Amivantamab Plus Lazertinib Demonstrates Activity After Osimertinib and/or Chemo in EGFR-Mutant NSCLC

Amivantamab-vmjw (Rybrevant) in combination with lazertinib demonstrated significant clinical activity with durable responses in patients with EGFR-mutated non–small cell lung cancer (NSCLC) who had progressed on osimertinib (Tagrisso), according to findings from an analysis of the phase 1 CHRYSALIS trial (NCT02609776) that were presented during the 2021 ESMO Congress.¹

The results suggested that the combination approach was more efficacious with potentially improved central nervous system (CNS) penetration compared with amivantamab monotherapy.

“The combination of amivantamab and lazertinib after osimertinib has higher activity and response duration compared with amivantamab monotherapy, with the potential for improved intracranial protection. This supports the simultaneous targeting of the intracellular and catalytic domains of EGFR,” said Natasha B. Leighl, BSc, MMSc, MD, a clinician investigator of the Cancer Clinical Research Unit at the Princess Margaret Cancer Centre, in a virtual presentation of the CHRYSALIS analysis.

Also presented during the 2021 ESMO Congress were the preliminary cohort A results of the ongoing phase 1 CHRYSALIS-2 trial (NCT04077463), which demonstrated efficacy with amivantamab plus lazertinib in patients who progressed on osimertinib and platinum-based chemotherapy and for whom no approved targeted therapies exist.²

“[Activity] in the target population was comparable to that previously reported in the post-osimertinib, chemotherapy-naïve setting, suggesting that intervening chemotherapy may not impact [the] activity of the combination,” lead study author of CHRYSALIS-2 Catherine Ann Shu, MD, an assistant professor of medicine at Columbia University Medical Center and clinical director of the Thoracic Medical Oncology Service at the Herbert Irving Comprehensive Cancer Center, said in a virtual presentation of the data.²

Previously reported data from the CHRYSALIS trial led the FDA to grant an accelerated approval to amivantamab on May 21, 2021, for the treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.³

Amivantamab is an EGFR-MET bispecific antibody that confers immune cell–directing activity. Lazertinib is a highly selective, third-generation EGFR TKI with brain penetrance potential and a broad therapeutic index, which makes it a tolerable agent at doses up to 240 mg.

In the CHRYSALIS trial, patients received 1050 mg or 1400 mg of single-agent amivantamab or 1050 mg or 1400 mg of amivantamab plus 240 mg of lazertinib or standard chemotherapy.

Patients who received the combination were a median age of 65 years (range, 39-85) and 29% had a history of brain metastases. Patients received a median of 2 prior lines of therapy (range, 1-4) and 38% had EGFR/MET-based resistance.

In CHRYSALIS-2, the target population (n = 80) included patients who received osimertinib, and platinum-based chemotherapy as their last line of therapy. The heavily pretreated population (n = 56) included patients who received platinum-based chemotherapy, osimertinib, with or without other therapies without restrictions on prior lines and treatment sequence.

All patients had to have metastatic, advanced NSCLC and harbor EGFR exon 19 deletions or L858R mutations. All patients received 1050 mg or 1040 mg of amivantamab plus 240 mg of lazertinib.

Patients included in the target population were a median age of 62 years (range, 31-82) and 43% had a history of brain metastases. Patients had a median of 3 prior lines of therapy (range, 2-4).

In the heavily pretreated population, patients were a median age of 63 years (range, 39-83) and 39% had a history of brain metastases. Patients had a median of 4 prior lines of therapy (range, 2-14).

The primary end point of CHRYSALIS-2 was overall response rate (ORR), with secondary end points of clinical benefit rate (CBR), duration of response (DOR), progression-free survival, overall survival, and adverse effects.

In this analysis of the CHRYSALIS trial, the combination of amivantamab and lazertinib led to an ORR of 36% (95% CI, 22%-51%) in patients with EGFR-mutant NSCLC who progressed on osimertinib (n = 45). The ORR was 19% with amivantamab monotherapy (95% CI, 12%-27%; n = 121). The median DOR was 9.6 months with the combination (95% CI, 5.3-not reached) vs 5.9 months with the single agent (95% CI, 4.2-12.6).

Additionally, documented CNS progression was 17% with single-agent amivantamab vs 7% with the combination of amivantamab and lazertinib.

In the target population, the results of CHRYSALIS-2 showed an ORR of 41% (95% CI, 24%-61%) with amivantamab plus lazertinib in patients with EGFR-mutated NSCLC who had progressed on osimertinib and platinum-based chemotherapy. The CBR was 69% (95% CI, 49%-85%).

Moreover, 8 of 12 responders remained progression free and on treatment at the time of the data cutoff. Five of 12 patients with stable disease remained on treatment.

Notably, amivantamab plus lazertinib demonstrated efficacy in the heavily pretreated population; the ORR was 21% (95% CI, 11%-36%), and the CBR was 51% (95% CI, 36%-66%).

Regarding safety in the CHRYSALIS analysis, the toxicity profiles of amivantamab alone and in combination with lazertinib were consistent with those reported from earlier data cutoffs, and no new safety signals were identified. Diarrhea was reported in 7% of patients treated with the monotherapy and 22% of patients treated with the doublet. Pneumonitis/interstitial lung disease (ILD) was reported in 2% vs 4% of patients, respectively.

Similar safety findings were reported in the CHRYSALIS-2 dataset, with the safety profile of the combination remaining consistent with previously reported findings. Three percent of patients experienced pneumonitis/ILD.

The combination regimen is currently being evaluated in various EGFR-mutated NSCLC populations. In CHRYSALIS-2, the doublet is being investigated in patients with EGFR exon 20 insertion mutated–NSCLC who progressed on platinum-based chemotherapy (cohort B), patients with uncommon EGFR-mutated NSCLC who are treatment naïve or have progressed on first- or second-generation EGFR TKI–based therapy (cohort C), and patients with tumor-biopsied, common EGFR-mutated NSCLC who progressed on osimertinib for biomarker validation (cohort D).

Enrollment on cohort A is completed; additional enrollment on cohorts B, C, and D are ongoing.

Additionally, the doublet is being compared with osimertinib in the ongoing phase 3 MARIPOSA trial (NCT04487080) in treatment-naïve patients with common EGFR mutations.

References

1. Leighl NB, Shu CA, Minchom A, et al. Amivantamab monotherapy and in combination with lazertinib in post-osimertinib EGFR-mutant NSCLC: analysis from the CHRYSALIS study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1192MO.
2. Shu CA, Goto K, Ohe Y, et al. Amivantamab plus lazertinib in post-osimertinib, post-platinum chemotherapy EGFR-mutant non-small cell lung cancer (NSCLC): preliminary results from CHRYSALIS-2. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1193MO.
3. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. News release. FDA. May 21, 2021. Accessed September 28, 2021. https://bit.ly/3EZbJrb