Amivantamab/Lazertinib/Chemotherapy Reveals Significant ORR Rates in NSCLC

The combination of amivantamab-vmjw (Rybrevant) plus lazertinib (Leclaza) and chemotherapy elicited high overall response rates (ORR) in patients with non–small cell lung cancer (NSCLC) who progressed on EGFR tyrosine kinase inhibitors (TKIs) as prior line of therapy, according to findings from the CHRYSALIS-2 study (NCT04077463).

Additionally, the safety profile of the lazertinib, amivantamab, carboplatin, pemetrexed, also known as the LACP regimen, was consistent with the individual agents. No new safety signals or additive toxicities were seen with the combination.

Findings were reported at the 2022 World Conference on Lung Cancer by Melina Elpi Marmarelis, MD, assistant professor of Medicine, the Hospital of the University of Pennsylvania.

In the phase 1 study, patients received 1400 mg of intravenous amivantamab weekly on a 21-day cycle for the first 4 doses up to cycle 2 day 1. Then, amivantamab at 1750 mg was administered every 3 weeks thereafter, in combination with 240 mg oral lazertinib daily, and 500 mg/m2 pemetrexed with carboplatin. Treatment with carboplatin was stopped after 4 cycles.

Of those enrolled in the trial, patients received a median of 2 (range, 1-3) prior lines of therapy, including osimertinib (Tagrisso; n = 14), gefitinib (Iressa; n = 3), and afatinib (Gilotrif; n = 3).

Findings revealed that at a minimum follow-up of 3 months, the best responses include 10 patients with confirmed partial response, 7 with stable disease, and 3 with progressive disease. The ORR demonstrated with the combination of lazertinib and amivantamab plus carboplatin and pemetrexed was 50% in the overall population (n = 20; 95% CI, 27-73). An ORR of 50% was also seen in 10 patients that had prior brain metastases (95% CI, 19-81).

Further, the most common treatment-emergent adverse events were neutropenia (85.0%), rash (75.0%), infusion related reaction (60.0%), stomatitis (60.0%), fatigue (50.0%), thrombocytopenia (40.0%), and nausea (40.0%).

In an interview with Targeted Oncology^TM, Marmarelis further discussed the findings revealed from the LACP cohort of the CHRYSALIS-2 study in NSCLC.

Targeted Oncology:With the standard of care platinum-based chemotherapy, what kind of responses are you seeing in patients with EGFR non–small cell lung cancer?

Marmarelis: After osimertinib, the AURA3 study [NCT02151981] looked at 1 of the arms looked at carboplatin pemetrexed and they saw an overall response rate of around 30% In those patients post a certain them so that's chemotherapy after disease progression on an EGFR TKI.

Can you discuss the early activity of amivantamab and lazeritinib as shown in phase 1?

Amivantamab and lazertinib have been shown to be an effective combination in post-osimertinib settings, partially because we know that MET activity or activity through the MET pathway is 1 of the resistance mechanisms after osimertinib. We're seeing response rates in the 30% to 40% range, depending on the cohort. The combination seems to be active and does have central nervous system activity, which is important in this patient population.

What hypothesis was drawn based on that earlier data? How did you explore this combination in the CHRYSALIS-2study?

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 overall response rate of about 50% and that was seen both in patients with baseline brain metastases and without. We also saw a clinical benefit rate of about 80%. Those are patients that 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 was 20 patients, 14 of which had prior osimertinib exposure, 6 of which 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.

Can you go into detail about the study design and methods used?

This 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, 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 a world low.

Can you discuss those findings presented at WCLC?

The primary efficacy end point was discussed, and the safety signals were as previously reported for me of amivantamab, lazertinib, and chemotherapy on their own. There was a slightly higher numerical rate of cytopenias seen and particullyar neutropenia in the first cycle. It's difficult to interpret based on the heterogeneous group of patients that had also received previous chemotherapy, and the fact that it was checked in between cycles, which is not standard clinical practice, may have elevated those numbers slightly. In general, there were no new safety signals for this combination.

In terms of efficacy, we did see an overall response rate of 50% and a clinical benefit rate of 80%. That was seen regardless of whether patients had baseline brain metastases or not. The other important finding is that with a median follow up of seven months, we did see that 15 out of 20 patients were still on treatment, and 10 out of the 10 patients that had a partial response have remained on treatment at the time of data cut off, suggesting that we are seeing some durable responses with this combination.

What would a phase 2 study of this combination look like? What further questions need to be answered regarding this combination and EGFR mutant non–small cell 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 [NCT04988295] is looking at the combination of amivantamab, lazertinib, and chemotherapy in post osimertinib settings. The PAPILLON study [NCT04538664] is looking at this combination in frontline, EGFR, exon 20, NSCLC patients. We look forward to those results.