Zofia Piotrowska, MD, of the Massachusetts General Hospital/Harvard Medical School, Boston, noted that MARIPOSA and MARIPOSA-2 are “two well-designed, randomized phase III trials, each meeting its primary endpoints and representing important advances for patients with EGFR-mutant lung cancer.” However, she expressed concern about the toxicity of amivantamab-vmjw and chemotherapy, especially in combination with lazertinib, and said the regimens’ true value will not be clear until overall survival data are available.
Zofia Piotrowska, MD
“Our goal is to develop new regimens that improve both progression-free and overall survival. If a new regimen extends progression-free survival without improving overall survival, we risk patients spending more of their lives on the new regimen, where the impact on quality of life becomes critical. With that in mind, the combination of amivantamab and lazertinib did increase toxicities” and trigger more treatment discontinuations as compared with osimertinib in MARIPOSA and with chemotherapy in MARIPOSA-2, Dr. Piotrowska pointed out.
These toxicities were chiefly dermatitis (paronychia and rash), infusion-site reactions, and venous thromboembolism; with the addition of chemotherapy, hematologic toxicity was also increased. “Amivantamab plus lazertinib certainly represents a new first-line option for EGFR-mutant non–small cell lung cancer, but mature overall survival data are needed. And, given a long treatment duration in the first line, chronic toxicities pose a particular challenge,” she said.
Turning to MARIPOSA-2, Dr. Piotrowski said she was impressed with the “clinically significant” doubling or near-doubling of response rate and progression-free survival with amivantamab plus lazertinib and chemotherapy (carboplatin and pemetrexed) and amivantamab plus lazertinib. However, although the hazard ratios for progression-free survival were robust, the early overall survival curves showed “no hint of separation yet,” she noted.
MARIPOSA-2 did suggest amvantamab-based treatment may offer protection against intracranial disease progression. However, given the similar risk reduction achieved with amivantamab plus lazertinib and chemotherapy as well as amivantamab plus chemotherapy, she questioned whether lazertinib is adding CNS-specific benefit or just contributing to toxicity. Again, she noted, “amivantamab plus lazertinib and chemotherapy led to the highest rates of toxicities, though amivantamab plus chemotherapy was also challenging.”
Rates of grade ≥ 3 treatment-emergent adverse events were 92% and 72%, respectively; more than one-third of patients on the four-drug regimen discontinued treatment, and 14 patients died, though not all were attributed to treatment, Dr. Piotrowska said. “It will be important to understand the contribution of lazertinib and whether there are patients who truly need it,” she added.
Considerations for Clinical Practice
The results of MARIPOSA offer another first-line option, giving clinicians three approaches now: osimertinib, based on FLAURA1; osimertinib plus carboplatin and pemetrexed, based on FLAURA22; and amivantamab plus lazertinib, based on MARIPOSA. Although not approved, sequencing of amivantamab and lazertinib is another possibility. Thus, clinicians should individualize treatment and the route of administration (amivantamab is given intravenously every 2 weeks). For most patients in her own practice, Dr. Piotrowska said, “osimertinib is likely to remain my first-line approach for now, given the lack of overall survival benefit and toxicity concerns with the combination regimens.”
The two MARIPOSA-2 regimens can be added to the second-line options for patients experiencing disease progression on osimertinib, though “the combined dermatologic and hematologic toxicities pose a challenge, particularly with the four-drug regimen but also with amivantamab plus chemotherapy,” stated Dr. Piotrowska. For her own patients with disease progression on osimertinib, she would be most likely to consider amivantamab plus chemotherapy for patients with CNS disease progression or a high burden of disease (because of the high response rate). “Given the safety and tolerability concerns as well as lack of overall survival benefit thus far, however, carboplatin plus pemetrexed will likely remain my preferred regimen for many patients.”
DISCLOSURE: Dr. Piotrowska reported financial relationships with Boehringer Ingelheim, Blueprint Medicines, Sanofi, Merck, Bayer, AstraZeneca, C4 Therapeutics, Cullinan Oncology, Janssen, Taiho Oncology, Takeda, Daiichi Sankyo, Eli Lilly, Plexus, PeerView, Research to Practice, Clinical Care Options, Ology, CEC, PER, Haymarket Medical Education, Georgetown, Philips Gilmore Oncology, DAVA Oncology, Aptitude Health, University of Arkansas, Curio Science, Taiwan Society of Thoracic Surgeons, Medscape/WebMD, OncLive, and Targeted Oncology; has received travel support from Janssen; and has received research support from Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, and Blueprint Medicines.
REFERENCES
1. Ramalingam SS, Vansteenkiste J, Planchard D, et al: Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382:41-50, 2020.
2. Jänne P, Planchard D, Cheng Y, et al: Osimertinib with/without platinum-based chemotherapy as first-line treatment in patients with EGFRm advanced NSCLC (FLAURA2). 2023 World Conference on Lung Cancer. Abstract PL03.13. Presented September 11, 2023.
