First-line and second-line benefit of amivantamab in advanced, EGFR-mutated NSCLC

The bispecific antibody amivantamab showed significant benefit as first-line and second-line treatment versus standard therapy in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC), results of 3 independent randomised, phase 3 trials showed.

EGFR mutations are present in 15–20% of non-squamous, advanced NSCLC. The standard of first-line treatment for EGFR-mutated, advanced NSCLC is osimertinib [1]. However, resistance to the treatment and disease progression are nearly inevitable. Moreover, patients with EGFR exon 20 insertions are largely insensitive to the common EGFR tyrosine kinase inhibitors [2]. Secondary EGFR and MET alterations may account for 25–50% of tumour resistance. Amivantamab is a novel EGFR-MET bispecific antibody with immune cell-directing activity and active against a wide range of EGFR and MET alterations [3] and was evaluated in the following randomised, phase 3 trials:

Prof. Nicolas Girard (Institut du Thorax Curie-Montsouris, France) presented results from the PAPILLON trial (NCT04538664), a phase 3 study evaluating the efficacy of the addition of amivantamab to standard first-line chemotherapy (carboplatin/pemetrexed) in EGFR exon 20 insertion, advanced NSCLC [4]. A total of 308 participants were randomised to amivantamab/chemotherapy or chemotherapy alone. The primary endpoint was progression-free survival (PFS). The addition of amivantamab to the first-line chemotherapy significantly improved median PFS: 11.4 months versus 6.7 months (HR 0.395; 95% CI 0.30–0.53; P<0.001). Also, the overall response rate (ORR), duration of response rate (DoR), and PFS after subsequent therapy (PFS2) were significantly improved in the amivantamab arm.

A significant improvement in PFS (HR 0.70; P<0.001) and PFS2 (HR 0.75; P=0.03) was also observed in MARIPOSA (NCT04487080), a phase 3 trial that evaluated the efficacy of first-line amivantamab/lazertinib versus osimertinib in 878 participants with (any) EGFR-mutated advanced NSCLC. Lazertinib is a 3^rd generation anti-EGFR tyrosine kinase inhibitor. These results were presented by Prof. Byoung Chul Cho (Yonsei University, Republic of Korea) [5]. The median DoR was improved in the amivantamab/lazertinib arm: 25.8 versus 16.8 months.

MARIPOSA-2 (NCT04988295) evaluated the efficacy of amivantamab/lazertinib/chemotherapy versus amivantamab/chemotherapy versus chemotherapy alone in participants with EGFR exon 19 deletion or L858R-mutated advanced NSCLC who progressed on osimertinib monotherapy. Dr Antonio Passaro (European Institute of Oncology IRCCS, Italy) presented the results [6]. The median PFS favoured both amivantamab/chemotherapy and amivantamab/lazertinib/chemotherapy over chemotherapy alone (HR 0.48; 95% CI 0.36–0.64; P<0.001 and HR 0.44; 95% CI 0.35–0.56; P<0.001, respectively). Also,

intracranial PFS was improved in both amivantamab-based arms versus chemotherapy alone as were the ORR (64%, 63%, and 36%, respectively) and the median DoR (9.4, 6.9, and 5.6 months, respectively).

In all 3 trials, toxicity was significantly increased in experimental arms (amivantamab vs chemotherapy; amivantamab/lazertinib vs osimertinib; amivantamab/lazertinib/chemotherapy and amivantamab/chemotherapy vs chemotherapy), making amivantamab a promising alternative treatment for advanced NSCLC.

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   1. Soria JC, et al. N Engl J Med 2018;378:113–125.
   2. Ou S-H, et al. JTO Clin Res. 2023;4:100558.
   3. Yun J, et al. Cancer Discov. 2020;10(8):1194–1209.
   4. Girard N, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR Exon 20 insertion-mutated advanced non-small cell lung cancer (NSCLC): Primary results from PAPILLON, a randomized phase III global study. Abstract LBA5, ESMO 2023, 20–24 October, Madrid, Spain.
   5. Cho BC, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Abstract LBA14, ESMO 2023, 20–24 October, Madrid, Spain.
   6. Passaro A, et al. Amivantamab plus chemotherapy (with or without lazertinib) vs chemotherapy in EGFR-mutated advanced NSCLC after progression on osimertinib: MARIPOSA-2, a phase III, global, randomized, controlled trial. Abstract LBA15, ESMO 2023, 20–24 October, Madrid, Spain.

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Posted on 19 December 202319 December 2023