Traditional Resistance to EGFR Inhibitors May Not Effect Responses With Amivantamab/Lazertinib in EGFR+ NSCLC

More than a third of patients who progressed on osimertinib (Tagrisso) therapy for EGFR-positive non–small cell lung cancer (NSCLC) had a response to the combination of amivantamab (Rybervant) plus lazertinib, according to results of a cohort of the CHRYSALIS trial (NCT02609776) presented during the 2021 ASCO Annual Meeting.¹ 

Biomarker analysis in the cohort also helped to identify patients that may be more likely to respond to the combination, which may not be based solely on the underlying genetic mechanisms of resistance, presenter Byoung Chul Cho, MD, PhD, suggested.

Amivantamab is a fully human bi-specific antibody targeting EGFR and MET that recently received FDA approval for the frontline treatment of adult patients with EGFR exon 20 insertion–mutant NSCLC.² Lazertinib is a potent third-generation EGFR tyrosine kinase inhibitor (TKI) that shows a promising safety profile, including low rates of EGFR-related toxicities.

Treatment with osimertinib has led to significant responses in patients with EGFR exon 19 deletion and exon 21 L858R mutations. However, resistance to osimertinib is more complex with many different forms of acquired resistance to the agent. Typically following progression on osimertinib, treatment with platinum-based chemotherapy is recommended, but limited activity is seen. The combination was explored as a potential new treatment option after progression on osimertinib.

The ongoing open-label, dose-escalation phase 1 CHRYSALIS study was a first-in-human study for amivantamab, either as monotherapy or in combination with lazertinib or chemotherapy, in patients with advanced NSCLC.

Cohort E, which is exploring the combination with lazertinib is aimed at establishing a recommended phase 2 dose for the combination and the safety and efficacy of the regimen. The recommended phase 2 dose was determined to be amivantamab at 1050 mg for patients below 80 kg and 1400 mg for those 80 kg or above administered intravenously weekly in cycle 1 and every 2 weeks subsequently, in combination with 240 mg oral daily lazertinib.

An expansion cohort for the combination enrolled 45 patients with osimertinib-relapsed, chemotherapy-naïve disease and analyzed biomarkers of next-generation sequencing (NGS) of tumor tissue and ctDNA as well as IHC for EGFR/MET expression.

Patients in the expansion cohort had a median age of 65 years (range, 39-85). Fifty-six percent of patients were female, 44% were White and 42% were Asian, and 56% were smokers. Two-thirds of patients had EGFR exon 19 deletion mutations, 31% had L858R mutations, but 1 patient had an unknown primary mutation. Brain metastases were also reported in 29% of patients. The median number of prior lines of therapy was 2 (range, 1-4).

Efficacy and Safety

Prior results for the combination regimen presented at the 2020 European Society for Medical Oncology (ESMO) Annual Congress showed promise for the regimen after a median follow-up of 4 months.³ The objective response rate (ORR) at the time was 36%, consisting of 1 confirmed complete response and 15 partial responses. The clinical benefit rate (CBR) was 60%.

At a median follow-up of 11.0 months (range, 1.0-15.0),1 the ORR was 36% (95% CI, 22%-51%) and the CBR was 64% (95% CI, 49%-78%). The median duration of response (DOR) was 9.6 months (95% CI, 5.3 to not reached [NR]) and 69% had a response lasting at least 6 months. The median progression-free survival (PFS) was 4.9 months (95% CI, 3.7-9.5).

The safety profile for the regimen was consistent with the previous experience presented at the 2020 ESMO meeting, which showed that adverse events (AEs) were observed in all patients in the cohort.³

In the updated findings presented during the ASCO meeting, treatment-related grade ≥3 AEs were reported in 16% of patients, 4% discontinued treatment, and 18% required a dose reduction. The most common AEs were infusion-related reactions (78%), rash (acneiform dermatitis, 51%; rash, 27%), and paronychia (49%), most of which were grade 1 or 2.

Biomarker Analysis

In the biomarker analysis, patients were characterized by their mechanism of resistance to osimertinib. Seventeen patients were identified to have either EGFR- (n = 11) or MET-based (n = 4) resistance by NGS testing; 2 patients had both EGFR and MET-based resistance. Seven patients also had additional co-occurring mutations, “reflecting complex and heterogeneous landscape of tumor at osimertinib resistance,” said Cho, of the Yonsei Cancer Center, Yonsei University College of Medicine in Seoul, Republic of Korea.

Mechanisms of resistance included most commonly EGFR C797S alterations in 7 patients, MET amplification in 5 patients, EGFR amplification in 3 patients, and EGFR L718X alterations in 3 patients. Additional alterations, such as PIK3CA E542X (n = 2), KRAS amplification (n = 1), CDK4 alteration (n = 1), and more were also observed.

Eight of these patients responded to treatment, for an ORR of 47% and the CBR was 82%.The median DOR in this subgroup was 10.4 months and the median PFS was 6.7 months.

Of the responders, 5 had EGFR-based resistance, 4 of which also showed co-occurring alterations, and 3 had MET-based resistance.

In the 28 patients without EGFR/MET-based resistance, the ORR was 29% and the CBR was 54%. The median DOR was 8.3 months and the median PFS was 4.1 months. All 8 responders had unknown resistance mechanisms. A majority of the nonresponders had 1 or 2 EGFR/MET-independent mechanisms of resistance, including most commonly PIK3CA E545K alteration in 3 patients and CCND1 amplification in 2.

Cho noted that an equal numeric value of patients responded to treatment with amivantamab and lazertinib in both subgroups, “suggesting the existence of a predictive biomarker other than genomic alteration.”

Twenty patients had sufficient tumor tissue for IHC staining after tumor NGS was completed. Ten of these patients were positive for EGFR/MET expression, which was defined as a combined EGFR+MET H score of ≥400. Among this subgroup, there were 10 partial responses, and 9 of these patients were positive for EGFR/MET expression on IHC.

Among IHC-positive patients, the ORR was 90% and the CBR was 100%; the median DOR was 9.7 months and the median PFS was 12.5 months.

Among 20 patients with both IHC and genomic data available, the investigators found that 4 patients in the IHC-positive subgroup had unknown genetic mechanisms of resistance, “suggesting that IHC may identify a patient subgroup who better respond to the combination regardless of underlying genetic resistance mechanisms.”

Next Steps

Cho noted that the biomarkers will potentially be validated prospectively in a cohort of the ongoing phase 1/1b CHRYSALIS-2 trial (NCT04077463). This trial contains 4 expansion cohorts for the combination of amivantamab and lazertinib. The fourth cohort, looking at the use of the regimen in patients with EGFR exon 19 deletion or L858R mutations following progression on osimertinib in the first- or second-line setting, will require tumor biopsy at entry for biomarker validation.

References

1. Bauml J, Chul Cho B, Park K, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. J Clin Oncol. 2020;39(suppl 15):9006. doi:10.1200/JCO.2021.39.15_suppl.9006

2. FDA approves first targeted therapy for subset of non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed June 4, 2021. https://bit.ly/3fCjEyT

3. Cho BC, Lee KH, Cho EK, et al. 1258O Amivantamab (JNJ-61186372), an EGFR-MET bispecific antibody, in combination with lazertinib, a 3rd-generation tyrosine kinase inhibitor (TKI), in advanced EGFR NSCLC. Ann Oncol. 2020;31(suppl 4):S813. doi:10.1016/j.annonc.2020.08.1572