Melina E. Marmarelis, MD

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 study design of the Chrysalis-2 trial (NCT04077463) and ongoing trials researching the combination of amivantamab (Rybrevant) and lazertinib (Leclaza) in patients with 

-mutated advanced non–small cell lung cancer (NSCLC).

There was a cohort of 20 patients in the phase 2 Chrysalis-2 trial, 14 of whom had previously received osimertinib (Tagrisso) and 6 of whom had received a first- or second-generation EGFR tyrosine kinase inhibitor for 

-positive NSCLC. The primary end point was safety, and clinical benefit rate was a secondary end point.

Patients received lazertinib and amivantamab weekly for 4 weeks, then every 3 weeks with carboplatin and pemetrexed (Alimta). Carboplatin was discontinued after 4 cycles whereas pemetrexed was given as maintenance. This cohort whose data were presented at the 2022 World Conference on Lung Cancer showed a high clinical benefit rate in addition to a tolerable safety profile.

Marmarelis says that though this cohort focused on safety, ongoing studies are investigating the efficacy of this combination. The MARIPOSA-2 trial (NCT04988295) is investigating this regimen in patients post osimertinib, and the PAPILLON study (NCT04538664) is evaluating it as frontline therapy for patients with 

 This [cohort of the Chrysalis-2 study] was a small cohort of 20 patients looking primarily at safety. Safety was the primary end point. There were secondary end points that were based on efficacy such as clinical benefit rate, which was defined as complete response, partial response, or stable disease for 11 weeks or greater based on RECIST 1.1.

The patients were given lazertinib daily, amivantamab weekly for the first 4 weeks and then every 3 weeks with chemotherapy. The chemotherapy agents were carboplatin and pemetrexed given every 3 weeks and carboplatin was given for a total of 4 cycles while pemetrexed was continued through maintenance. Patients were evaluated for safety and for efficacy. The results were presented at [the 2022 World Conference on Lung Cancer].

 The primary goal of this cohort that was presented was to look at the safety. There are several ongoing studies that are looking at this combination in different settings. MARIPOSA-2 is looking at the combination of amivantamab, lazertinib, and chemotherapy in post osimertinib settings. The PAPILLON study is looking at this combination in frontline [patients with]

 exon 20 NSCLC. We look forward to those results.

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Melina E. Marmarelis, MD, reports the study design of the Chrysalis-2 trial and ongoing trials researching the combination of amivantamab and lazertinib in patients with EGFR-mutated advanced non–small cell lung cancer.

Ongoing Trials Investigate Amivantamab Combinations for EGFR+ NSCLC

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 

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 

 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 

 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.

 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.

Melina E. Marmarelis, MD, reports the rationale and key findings from the Chrysalis-2 trial of patients with EGFR-mutated advanced non–small cell lung cancer.

Melina E. Marmarelis, MD | Authors

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Ongoing Trials Investigate Amivantamab Combinations for EGFR+ NSCLC

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