RYBREVANT / LAZCLUZE (amivantamab / lazertinib) - Non-small cell lung cancer (NSCLC)

The clinical benefit of RYBREVANT (amivantamab) 350 mg concentrate for solution for infusion and LAZCLUZE (lazertinib) 80 mg and 240 mg film-coated tablets is moderate in the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations.

Considering:

•  evidence of a superiority of the RYBREVANT (amivantamab) + LAZCLUZE (lazertinib) combination compared to osimertinib alone in a randomised study (MARIPOSA) conducted in patients with newly diagnosed locally advanced or metastatic NSCLC with common EGFR Exon 19 deletions or Exon 21 L858R substitution mutations, in terms of:
  • progression-free survival assessed by an independent review committee according to RECIST v1.1 criteria: HR = 0.70 (95% CI = [0.58; 0.85]; p=0.0002), with respective progression-free survival medians of 23.7 versus 16.6 months;
  • overall survival, with an HR of 0.75 (95% CI = [0.61; 0.92]; p=0.0048), a survival median that was not reached in the amivantamab + lazertinib group and of 36.7 months in the osimertinib group, and overall survival rates at 42 months of 56% and 44% respectively; 

and despite: 

•  the open-label design of the MARIPOSA study for the amivantamab + lazertinib group;
• a difference in progression-free survival primarily related to a reduction in progressions, whereas progression-free deaths were increased, with no test comparing the cumulative incidences of progression-free deaths between the groups;
• an additional short-term mortality (first 9-12 months of treatment, before crossover of the Kaplan-Maier overall survival curves) observed in the patients treated with the RYBREVANT (amivantamab) + LAZCLUZE (lazertinib) combination. To date, no data are available concerning the factors leading to this major risk in view of the prior selection of the patients;
• the safety profile of the amivantamab + lazertinib combination compared to osimertinib, marked by a high frequency of grade ≥ 3 AEs (75.1% and 42.8% respectively), serious AEs (48.7% and 33.4% respectively) and AEs having led to permanent discontinuation of at least one study treatment (34.9% and 13.6% respectively), as well as by the occurrence of:
  • dermatological reactions (in particular rashes) and infusion-related reactions in 88.6% and 62.9% of patients respectively,
  • venous thromboembolic events in 37.3% of patients;
• a possible heterogeneity of effect depending on age with a potential greater treatment effect in the subgroup of patients under 65 years of age in the MARIPOSA study; 
• the absence of data in patients with symptomatic brain metastases, these having been excluded from the study, limiting extrapolation of the results to this patient profile; 
• the fact that it is impossible to quantify the contribution of this combination compared to the osimertinib + pemetrexed + platinum salt (cisplatin or carboplatin) combination, due to concom itant development;
• possibly informative censoring for 11% of the patients in the amivantamab + lazertinib group and 9% of patients in the osimertinib group, related, in particular, to consent withdrawals (15 and 8 patients respectively) as well as to patients having missed 2 or more consecutive assessments (11 and 8 patients respectively);
• the absence of any formal conclusion concerning quality of life findings; 

the Committee deems that the RYBREVANT (amivantamab) 350 mg concentrate for solution for infusion + LAZCLUZE (lazertinib) 80 mg and 240 mg film-coated tablets combination provides a minor clinical added value (CAV IV) compared to TAGRISSO (osimertinib).