Amivantamab 350mg/7ml solution for infusion vials

Amivantamab, a newly introduced drug for locally advanced or metastatic NSCLC in patients with EXON-20 mutation, has shown promising results for prolonging progression-free survival and overall survival. Amivantamab’s toxicities are common, especially those related to skin and infusion. However, its cardiovascular related toxicities are less examined. Therefore, the aim of this study was to perform a systematic review and concentrate available data for the cardiovascular toxicities of amivantamab in patients with NSCLC. This review was performed according to the PRISMA guidelines, and relevant studies were searched on three scientific databases, PubMed, Cochrane Library and ScienceDirect. In total, four phase-3 randomized clinical trials, three phase-1 clinical trials, and two real-world study were included in this systematic review. The results revealed that grade ≥3 cardiovascular toxicities are low in amivantamab monotherapy (<10%), but their frequency increases when combined with lazertinib and overcome 20% when amivantamab is combined with both lazertinib and chemotherapy. In addition, up to 3% grade 5 cardiovascular events have been reported when amivantamab is combined with lazertinib. Pulmonary embolism and venous thromboembolism are the most common cardiovascular toxicities reported for amivantamab, and their risk increases when combined with lazertinib. These results indicate that amivantamab may be cardiotoxic, especially when combined with lazertininb, and cardioprotection should be considered in patients under amivantamab treatment. • Amivantamab is a promising agent for EGFR-mutated NSCLC, with clinical studies indicating its efficacy and manageable toxicity • Clinical and real-world studies have shown an important incident of cardiovascular toxicities in patients treated with amivantamab-based therapies • Thromboembolism is the most common cardiovascular toxicity of amivantamab-based therapies • Combination of amivantamab with lazertinib increases the cardiovascular toxicity of amivantamab-based therapies

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BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

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INTRODUCTION: Amivantamab plus lazertinib significantly improved progression-free and overall survival versus osimertinib in patients with previously untreated, EGFR-mutant advanced NSCLC. EGFR-targeted therapies are associated with dermatologic adverse events (AEs), which can affect quality of life (QoL). COCOON was conducted to assess prophylactic management and improve treatment experience. METHODS: In the phase 2 COCOON study (NCT06120140), participants with previously untreated, EGFR-mutant, locally advanced or metastatic NSCLC received intravenous amivantamab plus oral lazertinib and were randomized 1:1 to enhanced dermatologic management (COCOON DM) or standard of care (SoC DM) per local guidelines. COCOON DM included oral doxycycline or minocycline (100 mg twice daily; weeks 1-12), clindamycin 1% (on scalp daily; weeks 13-52), chlorhexidine 4% (on fingernails and toenails daily), and ceramide-based moisturizer (on body and face at least daily). Primary end point was incidence of grade 2 or higher dermatologic AEs of interest (DAEIs) by week 12. RESULTS: In total, 201 participants were randomized (99 to COCOON DM and 102 to SoC DM). At a median follow-up of 7.1 months, COCOON DM demonstrated significant reduction in the primary end point versus SoC DM (42% versus 75%; OR, 0.24; 95% confidence interval, 0.13-0.45; p < 0.0001). By week 12, the largest benefit with COCOON DM was observed in DAEIs involving the face and body (excludes paronychia; 26% versus 60%; p < 0.0001) and DAEIs involving the scalp (10% versus 26%; p = 0.0049). This benefit was maintained at 6 months, with significant reductions of DAEIs involving face, body, and scalp (excluding paronychia). Patient-reported outcomes favored COCOON DM, indicating reduced impact of dermatologic symptoms on QoL. CONCLUSION: An uncomplicated, widely available, prophylactic regimen (COCOON DM) reduced the incidence of DAEIs with amivantamab-lazertinib and the impact of symptoms on QoL.

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PURPOSE Non–small-cell lung cancer (NSCLC) with epidermal growth factor receptor ( EGFR) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell–directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with EGFR Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum EGFR Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with EGFR Exon20ins mutations after progression on platinum-based chemotherapy.

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PURPOSE Phase III studies of intravenous amivantamab demonstrated efficacy across epidermal growth factor receptor ( EGFR )–mutated advanced non–small cell lung cancer (NSCLC). A subcutaneous formulation could improve tolerability and reduce administration time while maintaining efficacy. PATIENTS AND METHODS Patients with EGFR -mutated advanced NSCLC who progressed after osimertinib and platinum-based chemotherapy were randomly assigned 1:1 to receive subcutaneous or intravenous amivantamab, both combined with lazertinib. Coprimary pharmacokinetic noninferiority end points were trough concentrations (C trough ; on cycle-2-day-1 or cycle-4-day-1) and cycle-2 area under the curve (AUC D1-D15 ). Key secondary end points were objective response rate (ORR) and progression-free survival (PFS). Overall survival (OS) was a predefined exploratory end point. RESULTS Overall, 418 patients underwent random assignment (subcutaneous group, n = 206; intravenous group, n = 212). Geometric mean ratios of C trough for subcutaneous to intravenous amivantamab were 1.15 (90% CI, 1.04 to 1.26) at cycle-2-day-1 and 1.42 (90% CI, 1.27 to 1.61) at cycle-4-day-1; the cycle-2 AUC D1-D15 was 1.03 (90% CI, 0.98 to 1.09). ORR was 30% in the subcutaneous and 33% in the intravenous group; median PFS was 6.1 and 4.3 months, respectively. OS was significantly longer in the subcutaneous versus intravenous group (hazard ratio for death, 0.62; 95% CI, 0.42 to 0.92; nominal P = .02). Fewer patients in the subcutaneous group experienced infusion-related reactions (IRRs; 13% v 66%) and venous thromboembolism (9% v 14%) versus the intravenous group. Median administration time for the first infusion was reduced to 4.8 minutes (range, 0-18) for subcutaneous amivantamab and to 5 hours (range, 0.2-9.9) for intravenous amivantamab. During cycle-1-day-1, 85% and 52% of patients in the subcutaneous and intravenous groups, respectively, considered treatment convenient; the end-of-treatment rates were 85% and 35%, respectively. CONCLUSION Subcutaneous amivantamab-lazertinib demonstrated noninferiority to intravenous amivantamab-lazertinib, offering a consistent safety profile with reduced IRRs, increased convenience, and prolonged survival.

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Targeted therapies have revolutionized treatment of non-small-cell lung cancer (NSCLC); however, epidermal growth factor receptor (EGFR) exon20ins mutations are resistant to tyrosine kinase inhibitors. Amivantamab utilizes multiple mechanisms of action to bypass the altered binding site conformation and recruits immune cells for anti-cancer activity. Amivantamab is approved in the frontline setting of EGFR exon20ins-mutated NSCLC in combination with carboplatin plus pemetrexed. Single-agent amivantamab is approved in second line or later for EGFR exon20ins. Furthermore, amivantamab with lazertinib for first line as well as amivantamab in combination with carboplatin and pemetrexed for second line after osimertinib have both been approved in the treatment of NSCLC harboring EGFR-sensitizing mutations. Now with multiple indications, we must learn how to manage the unique side effects of amivantamab to maximize treatment benefit for the patients. Side effects of amivantamab can be associated with inhibition of the EGFR and/or mesenchymal epithelial transcription factor (MET) signaling pathways. This work reviews the mechanism of action, pharmacology, clinical trial data, and covers management of toxicities. This guide is designed as a practical reference tool for clinicians, pharmacists, and basic science researchers.

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