Patients with EGFR-mutated non–small cell lung cancer and MET positivity may derive greater benefit from amivantamab plus lazertinib than patients who are MET-negative.
Data from a biomarker analysis of cohort D of the phase 1 CHRYSALIS-2 trial (NCT04077463) suggest that MET positivity according to immunohistochemistry (IHC) may correlate with superior treatment outcomes with amivantamab-vmjw (Rybrevant) plus lazertinib (Leclaza) for patients with EGFR-mutated non–small cell lung cancer (NSCLC) whose disease has progressed beyond osimertinib (Tagrisso) and who are chemotherapy naïve.1
Findings presented at the 2023 ASCO Annual Meeting showed that patients with MET-positive NSCLC (n = 28) experienced an overall response rate (ORR) of 61% (95% CI, 41%-79%) with the doublet. Conversely, the ORR achieved in the MET-negative population (n = 49) was only 14% (95% CI, 6%-27%).
The median duration of response (DOR) was 10.8 months (95% CI, 2.9-not evaluable [NE]) in the MET-positive population and 6.8 months (95% CI, 1.9-NE) in the MET-negative population. Clinical benefit rates (CBRs) achieved with amivantamab plus lazertinib were 86% (95% CI, 67%-96%) and 61% (95% CI, 46%-75%), respectively. Moreover, the median progression-free survival (PFS) was 12.2 months (95% CI, 8.0-NE) and 4.2 months (95% CI, 2.8-6.4), respectively. Seventeen of the MET-positive are still receiving treatment.
“MET positivity by immunohistochemistry may be a predictive biomarker for response to amivantamab plus lazertinib in the post-osimertinib, chemotherapy-naive setting,” lead study author Benjamin Besse, MD, PhD, stated in a presentation of the data. Besse is a professor of medical oncology at Paris-Saclay University and a full-time cancer specialist at Gustave Roussy Cancer Campus in Villejuif, France.
Previously reported data from cohort E of the phase 1 CHRYSALIS trial (NCT02609776) showed that amivantamab plus lazertinib produced sustained antitumor activity with acceptable safety in patients with EGFR-mutant NSCLC who had been exposed to osimertinib without exposure to platinum-based chemotherapy (n = 45).2,3 These patients experienced an ORR of 36% (95% CI, 22%-51%) with a median DOR of 9.6 months (95% CI, 5.3-not reached).
An exploratory analysis of 20 patients with available baseline biopsies revealed a subgroup of 10 patients expressing EGFR and MET by IHC staining. Those in this subgroup achieved a 90% response rate with the combination. In contrast, the 10 patients who were negative on IHC had an ORR of 10%. These results indicated that using IHC to identify high EGFR and MET expression may be a viable strategy for predicting who may respond to the regimen. Accordingly, researchers aimed to confirm the prognostic value of select biomarkers in additional cohorts.
At the 2023 ASCO Annual Meeting, investigators presented findings from their analysis of predictive biomarkers of response in cohort D of CHRYSALIS-2.1 Long-term efficacy and safety results from the CHRYSALIS trial were also presented at the meeting.3,4 At a median follow-up of 33.6 months, the estimated 12-month PFS rate with the doublet was 85%; these rates at 24 and 36 months were 65% and 51%, respectively. The median DOR, PFS, and overall survival (OS) were not estimable. Currently, the longest treatment duration is 37.2 months, and the longest DOR is 35.7 months.3
The open-label CHRYSALIS-2 study included a phase 1 dose-expansion portion to identify the recommended phase 2 dose (RP2D) for amivantamab and lazertinib; this was identified as 1050 mg of amivantamab (1400 mg if 80 kg or greater) plus 240 mg of oral lazertinib once a day. Once the RP2D was determined, efficacy was evaluated in 4 dose-expansion cohorts.
Of these, cohort D was designed to prospectively validate potential biomarkers identified through IHC or circulating tumor DNA (ctDNA) via next-generation sequencing (NGS). Patients included in this cohort had tumors that harbored EGFR exon 19 deletions or L858R mutations. These patients had not received prior chemotherapy but had experienced disease progression on or after treatment with osimertinib.
Plasma and tissue collection occurred at baseline, and a mandatory biopsy was performed in all patients prior to treatment with the combination. Predictive signature was assessed for several potential biomarkers using a predefined Bayesian process for retraining and/or validation.
The study’s primary end point was ORR. Other key end points included DOR, CBR, PFS, OS, and safety. Responses were assessed using RECIST v1.1 criteria.
The median age of patients in cohort D was 65 years (range, 32-84), with 69% of patients identifying as female and 32% identifying as male. The percentage of those with exon 19 deletions and L858R mutations was 63% and 38%, respectively. Regarding race, 54% of patients identified as White, 43% were Asian, 3% were Black, and 1% did not report this information. More than half of patients had an ECOG performance status of 1 (57%) and 44% had a status of 0. Twenty-five percent of patients had brain metastases at baseline, and the majority of patients had never smoked (61%). Seventy percent of patients had received osimertinib in the first line and 30% received the agent in the second line. The median number of prior lines of therapy received was 1 (range 1-3).
At the November 15, 2022, data cutoff, 108 patients were enrolled in cohort D and 62 were still receiving treatment. A total of 101 patients were deemed response evaluable. The median duration of treatment in this population was 4 months with amivantamab and 4.6 months with lazertinib.
At a median follow-up of 10.2 months, the ORR in this cohort was 30% (95% CI, 21%-40%). The median DOR was 10.8 months (95% CI, 5.5 months-NE), and the CBR was 69% (95% CI, 59%-78%). Moreover, the median PFS was 5.7 months (95% CI, 4.0-8.2), and median OS could not be estimated.
“Consistent with prior reports, amivantamab plus lazertinib demonstrated activity in patients with EGFR-mutated advanced NSCLC with disease progression on or after osimertinib,” Besse stated in the presentation.
Based on the signal observed in cohort E of the CHRYSALIS trial, investigators evaluated MET and EGFR 2+/3+ IHC in the first 50 patients enrolled in cohort D. However, this signature was no longer found to be predictive. Accordingly, a new signature based on MET-positive IHC was retrained, with a positivity threshold of 3+ staining displayed in 25% of tumor cells or more. This signature was determined to be predictive in the 50-patient training set and was validated in an additional 27 patients in the validation set.
Of the 101 efficacy-evaluable patients, 77 provided adequate tissue for staining. Assessment of these 77 patients revealed that 36% of patients had MET-positive tumors.
Baseline NGS of ctDNA was not found to be predictive of responses to the combination. Assessment of osimertinib-resistance mechanisms using IHC staining identified 19 patients with EGFR- or MET-dependent resistance. Twenty patients had osimertinib resistance that could instead be attributed to RAS/RAF/MEK alterations, PI3K, cell cycle genes and/or fusion events. Sixteen patients had unknown resistance mechanisms.
Patients in the EGFR- or MET-dependent population had an ORR of 37% with the combination, and those in the EGFR- or MET-independent population had an ORR of 15%. The ORR was 33% in patients with an unknown resistance mechanism.
Based on these findings, investigators determined that the type of osimertinib resistance mechanism did not affect the predictive ability of MET-positive IHC for the combination.
The regimen’s safety profile was consistent with previous reports of amivantamab plus lazertinib. Most adverse effects (AEs) were grades 1 and 2. The most reported group of AEs were rash related (78%), 10% of which were grade 3 or higher. Twenty-seven percent of patients reported any-grade venous thromboembolism treatment-emergent AEs (TRAEs); 10% of these were grade 3 or higher. Grade 1/2 pneumonitis/interstitial lung disease AEs were seen in 2% of patients.
EGFR inhibition–related AEs reported in at least 20% of patients included paronychia (any grade = 48%; grade 3 or greater = 4%), rash (48%; 5%), stomatitis (30%; 1%), dermatitis acneiform (25%; 2%), and pruritis (20%; 1%). MET inhibition–related peripheral edema (31%; 2%) and hypoalbuminemia (30%; 6%) were also reported. Other commonly reported AEs were infusion-related reactions (75%; 6%), nausea (32%; 0%), fatigue (27%; 2%), dyspnea (26%; 6%) dry skin (21%; 0%), and constipation (21%; 0%).
Twenty-two percent of patients experienced treatment-related dose interruptions of amivantamab and lazertinib. Treatment-related dose reduction and discontinuation occurred in 6% and 5% of patients, respectively.
Prospective validation of this biomarker is planned for 2 other cohorts in CHRYSALIS-2.
Disclosures: Dr Besse reported receiving institutional research funding from Abbvie, Amgen, Aptitude Health, AstraZeneca, Chugai Pharma, Daiichi Sankyo, Eisai, Ellipses Pharma, Genmab, Genzyme, Genzyme, Hedera Dx, Inivata, Ipsen, Janssen Oncology, MSD Oncology, PharmaMar, Roche/Genentech, Sanofi, socar, Taiho Pharmaceutical, Turning Point Therapeutics (Inst).