FDA Approves RYBREVANT® in Combination with Chemotherapy for Advanced NSCLC with EGFR Exon 20 Insertion Mutations

SUMMARY: The FDA on March 1, 2024, approved Amivantamab-vmjw (RYBREVANT®) with Carboplatin and Pemetrexed for the first-line treatment of locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. The FDA also granted traditional approval to Amivantamab-vmjw for adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. FDA previously granted accelerated approval for this indication based on Phase 1 CHRYSALIS study.

The American Cancer Society estimates that for 2024, about 234,580 new cases of lung cancer will be diagnosed and 125,070 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.

Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR mutations, and 90% of these mutations are either exon 19 deletions or L858R substitution mutation in exon 21. EGFR exon 20 insertion mutations are the third most common after L858R and exon 19 deletions and occur in about 2-3% patients with NSCLC and are insensitive to EGFR Tyrosine Kinase Inhibitors (TKIs) due to an altered conformation of the kinase active site. Next-Generation sequencing provides an alternative to Polymerase Chain Reaction (PCR)-based tests, which fail to identify 50% or more of exon 20 insertion mutations. Patients with EGFR exon 20 insertion mutations have a 5-year Overall Survival (OS) of 8% in the frontline setting, compared to an OS of 19% for patients with EGFR exon 19 deletions or L858R mutations. There is therefore a clinically unmet need for this patient group, as there are no approved targeted therapies available, and platinum-doublet chemotherapy remains the standard of care for these patients.

Amivantamab (RYBREVANT®) is a fully human bispecific antibody directed against EGFR and MET receptors, with immune cell-directing activity. Amivantamab binds extracellularly and simultaneously blocks ligand-induced phosphorylation of EGFR and c-MET, inhibiting tumor growth and promoting tumor cell death. Further, Amivantamab downregulates receptor expression on tumor cells thus preventing drug resistance mediated by new emerging mutations of EGFR or c-MET. By binding to the extracellular domain of the receptor protein, Amivantamab can bypass primary and secondary TKI resistance at the active site. Additionally, Amivantamab has been shown to engage macrophages, monocytes, and Natural Killer cells through its Fc domain. Amivantamab in combination with Carboplatin and Pemetrexed demonstrated synergy, with improvement in Response Rates, in previously published studies.

PAPILLON trial is an international, randomized, Phase III study, conducted to assess the efficacy and safety of Amivantamab plus chemotherapy as compared with standard chemotherapy alone, as first-line treatment, in patients with advanced NSCLC with EGFR exon 20 insertions. In this study, 308 patients (N=308) were randomly assigned 1:1 to receive Amivantamab plus chemotherapy (N=153) or chemotherapy alone (N=155), given in 3 week cycles. Amivantamab was given at a dose of 1400 mg (1750 mg for a body weight of 80 kg or more) IV weekly for the first 4 weeks, with the first infusion split over 2 days (at a dose of 350 mg on cycle 1, day 1, and the remainder on cycle 1, day 2). Starting at cycle 3 (week 7), the dose of Amivantamab was increased to 1750 mg IV (2100 mg for a body weight of 80 kg or more) administered every 3 weeks until disease progression. Carboplatin was administered at AUC 5 IV every 3 weeks for up to 4 cycles. Pemetrexed was administered at a dose of 500 mg/m2 IV every 3 weeks until disease progression. Both treatment groups were well balanced and the patients mutational status was determined by local testing of tissue samples in 92% of cases, and plasma samples in 8% of cases. Patients with treated brain metastases were eligible if they were asymptomatic. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive Amivantamab monotherapy. The Primary end point was Progression Free Survival (PFS) as determined by Blinded Independent Central Review. Secondary end points included Objective Response Rate (ORR), Overall Survival (OS), Duration of Response and Safety.

At a median follow-up of 14.9 months, the median PFS was significantly longer in the Amivantamab plus Chemotherapy group and was 11.4 months, compared to 6.7 months in the chemotherapy alone group (HR=0.40; P<0.001). At 18 months, the PFS in the Amivantamab plus chemotherapy group was 31% and 3% in the chemotherapy group. The Objective Response was 73% in the Amivantamab plus chemotherapy group and 47% in the chemotherapy alone group (P<0.001). Overall Survival results were immature at the time of current analysis, with a trend toward improvement in Overall Survival despite a high rate of crossover for the control arm (42%).

The most common adverse events associated with Amivantamab plus chemotherapy were reversible hematologic and EGFR-related toxic effects and included rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, diarrhea, nausea and vomiting. Approximately 7% of patients discontinued Amivantamab due to adverse reactions.

It was concluded that Amivantamab in combination with chemotherapy resulted in superior efficacy as compared with chemotherapy alone, in previously untreated advanced NSCLC patients with EGFR exon 20 insertions.

Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. Zhou C, Tang K-J, Cho BC, et al. for the PAPILLON Investigators. N Engl J Med 2023;389:2039-2051.

FDA Approves OPDIVO® in Combination with Chemotherapy for the First Line Treatment of Advanced Urothelial Carcinoma

SUMMARY: The FDA on March 6, 2024, approved Nivolumab (OPDIVO®) in combination with Cisplatin and Gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. The American Cancer Society estimates that in the United States for 2024, about 83,190 new cases of bladder cancer will be diagnosed and approximately 16,840 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of all urothelial cancers, and the latter can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Platinum-based chemotherapy remains the standard of care for the first line treatment of unresectable or metastatic urothelial carcinoma. Cisplatin-based chemotherapy is preferred over Carboplatin-based chemotherapy for eligible patients and has a response rate of over 40%, with a median Overall Survival (OS) of approximately 15 months. These responses, however, are not durable. To date, no novel agent has improved Overall Survival when added to platinum-based chemotherapy, for first-line treatment of metastatic urothelial carcinoma. There is an unmet need for more effective treatment.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Nivolumab presently is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma after previous platinum-based chemotherapy, as well as for adjuvant treatment of high-risk muscle-invasive urothelial carcinoma after radical resection.

Based on the data from Phase II studies, CheckMate 901 clinical trial was conducted to evaluate the benefit of a combination of Nivolumab plus Gemcitabine and Cisplatin, as compared with Gemcitabine and Cisplatin alone, in patients with previously untreated advanced urothelial carcinoma. CheckMate 901 is an international, open-label, randomized, Phase III trial, consisting of 2 parts. In the first part which is summarized below, Nivolumab plus Gemcitabine and Cisplatin was compared with Gemcitabine and Cisplatin alone, in patients with previously untreated, unresectable or metastatic urothelial carcinoma. In the second part of this study, which is ongoing, patients were assigned to receive either Nivolumab plus Ipilimumab or platinum-based chemotherapy.

In the current trial, 608 patients (N=608) with previously untreated unresectable or metastatic urothelial carcinoma were randomized assigned 1:1 to receive either Nivolumab 360 mg IV in combination with Cisplatin and Gemcitabine every 3 weeks for up to six cycles, followed by Nivolumab 480 mg IV every 4 weeks until disease progression, unacceptable toxic effects, or up to a maximum of 2 years, or Gemcitabine and Cisplatin alone every 3 weeks for up to six cycles. Patients who discontinued Cisplatin alone could be switched to Gemcitabine and Carboplatin for the remainder of the platinum-doublet cycles up to six cycles in total. Randomization was stratified by tumor PD-L1 expression and presence of liver metastasis. Patient characteristics were well-balanced between the two study groups. The median patient age was 65 years. The primary tumor site was the bladder in 75% of patients. 37% of patients had a high tumor PD-L1 expression (1% or more) and 21% of patients had evidence of liver metastases. The dual Primary endpoints were Overall Survival (OS) and Progression Free Survival (PFS) by Blinded Independent Central Review (BICR). Objective response rate (ORR) per BICR was an exploratory endpoint.

At a median follow up of 33.6 months, there was a statistically significant improvement in both Overall Survival and Progression Free Survival for Nivolumab in combination with Cisplatin and Gemcitabine followed by Nivolumab, compared to Cisplatin and Gemcitabine alone. The median OS was 21.7 months for patients who received Nivolumab in combination with Cisplatin and Gemcitabine and 18.9 months for those who received Cisplatin and Gemcitabine alone, (HR=0.78; P=0.02). Overall survival was 70.2% and 62.7%, respectively, at 12 months and 46.9% and 40.7%, respectively, at 24 months. The median PFS was 7.9 months and 7.6 months, respectively (HR=0.72; P=0.0012). The PFS was 34.2% and 21.8%, respectively, at 12 months and 23.5% and 9.6%, respectively, at 24 months.

The Objective Response Rate and Complete Response Rates were 57.6% and 21.7% respectively with Nivolumab combination therapy, versus 43.1% and 11.8% with Gemcitabine and Cisplatin alone. The median duration of Complete Response was 37.1 months with Nivolumab combination therapy and 13.2 months with Gemcitabine and Cisplatin alone. The most common treatment-related Adverse Events with the Nivolumab combination were anemia, nausea, and neutropenia.

It was concluded that a combination of Nivolumab with Gemcitabine and Cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma, compared to Gemcitabine and Cisplatin alone. The researchers added that this study provides evidence of the benefit of concurrent administration of an immune checkpoint inhibitor and chemotherapy in improving Overall Survival in this patient population.

Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma. van der Heijden MS, Sonpavde G, Powles T, et al., for the CheckMate 901 Trial Investigators. N Engl J Med 2023; 389:1778-1789.

AMTAGVI® (Lifileucel)

The FDA on February 16, 2024, granted accelerated approval to AMTAGVI®, a tumor-derived autologous T cell immunotherapy, for adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. AMTAGVI® is a product of Iovance Biotherapeutics, Inc.