Melina E. Marmarelis, MD, medical director of Penn Medicine Mesothelioma and Pleural Program and assistant professor of medicine at the Hospital of the University of Pennsylvania, reports the rationale and key findings from the Chrysalis-2 trial (NCT04077463) of patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC).
A cohort of the phase 1/1b Chrysalis-2 study investigated the combination of amivantamab-vmjw (Rybrevant), lazertinib (Leclaza), carboplatin, and pemetrexed in patients with NSCLC with EGFR exon 19 deletion mutations or L858R activating mutations.
Marmarelis says that osimertinib (Tagrisso), which is now standard of care in the frontline for patients with these EGFR mutations, may or may not have an identifiable resistance mutation. Investigators hoped this combination could improve outcomes after progression with a prior EGFR tyrosine kinase inhibitor (TKI). This combination cohort enrolled patients with a median of 2 prior therapies, 14 out of 20 of whom received prior osimertinib, whereas others received gefitinib (Iressa) or afatinib (Gilotrif). Five had received prior platinum-based chemotherapy.
At a median follow-up of 7.1 months, there was an overall response rate (ORR) of 50% and a clinical benefit rate of 85%. Five patients discontinued treatment, 3 due to disease progression and 2 due to chemotherapy-related toxicity. The safety profile showed no new safety signals or additive toxicity from the combination.
0:08 | After osimertinib, we know that about 50% of patients don’t have a resistance mechanism that we can identify. For those patients, chemotherapy is the next step. This trial was looking at combining a targeted therapy, the combination of amivantamab and lazertinib, with chemotherapy, which is a resistance mechanism–agnostic approach. The hypothesis was trying to improve outcomes after disease progression on osimertinib.
In terms of what we found, we did see an ORR of about 50% and that was seen both in patients with baseline brain metastases and without. We also saw a clinical benefit rate of [85%]. Those are patients [who] either had a complete response, a partial response, or stable disease for 11 weeks or greater. The patient population was a little bit mixed in this study; it was 20 patients, 14 of which had prior osimertinib exposure, 6 of [whom] had no prior osimertinib exposure, but were only treated previously with a first- or second-generation EGFR-TKI. Five patients had exposure to prior platinum-based chemotherapy, so a heterogeneous group.