adverse events were reported in 44% of patients in the cilta-cel group and in 39% of patients in the standard-of-care group. Lower rates of cytopenias, Cytokine Release Syndrome, and CAR-T–related neurotoxicity were seen in this study compared to previous cilta-cel studies suggesting that cilta-cel may have a better side-effect profile when used earlier in treatment.

It was concluded that a single cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. San-Miguel J, Dhakal B, Yong K, et al. N Engl J Med 2023;389:335-347.

Perioperative Pembrolizumab for Early Stage Non Small Cell Lung Cancer

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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.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

KEYTRUDA® (Pembrolizumab) 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.

KEYNOTE-671 trial is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival. Secondary end points included major pathological response, Pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. Event-Free Survival at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group (HR=0.58; P<0.001). The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02). A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and Pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Selinexor Maintenance in Advanced Endometrial Cancer

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SUMMARY: The American Cancer Society estimates that approximately 66,200 new cases of uterine cancer will be diagnosed in 2023 and about 13,030 individuals will die of the disease. Endometrial carcinoma is the second most prevalent gynecologic cancer in women worldwide, and its incidence has been increasing. Risk factors include age, factors that influence hormone levels such as obesity and estrogen replacement therapy, Type 2 diabetes, family history, diet and exercise, drugs such as Tamoxifen, and delayed menopause. Patients with advanced or recurrent endometrial cancer are often treated with a combination of Carboplatin and Paclitaxel. Treatment options following failure of first-line therapy for this patient group however are limited, with single agent response rates of 10-15% and 5-year survival rates of approximately 17%. There are no approved therapies in the maintenance setting for patients with advanced or recurrent endometrial cancer.

It is estimated that of the endometrial carcinoma molecular subtypes, TP53 wild-type tumors represent 75% of the newly diagnosed endometrial carcinoma and 50% of advanced/recurrent tumors. There are no specific targeted therapies available for patients with TP53 wild-type endometrial carcinoma.

Exportin 1 (XPO1) is an important nuclear export protein overexpressed in endometrial cancers. High XPO1 levels facilitate increased nuclear export of tumor suppressor proteins such as P53, P73, IkB and FOXO3a, pRb, BRCA1, as well as growth regulators such as Glucocorticoid Receptor and oncoprotein mRNA. This enables cancer cells to escape tumor suppressor protein mediated cell cycle arrest and apoptosis.

Selinexor (XPOVIO®) is first-in-class, oral selective XPO1 inhibitor that reactivates the tumor suppressor proteins by preventing nuclear transport and inhibits oncoprotein translation. Selinexor is approved in the US for the treatment of patients with Multiple Myeloma and Diffuse Large B-Cell Lymphoma. Selinexor demonstrated antitumor activity among patients with endometrial carcinoma in Phase I and II trials.

SIENDO/EC-042 is a Phase III randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of Selinexor as maintenance therapy in patients with TP53 wild-type advanced or recurrent endometrial carcinoma who have achieved a Partial or Complete Response after completing at least 12 weeks of platinum combination chemotherapy with or without immunotherapy for primary Stage IV or recurrent disease. Comprehensive tissue-based genomic profiling testing was performed, to identify and enroll patients whose tumors were TP53 wild-type. In this study, 263 eligible patients were randomly assigned in a 2:1 ratio to receive Selinexor 60 mg orally once weekly (N=174) or placebo weekly (N=89). The prespecified TP53 wild-type subgroup included 113 women assigned to Selinexor (N=77) or Placebo (N=36). The median age in the TP53 wild-type subgroup was 63 years and most patients had endometrioid histology and MSS/MMR proficient tumors. Patients were stratified based on whether they had primary Stage IV or recurrent disease, as well as Partial or Complete response to platinum combination chemotherapy before they were started on maintenance therapy with Selinexor. The Primary endpoint was investigator-assessed Progression Free Survival (PFS), with exploratory endpoints including histologic subtype and molecular subclassifications. Secondary end points included PFS by Blinded Independent Central Review, Overall Survival (OS), time to first subsequent therapy, and Health-Related Quality of Life. The primary analysis of Selinexor maintenance therapy showed improvements in median PFS for the intent-to-treat (ITT) population but were not clinically meaningful.

However, an exploratory analysis of a pre-specified subgroup of patients with TP53 wild-type endometrial cancer showed significant findings. At a median follow up of 25.3 months, it was noted that patients with TP53 wild-type tumors receiving Selinexor maintenance therapy had a median PFS of 27.4 months compared with 5.2 months in the placebo group, representing a 58% decrease in the risk of disease progression (HR=0.42; P=0.0003). This efficacy was observed regardless of MSS/MSI status, but women in the TP53 wild-type subgroup who had MSS/MMR proficient tumors demonstrated the greatest PFS benefit with Selinexor. In the subgroup with TP53 mutations/aberrations, the median PFS was shorter with Selinexor (4.2 months versus 5.4 months with placebo; HR=1.34: P=0.92). The most common adverse events with Selinexor in the TP53 wild-type subgroup included nausea (90.8%), vomiting (60.5%) and diarrhea (39.5%). Grade 3-4 events included neutropenia (18.4%) and thrombocytopenia (9.2%).

The authors concluded that TP53 status is a robust prognostic biomarker for endometrial carcinoma and Selinexor maintenance in TP53 wild-type endometrial carcinoma demonstrated durable Progression Free Survival benefit in a pre-specified subgroup analysis, and offers the potential to prolong response to prior systemic therapy.

Long-term follow up of selinexor maintenance in patients with TP53wt advanced or recurrent endometrial cancer: A pre-specified subgroup analysis from the phase 3 ENGOT-EN5/GOG-3055/SIENDO study. Slomovitz B. American Society of Clinical Oncology Plenary Series. July 25, 2023; virtual; abstract 427956.

Review of 44-month follow-up data and primary analysis for cabozantinib + nivolumab in 1L aRCC

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Written by Thomas Hutson, D.O., Pharm. D.
 Sponsored by Exelixis, Inc.

At the 2023 GU Cancer Symposium jointly sponsored by ASCO, ASTRO, and SUO, Dr Maurice Burotto presented the minimum 3-year follow-up efficacy and safety data for the ITT population in the Phase 3 CheckMate-9ER trial. These extended follow-up analysis results continue to support cabozantinib + nivolumab as a first-line treatment for patients with advanced RCC.1,2

CheckMate‐9ER was a randomized (1:1), open‐label, Phase 3 trial vs sunitinib in 651 patients with previously untreated aRCC with a clear‐cell component.1,3

  • Dosing: cabozantinib 40 mg (starting dose) PO once daily in combination with nivolumab 240 mg flat dose IV every 2 weeks vs sunitinib 50 mg (starting dose) PO once daily for 4 weeks, followed by 2 weeks off, per cycle.1
    • The starting dose of cabozantinib is 40 mg when used in combination with nivolumab, unlike the 60‐mg recommended starting dose for single‐agent therapy1
  • Endpoints assessed1,3-6:
    • Primary endpoint was PFS*
    • Secondary endpoints were OS, ORR,* and safety
    • Quality of life: evaluated as an exploratory endpoint using the FKSI‐19 scale, and the clinical significance of the results is unknown
    • Additional exploratory endpoints: biomarkers, pharmacokinetics, immunogenicity, and PFS‐2
  • Updated efficacy analysis: conducted when 271 events were observed based on the pre‐specified number of events for the pre‐planned final analysis of OS1,7,8
  • Patient population in CheckMate-9ER was representative of the aRCC population seen in clinical practice (cabozantinib + nivolumab, n=323; sunitinib, n=328)1,3,4,9-11
    • IMDC risk categories3
      • Favorable: 23% of cabozantinib + nivolumab patients; 22% of sunitinib patients
      • Intermediate: 58% of cabozantinib + nivolumab patients; 57% of sunitinib patients
      • Poor: 19% of cabozantinib + nivolumab patients; 21% of sunitinib patients
    • Prior nephrectomy: 69% of cabozantinib + nivolumab patients; 71% of sunitinib patients9
    • Liver metastases: 23% of cabozantinib + nivolumab patients; 16% of sunitinib patients3
    • Bone metastases: 24% of cabozantinib + nivolumab patients; 22% of sunitinib patients3
    • ≥2 metastatic sites: 80% of cabozantinib + nivolumab patients; 78% of sunitinib patients3

Primary analysis results (median follow‐up time of 18.1 months; range: 10.6‐30.6 months)3:

  • Median PFS was 16.6 months for cabozantinib + nivolumab (95% CI: 12.5-24.9; n=323) compared with 8.3 months for sunitinib (95% CI: 7.0-9.7); HR=0.51 (95% CI: 0.41-0.64)1*
  • Probability of OS at 12 months was 85.7% for cabozantinib + nivolumab (95% CI: 81.3-89.1) compared with 75.6% for sunitinib (95% CI: 70.5-80.0); HR=0.60 (98.89% CI: 0.40-0.89). The median OS was not reached in either group3
  • ORR was 55.7% for cabozantinib + nivolumab (95% CI: 50.1-61.2; n=323) compared with 27.1% for sunitinib (95% CI: 22.4-32.3; n=328)1*

Updated pre-planned analysis of OS (median follow‐up: 32.9 months; range: 25.4‐45.4 months)1,7,8:

  • Median OS was 37.7 months for cabozantinib + nivolumab (95% CI: 35.5‐NR; n=323) compared with 34.3 months for sunitinib (95% CI: 29.0‐NR; n=328); HR=0.70 (95% CI: 0.55‐0.90)

 More than 2 years of additional follow-up from the primary analysis, which makes it the longest available for CheckMate-9ER (median follow‐up: 44 months; range: 36.5-56.5 months):2

  • Median PFS was 16.6 months for cabozantinib + nivolumab (95% CI: 12.8-19.5; n=323) compared with 8.4 months for sunitinib (95% CI: 7.0-9.7; n=328); HR=0.59 (95% CI: 0.49-0.71)2
  • ORR was 56.0% for cabozantinib + nivolumab (95% CI: 50.4-61.5; n=323) compared with 28.0% for sunitinib (95% CI: 23.3-33.2; n=328)2
  • Median OS (depicted in graph below) was 49.5 months for cabozantinib + nivolumab (95% CI: 40.3-NR; n=323) compared with 35.5 months for sunitinib (95% CI: 29.2-42.3); HR=0.70 (95% CI: 0.56-0.87)2,12
    • The median OS for cabozantinib + nivolumab patients was 14 months longer than the sunitinib arm.2,12 This substantial difference was derived without adjustment for subsequent cancer therapy3

44-month follow-up analysis2,12

OS: Median follow-up time of 44.0 months; range: 36.5-56.5 months

OS-Cabo-Opdivo-RCC

PFS and ORR results in patients with bone, liver, and/or lung metastasis shown below13:

ORR-Cabo-Opdivo-RCC

These exploratory analyses are descriptive in nature. Subgroups were not powered to show differences between treatment arms, and results should be considered hypothesis generating.7

In CheckMate-9ER, serious adverse reactions occurred in 48% of patients receiving cabozantinib + nivolumab.1 Serious adverse reactions reported in ≥2% of patients were diarrhea, pneumonia, pneumonitis, pulmonary embolism, urinary tract infection, and hyponatremia.1 Fatal intestinal perforations occurred in 3 (0.9%) patients.1 The most common adverse reactions (≥20%) in patients receiving cabozantinib + nivolumab (n=320) vs sunitinib (n=320) were diarrhea (64% vs 47%), fatigue (51% vs 50%), hepatotoxicity (44% vs 26%), palmar‐plantar erythrodysesthesia (40% vs 41%), stomatitis (37% vs 46%), rash (36% vs 14%), hypertension (36% vs 39%), hypothyroidism (34% vs 30%), musculoskeletal pain (33% vs 29%), decreased appetite (28% vs 20%), nausea (27% vs 31%), dysgeusia (24% vs 22%), abdominal pain (22% vs 15%), upper respiratory tract infection (20% vs 8%), and cough (20% vs 17%).1

  • Cabozantinib may be interrupted or reduced due to adverse events to 20 mg daily or 20 mg every other day.1 The average dosage of cabozantinib in CheckMate-9ER was 30 mg14
    • If previously receiving 20 mg once every other day, resume at same dosage. If not tolerated, discontinue cabozantinib1
    • Adverse reactions leading to discontinuation of either cabozantinib or nivolumab occurred in 20% of patients, which included 8% for only cabozantinib and 7% for only nivolumab.3 It is important to note that 6% of patients in the CheckMate‐9ER trial discontinued both cabozantinib and nivolumab at the same time due to adverse events, compared with 17% of patients in the sunitinib arm who permanently discontinued their treatment3
  • Cabozantinib should be permanently discontinued for Grade 3 or 4 hemorrhage, development of a GI perforation or Grade 4 fistula, acute myocardial infarction or Grade 2 or higher cerebral infarction, Grade 3 or 4 arterial thromboembolic events or Grade 4 venous thromboembolic events, Grade 4 hypertension/hypertensive crisis or Grade 3 hypertension/hypertensive crisis that cannot be controlled, nephrotic syndrome, or reversible posterior leukoencephalopathy syndrome1
  • For patients being treated with cabozantinib + nivolumab, if ALT or AST >10x ULN or >3x ULN with concurrent total bilirubin ≥2x ULN, both cabozantinib + nivolumab should be permanently discontinued1

In summary, the 44-month follow-up data indicate that:

  • After a minimum follow-up of 3 years, survival and response benefits were maintained with cabozantinib + nivolumab, showing consistent outcomes as in previous follow-ups1,2
  • Median OS with cabozantinib + nivolumab improved by 11.8 months since the previous follow-up analysis. Median OS with cabozantinib + nivolumab was 49.5 months compared with 35.5 months for sunitinib1,2,7,8,12
    • The median OS for cabozantinib + nivolumab patients was substantially longer (14 months) than the sunitinib arm. This difference was derived without adjustment for subsequent cancer therapy2,3
  • No new safety signals emerged with additional follow-up in either arm2
  • Among patients treated with cabozantinib + nivolumab, the discontinuation rate due to ARs to cabozantinib alone was 10% and nivolumab alone was 10%, vs 11% for sunitinib.2 This may allow patients receiving cabozantinib + nivolumab to stay on therapy and thus allow them to achieve efficacy benefits

Dr Hutson received a fee for participating in this program, and his comments reflect his opinions and are not intended to constitute medical advice for individual patients.

[Footnotes]

*PFS and ORR were assessed by BICR.1

1L=first‐line; ALT=alanine aminotransferase; AR=adverse reaction; aRCC=advanced RCC; ASCO=American Society of Clinical Oncology; AST=aspartate aminotransferase; ASTRO=American Society for Radiation Oncology; BICR=blinded independent central review; CI=confidence interval; CR=complete response; FKSI‐19=Functional Assessment of Cancer Therapy‐Kidney Symptom Index 19; HR=hazard ratio; IMDC=International Metastatic RCC Database Consortium; IV=intravenous; NR=not reached; ORR=objective response rate; OS=overall survival; PFS=progression‐free survival; PFS‐2=PFS after subsequent therapy; PO=by mouth; PR=partial response; RCC=renal cell carcinoma; SUO=Society of Urologic Oncology; ULN=upper limit of normal.

INDICATIONS

CABOMETYX® (cabozantinib) is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

CABOMETYX, in combination with nivolumab, is indicated for the first-line treatment of patients with advanced RCC.

CABOMETYX is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.

CABOMETYX is indicated for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC, HCC, and DTC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage and prior to surgery as recommended. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.

Perforations and Fistulas: Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of fistulas and perforations, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.

Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic events that require medical intervention.

Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension was reported in 37% (16% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Permanently discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.

Diarrhea: Diarrhea occurred in 62% of CABOMETYX patients. Grade 3 diarrhea occurred in 10% of CABOMETYX patients. Monitor and manage patients using antidiarrheals as indicated. Withhold CABOMETYX until improvement to ≤ Grade 1, resume at a reduced dose.

Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 45% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.

Hepatotoxicity: CABOMETYX in combination with nivolumab can cause hepatic toxicity with higher frequencies of Grades 3 and 4 ALT and AST elevations compared to CABOMETYX alone.

Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes than when the drugs are administered as single agents. For elevated liver enzymes, interrupt CABOMETYX and nivolumab and consider administering corticosteroids.

With the combination of CABOMETYX and nivolumab, Grades 3 and 4 increased ALT or AST were seen in 11% of patients. ALT or AST >3 times ULN (Grade ≥2) was reported in 83 patients, of whom 23 (28%) received systemic corticosteroids; ALT or AST resolved to Grades 0-1 in 74 (89%). Among the 44 patients with Grade ≥2 increased ALT or AST who were rechallenged with either CABOMETYX (n=9) or nivolumab (n=11) as a single agent or with both (n=24), recurrence of Grade ≥2 increased ALT or AST was observed in 2 patients receiving CABOMETYX, 2 patients receiving nivolumab, and 7 patients receiving both CABOMETYX and nivolumab. Withhold and resume at a reduced dose based on severity.

Adrenal Insufficiency: CABOMETYX in combination with nivolumab can cause primary or secondary adrenal insufficiency. For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold CABOMETYX and/or nivolumab and resume CABOMETYX at a reduced dose depending on severity.

Adrenal insufficiency occurred in 4.7% (15/320) of patients with RCC who received CABOMETYX with nivolumab, including Grade 3 (2.2%), and Grade 2 (1.9%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of CABOMETYX and nivolumab in 0.9% and withholding of CABOMETYX and nivolumab in 2.8% of patients with RCC.

Approximately 80% (12/15) of patients with adrenal insufficiency received hormone replacement therapy, including systemic corticosteroids. Adrenal insufficiency resolved in 27% (n=4) of the 15 patients. Of the 9 patients in whom CABOMETYX with nivolumab was withheld for adrenal insufficiency, 6 reinstated treatment after symptom improvement; of these, all (n=6) received hormone replacement therapy and 2 had recurrence of adrenal insufficiency.

Proteinuria: Proteinuria was observed in 8% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. For Grade 2 or 3 proteinuria, withhold CABOMETYX until improvement to ≤ Grade 1 proteinuria, resume CABOMETYX at a reduced dose. Discontinue CABOMETYX in patients who develop nephrotic syndrome.

Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution, resume at a reduced dose

Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.

Thyroid Dysfunction: Thyroid dysfunction, primarily hypothyroidism, has been observed with CABOMETYX. Based on the safety population, thyroid dysfunction occurred in 19% of patients treated with CABOMETYX, including Grade 3 in 0.4% of patients.

Patients should be assessed for signs of thyroid dysfunction prior to the initiation of CABOMETYX and monitored for signs and symptoms of thyroid dysfunction during CABOMETYX treatment. Thyroid function testing and management of dysfunction should be performed as clinically indicated.

Hypocalcemia: CABOMETYX can cause hypocalcemia. Based on the safety population, hypocalcemia occurred in 13% of patients treated with CABOMETYX, including Grade 3 in 2% and Grade 4 in 1% of patients. Laboratory abnormality data were not collected in CABOSUN.

In COSMIC-311, hypocalcemia occurred in 36% of patients treated with CABOMETYX, including Grade 3 in 6% and Grade 4 in 3% of patients.

Monitor blood calcium levels and replace calcium as necessary during treatment. Withhold and resume at reduced dose upon recovery or permanently discontinue CABOMETYX depending on severity.

Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.

ADVERSE REACTIONS

The most common (≥20%) adverse reactions are:

CABOMETYX as a single agent: diarrhea, fatigue, PPE, decreased appetite, hypertension, nausea, vomiting, weight decreased, constipation.

CABOMETYX in combination with nivolumab: diarrhea, fatigue, hepatotoxicity, PPE, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough, and upper respiratory tract infection.

DRUG INTERACTIONS

Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.

Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage. Avoid St. John’s wort.

USE IN SPECIFIC POPULATIONS

Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.

Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. Avoid CABOMETYX in patients with severe hepatic impairment.

Please see accompanying full Prescribing Information by clicking here.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.

 References

  1. CABOMETYX® (cabozantinib) Prescribing Information. Exelixis, Inc.
  2. Burotto M, Powles T, Escudier B, et al. Nivolumab plus cabozantinib versus sunitinib for first-line treatment of advanced renal cell carcinoma: 3-year follow-up from the phase 3 CheckMate 9ER trial. Poster presented at Cancer Immunotherapy and Immunomonitoring Conference; April 24-27, 2023.
  3. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma. N Engl J Med. 2021;384(9):829‐841.
  4. Motzer RJ, Choueiri TK, Powles T, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal cell carcinoma: outcomes by sarcomatoid histology and updated trial results with extended follow‐up of CheckMate 9ER. Poster presented at Genitourinary Cancers Symposium; February 11‐13, 2021
  5. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma [supplementary appendix]. N Engl J Med. 2021;384(9):829-841.
  6. Choueiri TK, Powles T, Burotto M, et al; CheckMate 9ER Investigators. Nivolumab plus cabozantinib versus sunitinib for advanced renal‐cell carcinoma [protocol]. N Engl J Med. 2021;384(9):829‐841.
  7. Motzer RJ, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib in first‐line treatment for advanced renal cell carcinoma (CheckMate 9ER): long‐term follow‐up results from an open‐label, randomized, phase 3 trial. Lancet Oncol. 2022;23(7):888‐898.
  8. Powles T, Choueiri TK, Burotto M, et al. Final overall survival analysis and organ‐specific target lesion assessments with 2‐year follow‐up in CheckMate 9ER: nivolumab plus cabozantinib versus sunitinib for patients with advanced renal cell carcinoma. Poster presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium; February 17‐19, 2022
  9. Data on file. Topline 9ER. Exelixis, Inc.
  10. Savard M-F, Wells JC, Graham J, et al. Real-world assessment of clinical outcomes among first-line sunitinib patients with clear cell metastatic renal cell carcinoma (mRCC) by the International mRCC Database Consortium risk group. Oncologist. 2020;25(5):422-430.
  11. Heng DYC, Xie W, Regan MM, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. 2009;27(34):5794-5799.
  12. Data on file. Exelixis, Inc.
  13. Data on file. Exelixis, Inc.
  14. Data on file. Final Clinical Study Report for Study CA2099ER. Bristol Myers Squibb.

©2023 Exelixis, Inc. CA‐2644-1          07/23

OPDIVO® and the related logo are registered trademarks of Bristol‐Myers Squibb Company

Ovarian Ablation or Suppression May Lower the Risk of Breast Cancer Recurrence

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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 HR-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy.

It has been hypothesized that estrogen in breast cancer acts as a catalyst/promoter for cancer growth, by stimulating the division and proliferation of breast tissue and increasing the risk for cancer causing mutations. A recently published study (Nature 2023;618:1024–1032) suggests that estrogen might be involved in the genomic reshuffling that gave rise to cancer-gene activation in breast cancer, acting as an initiator as well.

The researchers in this study postulated that suppressing ovarian function of women with breast cancer may improve outcome by preventing estrogenic stimulation of any residual/microscopic cancer, particularly among pre-menopausal women with Estrogen Receptor (ER)-positive tumors. To further clarify this benefit, the researchers from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials, that compared ovarian ablation or suppression with no ovarian ablation or suppression. Primary analyses included only premenopausal women age less than 55 years, with ER-positive or unknown tumors, stratified into those who received no chemotherapy, or remained premenopausal following chemotherapy, and those whose menopausal status following chemotherapy was not ascertained.

The following observations were noted from this meta-analysis:

–Fewer breast cancer recurrences were seen overall with ovarian ablation/suppression than control (RR=0.82, P< 0.0001).

• Among women receiving no chemotherapy or remaining premenopausal after chemotherapy (N=7,213), similar benefits were seen and the reduction in recurrent breast cancer was significant with ovarian ablation/suppression than control. The breast cancer recurrence rate at 15 years was 39.3% in the control group versus 29.5% in the ovarian ablation or suppression group, with an absolute benefit of 9.8% and a Rate Ratio (RR) of 0.71 (P<0.0001).

• Breast cancer mortality and all-cause mortality in the ovarian ablation or suppression group at 15 years, were improved by 8.0% (20.9% versus 28.9%; RR 0.69, P<0.0001) and 7.2% (26.0% versus 33.1%; RR = 0.73, P< 0.0001), respectively, with no increase in deaths without recurrence (RR = 0•88, P=0.33).

• Among those women who were premenopausal before chemotherapy and whose menopausal status was uncertain after chemotherapy (N=7,786), the rate of recurrence at 15 years was 43.1% in those who received ovarian ablation/suppression and 44.4% in the control group (RR=0.91; P =0.03).

• Recurrence reductions were significantly larger among premenopausal women under 45 years, than among those 45-54 years, and did not differ significantly by tumor characteristics. Among premenopausal women under 45 years (N=4,437), the recurrence rate was 41.3% in the control group and 30.4% with ovarian ablation or suppression, representing a 15-year benefit of 10.9% and a Rate Ratio of 0.66 (P<0.00001). Among those women 45-54 years (N=2,776), the recurrence rate was 36.1% in the control group and 28.6% with ovarian ablation or suppression, suggesting a 15-year benefit of 7.5% and Rate Ratio of 0.82 (P=0.02).

• Among those taking Tamoxifen, the benefit with ovarian ablation or suppression was less, and was only 4.5% (RR = 0.80; P =0.002).

The authors concluded that ovarian ablation or suppression in pre-menopausal women less than 45 years with ER-positive breast cancer, substantially reduces the 15-year risk of recurrence and death from breast cancer, without increasing mortality from other causes.

Effects of ovarian ablation or suppression on breast cancer recurrence and survival: Patient-level meta-analysis of 14,993 pre-menopausal women in 25 randomized trials. Gray RG, Bradley R, Braybrooke J, et al. J Clin Oncol 41, 2023 (suppl 16; abstr 503)

FDA Approves Quizartinib for Newly Diagnosed Acute Myeloid Leukemia

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SUMMARY: The FDA on July 20, 2023 approved Quizartinib (VANFLYTA®) with standard Cytarabine and Anthracycline induction and Cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for the treatment of adult patients with newly diagnosed Acute Myeloid Leukemia (AML) that is FLT3 Internal Tandem Duplication (ITD)-positive, as detected by an FDA-approved test. FDA also approved LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic for Quizartinib.

The American Cancer Society estimates that in 2023, 20,380 new cases of Acute Myeloid Leukemia (AML) will be diagnosed in the United States and 11,310 patients will die of the disease. AML is one of the most common types of leukemia in adults and can be considered as a group of molecularly heterogeneous diseases with different clinical behavior and outcomes. A significant percentage of patients with newly diagnosed AML are not candidates for intensive chemotherapy, or have disease that is refractory to standard chemotherapy. Even with the best available therapies, the 5-year Overall Survival in patients 65 years of age or older is less than 5%. Cytogenetic analysis has been part of routine evaluation when caring for patients with AML. By predicting resistance to therapy, tumor cytogenetics will stratify patients based on risk, and help manage them accordingly. Even though cytotoxic chemotherapy may lead to long term remission and cure in a minority of patients with favorable cytogenetics, patients with high-risk features such as unfavorable cytogenetics, molecular abnormalities, prior myelodysplasia, and advanced age, have poor outcomes with conventional chemotherapy alone. More importantly, with the understanding of molecular pathology of AML, personalized and targeted therapies are becoming an important part of the AML treatment armamentarium.

The Fms-Like Tyrosine kinase 3 (FLT3) protein is a receptor tyrosine kinase in the PDGF family of growth factor receptors located on the hematopoietic stem cell surface (transmembrane). FLT3 normally promote cell survival, growth, and differentiation. FLT3 plays an important role in both normal and malignant hematopoiesis by activating key signaling pathways. Activating mutations in the FLT3 receptor is the most common genetic abnormality in AML. Approximately 25% of patients with newly diagnosed AML have FLT3-ITD mutations and approximately 7% have point mutations in the Tyrosine Kinase Domain (TKD). FLT3-ITD (Internal Tandem Duplication) mutation is caused by tandem duplication within the coding region of the gene. The presence of FLT3-ITD mutations can negate the benefit of any other favorable molecular and cytogenetic features. Patients with FLT3-ITD mutations have poor outcomes with shorter remission duration and significantly decreased Leukemia Free and Overall Survival.

Quizartinib is an oral, highly potent, selective, Type 2 FLT3 inhibitor. This agent in combination with chemotherapy showed antitumor activity with an acceptable safety profile in patients with FLT3-ITD-positive newly diagnosed AML.

QuANTUM-First is a randomized, double-blind, placebo controlled, global, Phase III trial in which the efficacy of Quizartinib with chemotherapy was evaluated in patients with newly diagnosed FLT3-ITD positive AML aged 18–75 years. In this study, 539 patients (N=539) with newly diagnosed FLT3-ITD positive AML were randomly assigned 1:1 to receive chemotherapy plus Quizartinib (N=268) or placebo (N=271). Treatment consisted of induction with standard 7 plus 3 induction regimen of Cytarabine 100 mg/m2 daily (or 200 mg/m2 daily per institutional standard) by continuous IV from Days 1-7 and anthracycline (Daunorubicin 60 mg/m2 daily or Idarubicin 12 mg/m2 daily, by IV infusion on Days 1, 2, and 3, then Quizartinib 40 mg orally or placebo once daily, starting on day 8, for 14 days. Patients in complete remission or complete remission with incomplete neutrophil or platelet recovery received standard consolidation with high-dose Cytarabine plus Quizartinib (40 mg orally daily) or placebo, allo- Hematopoietic Stem Cell Transplantation (HSCT), or both as consolidation therapy, followed by continuation of single-agent Quizartinib or placebo for up to 3 years. There was no re-randomization at the initiation of post-consolidation therapy. Patients who proceeded to HSCT initiated maintenance therapy after HSCT recovery. FLT3-ITD status was determined prospectively with a clinical trial assay and verified retrospectively with the companion diagnostic LeukoStrat CDx FLT3 Mutation Assay. This study included patients aged 18 to 75 years, 55% male and 45% female, with newly diagnosed primary or secondary AML harboring a FLT3-ITD activating mutation, with an allelic ratio of 3% or more. The median age was 56 years. The aim of this study was to assess the effect of Quizartinib versus placebo on Overall Survival in patients with FLT3-ITD-positive newly diagnosed AML. The Primary end point of the trial was Overall Survival (OS). Secondary end points included Event-Free Survival (EFS), post induction rates of Complete Remission (CR) rate, composite CR (CRc) rate, Safety, and pharmacokinetics.

At a median follow up of 39.2 months, the median Overall Survival was 31.9 months for Quizartinib versus 15.1 months for placebo (HR=0.78; P=0.032), a 22% reduction in the risk of death. The CR rate in the Quizartinib group was 55%, with median response duration of 38.6 months, whereas the CR rate in those receiving placebo was 55% with median response duration of 12.4 months. Approximately 42% of patients treated with Quizartinib versus 38% treated with placebo were MRD negative at the time of Complete Remission or Complete Remission with incomplete neutrophil or platelet recovery. However, patients in both groups who were MRD negative had improved Overall Survival (HR 0.57), compared with those who remained MRD positive. The most common Grade 3 or 4 adverse events were febrile neutropenia, hypokalaemia, and pneumonia in both groups, and neutropenia in the Quizartinib group.

It was concluded that the addition of Quizartinib to standard chemotherapy with or without allo-HSCT, followed by continuation monotherapy for up to 3 years, resulted in improved Overall Survival in adults patients with FLT3-ITD-positive newly diagnosed AML, and provides a new, effective, and generally well tolerated treatment option for this patient group. The authors added that this is the first time a FLT3 inhibitor was studied in patients aged 18-75 years and is specifically approved for patients who have the worst FLT3 mutation, the ITD mutation.

Quizartinib plus chemotherapy in newly diagnosed patients with FLT3-internal-tandem-duplication-positive acute myeloid leukaemia (QuANTUM-First): a randomised, double-blind, placebo-controlled, phase 3 trial. Erba HP, Montesinos P, Kim H-J, et al. on behalf of the QuANTUM-First Study Group. The Lancet 2023;401:1571-1583.

Late Breaking Abstract – ASCO 2023: Chemotherapy De-escalation using PET Response-Adapted Strategy in Patients with HER2-positive Early 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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.

Trastuzumab is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. Pertuzumab is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways. Dual HER2 blockade with Trastuzumab and Pertuzumab, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies.

Pathological Complete Response (pCR) after neoadjuvant therapy has strong prognostic significance in HER2+ breast cancer, and pCR rates in HER2+/HR- negative tumors exceed those in HER2+/HR+ tumors, and this in turn correlates with superior Event Free Survival. The FDA approved anti-HER2 dual blockade with Pertuzumab and Trastuzumab, given along with chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer, based on the NeoSphere trial, and for metastatic disease based on positive survival results in the CLEOPATRA trial. The role of chemotherapy free anti-HER2 dual blockade however has remained unclear.

PHERGain is a multinational, multicenter, randomized, open-label, non-comparative, Phase II trial, designed to explore the feasibility of dual HER2 blockade with a chemotherapy de-escalation strategy, using a response-adapted design. This study design allowed the identification of treatment responders earlier in the study, and non-responders were switched to Standard-of-Care treatment. In this study, 356 patients with Stage I-IIIA, invasive, HER2-positive operable breast cancer, with tumor size 1.5 cm or more, and with at least one breast lesion evaluable by FDG-PET, were included. Patients were randomized 1:4 to receive either Docetaxel 75 mg/m2 IV, Carboplatin AUC 6 mg/mL IV, Trastuzumab 600 mg SC given as a fixed dose, and Pertuzumab 840 mg IV given as a loading dose, followed by 420 mg IV maintenance doses (TCHP) – Group A (N=71) or Trastuzumab and Pertuzumab alone (HP) – Group B (N=285). Patients were stratified by Hormone Receptor status and Hormone Receptor-positive patients allocated to Group B were additionally given Letrozole if postmenopausal (2.5 mg/day orally) or Tamoxifen if premenopausal (20 mg/day orally). Centrally reviewed FDG-PET scans were done before randomization and after two treatment cycles. Patients assigned to Group A completed six cycles of treatment (given every 3 weeks) regardless of FDG-PET results. Patients assigned to Group B initially received two cycles of Trastuzumab and Pertuzumab. FDG-PET responders (reduction in breast lesions of at least 40% from baseline) in Group B continued this treatment for six additional cycles. FDG-PET non-responders in this group were switched to six cycles of Docetaxel, Carboplatin, Trastuzumab, and Pertuzumab (TCHP). Surgery was performed 2-6 weeks after the last dose of study treatment. Adjuvant treatment was selected according to the neoadjuvant treatment administered, pathological response, hormone receptor status, and clinical stage at diagnosis. The co-Primary endpoints were the proportion of FDG-PET responders in Group B with a pathological Complete Response in the breast and axilla (ypT0/is ypN0), as determined by a local pathologist after surgery, following eight cycles of treatment, as well as 3-year invasive Disease-Free Survival (DFS) of patients in Group B. In an earlier analysis of this study, at a median follow-up was 5.7 months, 80% of the patients in Group B were FDG-PET responders, of whom 38% had a pathological Complete Response, achieving the first Primary endpoint (Perez-Garcia JM, Lancet Oncol 2021).

The researchers herein presented the results of the second Primary endpoint, 3-year invasive DFS, among patients included in Group B who underwent surgery based on an Intent-to-Treat (ITT) analysis. In Group A, 89% proceeded to surgery and 93.7% proceeded to have surgery in Group B. The 3-year invasive DFS among the 80% of patients in Group B who were FDG-PET responders was 95.4%, meeting the second Primary endpoint (P<0.001). Further, a subgroup analysis showed that of the patients in Group B who were FDG-PET responders and who also achieved a pathological Complete Response (38%), none received chemotherapy at any point in the 3 years they were in the study. These patients had a 3-year invasive DFS of 98.8%, and only one patient experienced invasive event (locoregional ipsilateral recurrence).
As expected, treatment-related Adverse Events and serious Adverse Events were significantly higher in patients assigned to Group A than to Group B, and Group B patients with pathological Complete Response had the lowest incidence of Grade 3 or more Adverse Events.

The authors concluded that among patients with HER2-positive early operable breast cancer, a PET-based, pathological Complete Response-adapted strategy was associated with a substantial 3-year invasive Disease Free Survival. The authors added that this treatment approach identifies about a third of HER2-positive early breast cancer patients who may safely omit chemotherapy and avoid the risk of treatment-related toxicities.

3-year invasive disease-free survival (iDFS) of the strategy-based, randomized phase II PHERGain trial evaluating chemotherapy (CT) de-escalation in human epidermal growth factor receptor 2-positive (HER2[+]) early breast cancer (EBC). Cortes J, Pérez-García JM, Ruiz-Borrego M, J Clin Oncol 41, 2023 (suppl 17; abstr LBA506)

Late Breaking Abstract – ASCO 2023: Tumor Treating Fields Plus Standard of Care Improves Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer

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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.

Tumor Treating Fields (TTFields) delivery system is a non-invasive novel external therapeutic device that slows and reverses tumor growth by disrupting mitosis. The battery operated portable at-home TTF delivery system generates low intensity, intermediate frequency, alternating electrical fields delivered locoregionally to the tumors through 2 pairs of arrays applied to the chest. These electrical fields exert selective toxicity in dividing cells by interfering with organelle assembly in the cell and thereby facilitates apoptosis (programmed cell death), by preventing cell division. The non-dividing cells are not affected by these electrical fields. Patients wear the device for at least 18 hours a day and for at least four weeks. Currently, TTF therapy is approved for Glioblastoma and Malignant Pleural Mesothelioma. Preclinical NSCLC studies have shown that TTFields enhance the antitumor immune response, through disruption of mitosis and subsequent induction of immunogenic cell death. Further, TTFields synergize with taxanes and Immune Checkpoint Inhibitors (ICIs). This was the rationale for the development and design of the LUNAR Phase III trial.

The LUNAR study is a global, randomized, Phase III trial in which the safety and efficacy of Tumor Treating Fields therapy with Standard of Care, was compared to Standard of Care alone, in patients with metastatic Non Small Cell Lung Cancer (NSCLC), who had progression on or after Platinum-based chemotherapy. In this study, 276 eligible patients (N=276) were randomized 1:1 to receive either Tumor Treating Fields therapy (150 kHz) plus Standard of Care, which included investigator’s choice of an Immune Checkpoint Inhibitor (ICI) or Docetaxel, or Standard of Care alone. To be eligible for this study, patients had to be 22 years or older, have metastatic NSCLC, should have progressed on or after a platinum-based therapy, and have an ECOG performance status of 0-2. Both treatment groups were well balanced. The median age was 64 years, 65% were male, 96% of patients had an ECOG PS of 0-1, 56% had non-squamous histology, 89% had one prior line of systemic therapy and 31% received prior therapy with ICI. Patients were followed every 6 weeks and continued on therapy until disease progression or intolerable toxicities. The Primary endpoint was Overall Survival (OS). Secondary endpoints included were OS in ICI and Docetaxel subgroups, Progression Free Survival (PFS) and toxicities.

This study met its Primary end point of Overall Survival and OS was significantly extended with Tumor Treating Fields therapy plus Standard of Care versus Standard of Care. After a minimum follow up of 12 months, the median Overall Survival with Tumor Treating Fields therapy plus Standard of Care was 13.2 months versus 10.0 months with Standard of Care alone (HR=0.74; P=0.037) and 1-year survival rates were 53% and 42% respectively (P=0.040). In patients receiving an Immune Checkpoint Inhibitor (N=134), the addition of Tumor Treating Fields therapy significantly improved median OS versus ICI alone (18.5 months versus 10.6 months; HR=0.63; P=0.032). In those patients treated with Docetaxel, the median OS was numerically higher at 11.1 months with Tumor Treating Fields therapy plus Docetaxel versus 8.9 months with Docetaxel alone (HR=0.87). There was no significant difference in the median PFS between the two treatment groups and were 4.8 months and 4.1 months respectively. The rate of Adverse Events was similar between the treatment groups and majority of the Tumor Treating Fields associated toxicities were Grade 1 and 2 local skin irritations.

The authors concluded that in this Phase III study, the addition of Tumor Treating Fields therapy to Standard of Care therapy significantly extended Overall Survival in patients with metastatic NSCLC following platinum failure, without increasing systemic toxicities, and Tumor Treating Fields therapy may be a potentially paradigm-shifting new treatment modality.

Tumor treating fields (TTFields) therapy with standard of care (SOC) in metastatic non-small cell lung cancer (mNSCLC) following platinum failure: Randomized phase 3 LUNAR study. Leal T, Kotecha R, Ramlau R, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA9005)

Late Breaking Abstract – ASCO 2023: Biomarker-Driven ELAHERE® Improves Survival in Platinum-Resistant Ovarian Cancer

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SUMMARY: It is estimated that in the United States, approximately 19,710 women will be diagnosed with ovarian cancer in 2023, and 13,270 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women, and accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. About 85% of all ovarian cancers are epithelial in origin, and 70% of all epithelial ovarian cancers are High-Grade serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival (OS) rate of about 20-30%. Treatment options for patients with platinum-resistant ovarian cancer are limited, and patients are often treated with single-agent chemotherapy, with an Overall Response Rate (ORR) of between 4% and 13%, short duration of response, and significant toxicities.

Approximately 35-40% of ovarian cancer patients express high levels of Folate Receptor alpha (FR alpha), and this expression correlates with advanced stages of disease and more malignant phenotypes. There is limited expression of Folate Receptor alpha in normal tissues and is limited to the choroid plexus, proximal renal tubules, placenta, and endometrium. Testing for Folate Receptor alpha can be performed on fresh or archived tissue.

ELAHERE® (Mirvetuximab soravtansine-gynx) is a first-in-class Antibody Drug Conjugate (ADC), directed against FR alpha, a cell-surface protein highly expressed in ovarian cancer. It is comprised of a Folate Receptor alpha-binding antibody, cleavable linker, and the maytansinoid payload DM4, which is a potent tubulin inhibitor, disrupting microtubule formation, and thereby designed to kill the targeted cancer cells. Microtubules are major components of the cytoskeleton that give shape and structure to cells. ELAHERE® is the first FDA approved ADC for platinum-resistant disease. In the single-arm SORAYA trial, ELAHERE® demonstrated an ORR of 31.7% and median Duration of Response of 6.9 months, in patients with platinum-resistant ovarian cancer and prior Bevacizumab exposure. These response rates were consistently seen regardless of the number of prior therapies or the use of a prior PARP inhibitor. As a result, the FDA in November 2022 granted accelerated approval to ELAHERE®.

MIRASOL is a confirmatory randomized Phase III trial, conducted to evaluate the efficacy and safety of ELAHERE® versus Standard-of-Care chemotherapy, in patients with pretreated, platinum-resistant ovarian, peritoneal, or fallopian tube cancer, whose tumors express high levels of FR alpha. In this study, 453 eligible patients (N=453) were randomized 1:1 to receive ELAHERE® 6 mg/kg (based on adjusted ideal body weight) IV infusion once every three weeks, until disease progression or unacceptable toxicity (N=227), or investigators choice of single-agent chemotherapy – Paclitaxel, Pegylated Liposomal Doxorubicin, or Topotecan (N=226)). Both treatment groups were well balanced. Approximately 13% of patients had BRCA mutations, 14% of patients had one prior line of therapy, 39% had two prior lines and 47% had three prior lines of therapy. About 62% received prior Bevacizumab and 55% received prior therapy with PARP inhibitors. The Primary efficacy endpoint was Progression Free Survival (PFS). Secondary endpoints included Overall Response Rate (ORR), Overall Survival (OS), and Patient-Reported Outcomes in hierarchical order, as well as Safety and tolerability. The median follow up was 13.1 months.

This study met its Primary and key Secondary endpoints with statistically significant improvement in PFS, ORR and OS. The PFS in the ELAHERE® group was 5.62 months compared to 3.98 months in the chemotherapy group (HR=0.65; P<0.0001). The ORR was also higher in the ELAHERE® group at 42% compared with 16% in the chemotherapy group (P<0.0001). The median Overall Survival rate was 16.46 months among patients who received ELAHERE® compared with 12.75 months among those who received single-agent chemotherapy (P=0.0046). The PFS and OS outcomes favored the ELAHERE® group, irrespective of prior exposure to Bevacizumab. Treatment with ELAHERE® was associated with a lower rate of Grade 3 or more Adverse Events and a lower discontinuation rate (9% compared with 16% for the chemotherapy group). The most common adverse reactions including laboratory abnormalities associated with ELAHERE® were vision impairment, keratopathy, fatigue, nausea, peripheral neuropathy, increase in ALT and AST and cytopenias. Product labeling includes a boxed warning for ocular toxicity. The ocular events were reversible and primarily included low-grade blurred vision and keratopathy, which were managed with protocol-defined dose modifications. Approximately 60% of patients with symptoms had resolution prior to their next cycle of treatment, and less than 1% of patients discontinued therapy due to an ocular event.

It was concluded that treatment with ELAHERE® demonstrated a statistically significant improvement in Progression Free Survival and Overall survival, compared to chemotherapy, in patients with platinum-resistant ovarian cancer and high FR alpha expression, independent of Bevacizumab use, and may be the new standard-of-care for this patient group. ELAHERE® is the first FDA-approved Antibody Drug Conjugate and biomarker directed therapy for ovarian cancer, since the approval of PARP inhibitors.

Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: Initial report of mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high folate receptor-alpha expression. Moore KN, Angelergues A, Konecny GE, et al. J Clin Oncol 41, 2023 (suppl 17; abstr LBA5507)