FDA Approval Summary: Amivantamab for the Treatment of Patients with Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations

Metastatic non–small cell lung cancer (NSCLC) is in most cases a fatal disease, with a 5-year survival rate of < 10% (1). Exon 20 insertion mutations in the EGFR gene have been identified as oncogenic drivers in NSCLC and are reported to be present in approximately 2%–3% of cases of advanced NSCLC (2). In comparison with many other EGFR oncogenic driver mutations, NSCLC with EGFR exon 20 insertion mutations does not respond well to treatment with currently approved EGFR tyrosine kinase inhibitors (TKI; ref. 3). Current treatment options for patients with NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed following platinum-based chemotherapy are the same therapies as those used for patients with NSCLC without a specific driver mutation (4). This includes ramucirumab plus docetaxel [overall response rate (ORR), 23%] (5) or single-agent chemotherapy (ORR, 10%–15%; ref. 6), as well as treatment with anti-PD-(L)1 antibody as a single agent for patients who did not receive such treatment as part of first-line therapy (associated with ORR, 14%–19%; ref. 7). While data regarding response to immunotherapy in this specific patient population is limited and conflicting, there is no clear indication that patients with NSCLC with EGFR exon 20 insertion mutations are less likely to respond to such therapy than patients with wild-type (WT) EGFR (8, 9, 10). Prior to the approval of amivantamab, there was no targeted therapy approved specifically for the treatment of patients with NSCLC with EGFR exon 20 insertion mutations. After amivantamab's approval, mobocertinib, an orally administered irreversible kinase inhibitor targeting EGFR and HER2 receptors, received accelerated approval in September 2021 for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy (11, 12).

Breakthrough Therapy Designation was granted to amivantamab on March 9, 2020, for the treatment of patients with metastatic NSCLC with EGFR exon 20 insertion mutation, whose disease has progressed on or after platinum-based chemotherapy (11). The biologics license application was submitted on November 24, 2020, and was granted priority review status; the applicant voluntarily used the Assessment Aid, which is designed to facilitate the FDA's assessment of marketing applications (12). This application was reviewed under FDA's Project ORBIS, in collaboration with the Brazilian Health Regulatory Agency (ANVISA) and UK's Medicines and Healthcare products Regulatory Agency (MHRA); the application reviews were ongoing at these other regulatory agencies at the time of FDA approval (13).

Amivantamab is a low-fucose, fully human, IgG1-based bispecific antibody against the EGFR and mesenchymal–epithelial transition (MET) receptor with an established pharmacologic class of bispecific EGFR-directed and MET receptor–directed antagonist (14, 15). In binding studies, amivantamab bound to human EGFR and MET with K_D values of 1.43 and 0.04 nmol/L, respectively. Amivantamab bound to the extracellular domains of human and cynomolgus monkey EGFR and MET with similar EC₅₀ values, but not to rat EGFR or rat MET. In addition, amivantamab bound to lung cancer cell lines of various EGFR and MET status with IC₅₀ values ranging from 0.9 to 12.1 nmol/L. Amivantamab at concentrations of 0.1, 0.5, and 1 mg/mL dose-dependently inhibited proliferation of Ba/F3 cells expressing different exon 20 insertion mutations. Binding of amivantamab to EGFR and MET prevented binding of their ligands, EGF and hepatocyte growth factor, with IC₅₀ values of 10 and 30 nmol/L, respectively. Amivantamab inhibited ligand-induced receptor phosphorylation in NSCLC cell lines with both WT and mutant EGFR (L858R, T790M) with WT MET with IC₅₀ values ranging from 0.49 to 29 nmol/L. In mice bearing patient-derived tumors with exon 20 insertion mutations, amivantamab demonstrated antitumor activity and decreased protein expression and phosphorylation of EGFR and MET in the tumor tissue (15).

The approved dosing regimen is based on baseline body weight (BW) and is 1,050 mg for patients with BW <80 kg and 1,400 mg for patients with BW ≥80 kg, administered intravenously weekly for 4 weeks and then every 2 weeks thereafter. To mitigate the risk of infusion-related reactions (IRR), product labeling recommends slower initial infusion rates and splitting of doses in week 1, with 350 mg on day 1, and the remaining dose (700 mg for BW <80 kg, and 1,050 mg for BW ≥80 kg) on day 2 (15, 16).

Amivantamab was investigated at doses up to 1,750 mg with no MTD defined. Amivantamab systemic exposures increased proportionally over a dose range of 350 to 1,750 mg, and increases in BW increased the volume of distribution and clearance of amivantamab. Similar amivantamab exposures were achieved for patients with BW <80 kg at dose of 1,050 mg and patients with BW ≥80 kg at dose of 1,400 mg based on population pharmacokinetic analysis. The incidence of antibodies to amivantamab was 1% in the clinical trial of patients with locally advanced or metastatic NSCLC (16).

The efficacy of amivantamab in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy was evaluated in a multicenter, nonrandomized, open-label, dose escalation and multicohort dose expansion clinical trial (CHRYSALIS, NCT02609776). Patients with untreated brain metastases or with previously treated but symptomatic or clinically unstable brain metastases and patients with a history of interstitial lung disease (ILD) requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study. The major efficacy outcome measure was overall response rate as assessed by blinded independent central review (BICR) according to RECIST v1.1, with duration of response (DOR) per BICR a secondary efficacy outcome measure (16).

As prophylaxis for IRR, the protocol required administration of an antihistamine and acetaminophen prior to each scheduled infusion and intravenous glucocorticoid prior to week 1 dosing. Following treatment of approximately 30 patients, given the high incidence of IRR occurring during cycle 1, the protocol was amended to administer the initial cycle 1 dose as a split infusion on week 1 days 1 and 2 and to require infusion of amivantamab via a peripheral vein for all cycle 1 doses. Infusion via central line was allowed for subsequent dosing starting with the cycle 2 day 1 dose (16).

The efficacy population from CHRYSALIS supporting this marketing application included 81 consecutively enrolled patients with EGFR exon 20 insertion mutation-positive NSCLC with measurable disease and a history of disease progression on or after platinum-based chemotherapy who received at least one dose of amivantamab at the dose(s) to be approved and started treatment on or before February 5, 2020 (Table 1). Among 81 patients with EGFR exon 20 insertion mutation–positive NSCLC previously treated with platinum-based chemotherapy, 46% had received PD-1/PD-L1 inhibitor and 22% of patients had received an EGFR TKI. The demographic and baseline disease characteristics of the efficacy population generally reflect the known profile of patients with this disease in the United States (Table 1), except for underrepresentation of Black or African American (2.5%). EGFR exon 20 insertion mutation status was identified by prospective local testing using tissue (94%) and/or plasma (6%) samples (16).

The confirmed ORR by BICR was 40% [95% confidence interval (CI): 29–51] and the median DOR was 11.1 months (95% CI: 6.9–not evaluable; Table 2). A total of 63% of responders had a DOR ≥ 6 months and 12% of responders had a DOR ≥ 12 months. At the data cutoff, the response was ongoing for 41% responders. The ORRs observed in the subgroups of patients who received prior immunotherapy (n = 37), those who did not receive prior immunotherapy (n = 44), and those who received EGFR TKI therapy (n = 18) were 46% (95% CI: 29–63), 34% (95% CI: 21–50), and 50% (26–74), respectively (Supplementary Table S1). Overall, the results appear consistent across these subgroups with ORR CIs overlapping but interpretation limited because of small sample size.

The safety review of amivantamab included data from 302 patients with NSCLC from CHRYSALIS who were treated with one dose of amivantamab at the dose(s) to be approved (1,050 mg for patient BW <80 kg and 1,400 mg for patient BW ≥80 kg), including 129 patients with NSCLC with EGFR exon 20 insertion mutations and disease progression following platinum-based chemotherapy (16).

Among the 302 patients, 36% were exposed to amivantamab for 6 months or longer and 12% were exposed for greater than one year. The most common treatment emergent adverse reactions and laboratory abnormalities occurring with amivantamab are presented in Tables 3 and 4.

Serious adverse reactions occurred in 30% of patients. Permanent discontinuation due to an adverse reaction occurred in 11% of patients; the most frequent (≥1%) adverse reactions leading to permanent discontinuation were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash. Fatal adverse reactions occurred in 3 patients (2.3%), with two fatal events of pneumonia and one event reported as sudden death. Dose interruptions due to an adverse reaction occurred in 78% of patients. IRR requiring infusion interruptions occurred in 59% of patients (16). Other than IRR, the most common reasons for dose interruptions due to an adverse reaction (≥5%) included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea. Adverse reactions requiring dosage reductions in ≥2% of patients included rash and paronychia.

Serious risks identified for inclusion in the Warnings and Precautions section of the USPI included IRR, ILD/pneumonitis, dermatologic adverse reactions, and ocular toxicity. IRR occurred in 66% of patients treated with amivantamab, with median time to onset 1 hour (range: 0.1–18 hours) after the start of the infusion. Over 90% of IRRs occurred on day 1 or 2 of the week 1 infusion (incidence 65% with week 1 day 1 infusion, 3.4% week 1 day 2, 0.4% week 2, and 1.1% with subsequent infusions). Grade 3 and 4 IRR occurred in 2.2% and 0.4% of patients, respectively, and amivantamab was permanently discontinued because of IRR in 1.3% of patients (16).

ILD/pneumonitis occurred in 3.3% of patients (grade 3 0.7%), and 1% of patients discontinued amivantamab due to ILD/pneumonitis. Rash (including dermatitis acneiform) occurred in 74% of patients (grade 3 3.3%), and 1 patient (0.3%) had toxic epidermal necrolysis. Median time to onset of rash was 14 days (range: 1–276 days), and 0.7% of patients discontinued amivantamab due to rash. Ocular toxicity associated with amivantamab included keratitis (0.7%), dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis (0.3%; refs. 15, 16).

Patients with EGFR exon 20 insertion mutations represent a distinct subset of patients with EGFR-mutated NSCLC (common or uncommon EGFR oncogenic driver mutations), and generally associated with limited response to EGFR TKIs (5). The ORR per BICR of 40% (95% CI: 29–51) with a median DOR of 11.1 months in the CHRYSALIS study is consistent with an improvement over available therapy for the intended patient population (15, 16). This was the first FDA approval for a targeted therapy specifically for the treatment of NSCLC harboring EGFR exon 20 insertion mutations and provides this patient population with a high unmet medical need an additional therapeutic option. After the amivantamab approval, mobocertinib, an oral, first-in class, irreversible kinase inhibitor targeting EGFR and HER2 receptors, received accelerated approval in September 2021 for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy (12).

Despite required premedication for amivantamab therapy, IRR occurred in the majority (∼65%) of patients treated with amivantamab. Over 90% of IRR occurred on day 1 or 2 of the initial week 1 infusion, and most IRR were grades 1–2 in severity. To address this issue, product labeling includes clear instructions regarding premedication, slower initial infusion rates and splitting of doses in week 1, with 350 mg on day 1, and the remaining dose [700 mg for BW <80 kg, and 1,050 mg for BW ≥80 kg) on day 2, administration via a peripheral line on week 1 and week 2, and management of IRR with interruption of infusion and reduction in infusion rate or permanent discontinuation based on severity (15, 16).

Given the relatively limited duration of follow-up and the number of patients in the primary efficacy analysis population for this application, the submitted data were considered adequate to support accelerated approval rather than regular approval (11, 15). As a postmarketing requirement, Janssen agreed to complete a randomized clinical trial to verify and confirm the clinical benefit of amivantamab for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations (16). Results from the ongoing, randomized trial initiated on October 13, 2020, investigating amivantamab in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed alone as first-line treatment in patients with advanced NSCLC harboring EGFR exon 20 insertion mutations with a primary endpoint of progression-free survival may be used to verify the clinical benefit of amivantamab. At the time of accelerated approval, enrollment was underway, and the final report submission is expected in February 2023.

In addition, Janssen agreed to a postmarketing commitment (PMC) to collect and submit additional clinical trial data to further characterize the safety and efficacy of amivantamab in Black or African American patients with EGFR exon 20 insertion mutated NSCLC as real-world data reported 9.4% of U.S. patients with NSCLC with EGFR exon 20 insertion mutations were Black or African American and in the primary efficacy population of the global CHRYSALIS study, 2.3% of patients were Black or African American (16). This PMC was requested on the basis of the relative underrepresentation of Black or African American patients in the primary efficacy population of CHRYSALIS relative to the proportion of Black or African American patients expected among the population of patients with EGFR exon 20 insertion–mutated NSCLC in the United States (16).

Finally, the FDA Center for Devices and Radiological Health contemporaneously approved the Guardant360 CDx (Guardant Health, Inc.) as a plasma-based companion diagnostic to select patients with EGFR exon 20 insertion mutations for the safe and effective use of amivantamab. Subsequently, the Oncomine Dx Target Test (ODxT Test, Life Technologies Corporation), a tissue-based CDx was also approved for the same indication for use (16). As a result of difference in sensitivities between plasma and tissue tests, a negative result from a plasma specimen may not provide assurance that the patient's tumor is negative for genomic findings. In such circumstances, tumor tissue testing is recommended, if feasible (15).

As part of the Agency-wide effort to assess the impact of the COVID-19 pandemic on clinical trials, FDA evaluated protocol changes and protocol deviations that occurred in CHRYSALIS due to the pandemic. Notable protocol modifications included permitting alternative sites for imaging and laboratory assessments and telehealth assessments for adverse events. In the primary efficacy population, 26 patients (32%) had protocol deviations related to the COVID-19 pandemic, including 15 patients (58%) missing data (e.g., labs, vitals, physical exam), 7 patients (27%) with missed visit or exceeded study visit window, and 4 patients (15%) with assessments performed remotely. These study adaptations did not impact the assessment of overall efficacy or safety (16).

This application was reviewed under FDA's Project ORBIS (14), in collaboration with several international ORBIS partners including Brazil's National Health Surveillance Agency (ANVISA), Health Canada, Mexico's Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), Singapore Health Sciences Authority (HAS), Swissmedic Switzerland, and the UK's MHRA.

Amivantamab was granted approval by ANVISA in September 2021, conditional marketing authorization by MHRA in November 2021, and a Notice of Compliance with conditions by Health Canada in March 2022.

Amivantamab demonstrated substantial evidence of effectiveness and a favorable benefit-risk profile as a single agent for the treatment of patients with NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. The observed ORR, coupled with the durability of responses, is consistent with a meaningful advantage over available therapies. This indication was approved under accelerated approval, and a randomized clinical trial intended to verify the clinical benefit of amivantamab is currently ongoing with the final report submission due in February 2023.

J.A. Beaver reports all work on this article was completed while employed by FDA. J.A. Beaver is now employed by Treeline Biosciences. No disclosures were reported by the other authors.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.