Amivantamab-lazertinib combination safe in EGFR-mutated NSCLC
Click Here to Manage Email Alerts
Amivantamab and lazertinib can be combined safely at their monotherapy doses for patients with advanced EGFR-mutated non-small cell lung cancer, according to results of the phase 1 CHRYSALIS study presented at ESMO Virtual Congress 2020.
Researchers reported encouraging preliminary activity with the combination among patients who relapsed after treatment with osimertinib (Tagrisso, AstraZeneca), a third-generation, irreversible EGFR-directed tyrosine kinase inhibitor approved for first-line treatment of patients with metastatic NSCLC whose tumors harbor EGFR mutations.
“Amivantamab is a fully human bispecific antibody that targets EGFR and MET, has immune cell-directing activity and previously demonstrated clinical activity across diverse EGFR-mutant NSCLC,” Byoung Chul Cho, MD, oncologist in the department of internal medicine at Yonsei University in South Korea, said during a presentation. “It was granted FDA breakthrough therapy designation for EGFR-mutant [NSCLC harboring exon 20 insertion mutations] after chemotherapy.”
Preclinical studies have shown the combination of amivantamab (Janssen) and the third-generation EGFR TKI lazertinib (Janssen) leads to synergistic inhibition of tumor growth.
Cho and colleagues aimed to identify a recommended phase 2 combination dose.
Their study included 71 patients (median age, 61 years; range, 36-79) with NSCLC and EGFR exon 19 deletion or L858R mutations.
In part 1 of the study, researchers assigned patients to IV amivantamab at escalating doses of 700 mg to 1,050 mg once weekly for 28 days, followed by the same doses biweekly, in combination with oral lazertinib at the standard monotherapy dose of 240 mg daily.
Trial protocol had no restriction on prior therapy (median prior lines, 1; range, 0-9).
Researchers designated the maximally assessed doses of 1,050 mg (1,400 mg for those 80 kg) amivantamab and 240 mg lazertinib as the recommended phase 2 combination doses.
Interim safety data showed adverse events such as rash (78%), infusion-related reactions (61%), paronychia (42%), stomatitis (31%), pruritus (24%) and diarrhea (14%).
Only 7% of treatment-related adverse events were grade 3 or higher.
Among 23 patients in part 1 of the study with measurable disease, researchers reported an overall response rate of 43.5% (95% CI, 23.2-65.5). Ten patients achieved partial responses and nine patients had stable disease.
Median treatment duration was 8.2 months (range, 0.5-10.7), with 13 patients remaining on treatment at data cutoff.
Researchers also reported early antitumor activity among 14 of 20 response-evaluable patients in a dose-expansion cohort who progressed on osimertinib. This included one complete response, seven partial responses and six patients with stable disease.
“Amivantamab can be safely combined with lazertinib, with no dose-limiting toxicities identified during the dose escalation,” Cho said. “[This combination] is efficacious in advanced EGFR-mutated NSCLC, and new studies looking at this combination have already begun.”
Perspective
Back to Top
Fred R. Hirsch, MD, PhD
This an early study, but that doesn’t mean there isn’t value here.
Third-generation TKIs have a lot of promise, but we need to learn more about them and their differences from the other generations of TKIs.
Combining these with amivantamab, a bispecific antibody targeting EGFR and MET, is a promising avenue. As we know, MET abnormalities occur in about 10% of EGFR TKI-resistant tumors. So, finding something to target them is a good idea and has scientific rationale.
The data are encouraging in this early phase. We are already seeing great responses, and I think this could be a good treatment option in the future.
We haven’t seen the full data set from the part 2 dose-expansion cohort, but the researchers report that they’ve observed antitumor activity. This cohort will be the most important in terms of learning about how this works.
Seeing the part one cohort responding so well makes me think it will continue to work and should be tested in larger trials.
Perspective
Back to Top
Jorge J. Nieva, MD
MET amplification remains a key driver of resistance to EGFR tyrosine kinase therapy, and strategies that target MET have the potential to improve outcomes for patients who experience disease progression after first-line osimertinib.
Researchers used a combination of an EGFR- and MET-targeting bispecific antibody, amivantamab, with the third-generation EGFR TKI lazertinib in patients who had disease progression after osimertinib.
The phase 1 portion of the clinical trial established the recommended dose of the combination, which for patients under 80 kg is 1,050 mg amivantamab and 240 mg lazertinib. This produced the usual but manageable toxicities of EGFR blockade, including rash, stomatitis and paronychia.
The toxicity appears to be worth it. With an ORR of 43.5% and median treatment duration of 8.2 months, the combination therapy provided results comparable to the expected outcome of second-line chemotherapy.
Although the current standard for patients who failed osimertinib is platinum-based chemotherapy, the development of targeted agents that can delay the start of chemotherapy will be welcomed by future patients. Unfortunately, this abstract did not provide us with a biomarker that will identify those patients who are most likely to benefit from the addition of amivantamab to ongoing third-generation EGFR blockade and who would be best served by moving to chemotherapy. Hopefully, those data will be forthcoming soon.
Collapse
Cho BC, et al. Abstract 1258O. Presented at: European Society for Medical Oncology Virtual Congress 2020; Sept. 19-21, 2020.
Click Here to Manage Email Alerts