Amivantamab/Lazertinib Combo Demonstrates Durable Activity in EGFR-Mutated NSCLC

Catherine A. Shu, MD

The combination of amivantamab-vmjw (Rybrevant) and lazertinib produced encouraging responses with acceptable safety in patients with EGFR-mutated non–small cell lung cancer (NSCLC) who progressed on osimertinib (Tagrisso) and platinum-based chemotherapy, according to updated data from cohort A of the phase 1 CHRYSALIS-2 trial (NCT04077463).¹

At a median follow-up of 10.0 months (range, 0.3-20.2), the doublet resulted in an objective response rate (ORR) of 33% (95% CI, 26%-41%) per blinded independent central review (BICR) in this patient population (n = 162). Among those who responded to treatment, 1% achieved a complete response, 32% experienced a partial response (PR), 0.6% had an unconfirmed PR, 43% had stable disease, and 17% experienced disease progression.

“The activity of [the combination] is comparable to that in previously reported post-osimertinib, chemotherapy-naïve population, suggesting that intervening chemotherapy does not impact amivantamab plus lazertinib activity,” Catherine A. Shu, MD, lead study author, medical oncologist, and clinical director of the Thoracic Medical Oncology Service at Columbia University Herbert Irving Comprehensive Cancer Center, said in an oral presentation on the data during the 2022 ASCO Annual Meeting. “[The] safety profile of amivantamab plus lazertinib is consistent with prior reports, [and no] new safety signals were identified.”

A total of 162 patients with NSCLC and EGFR exon 19 deletion or L858R who progression on osimertinib and platinum-based chemotherapy were enrolled to cohort A of CHRYSALIS-2. These patients were given the recommended phase 2 combination dose of 240 mg of lazertinib plus 1050 mg of amivantamab.

The primary end point of the trial was ORR, and other end points included duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and adverse effects (AEs).

At baseline, the median age of those in cohort A was 61.5 years (range, 31-83), 65% were female, 61% were Asian, 70% had an ECOG performance status of 1, and 69% were non-smokers. Forty-one percent of patients had brain metastases at baseline; 19% had untreated metastases and 22% had treated metastases.

The median number of prior lines of therapy received was 3 (range, 2-14). Twenty-three percent of patients received prior frontline osimertinib followed by platinum-based chemotherapy, 42% previously received first- or second-generation EGFR TKI followed by osimertinib and then platinum-based chemotherapy, and 35% were heavily pretreated or out of sequence.

Additional data showed that the median DOR with the doublet was 9.6 months (95% CI, 7.0–not evaluable [NE]). Moreover, the CBR with the combination was 57% (95% CI, 49%-65%). The investigator-assessed ORR was 28% (95% CI, 22%-36%), with a median DOR of 8.4 months (95% CI, 5.6-NE). The median PFS with the regimen was 5.1 months (95% CI, 4.2-6.9) and the median OS was 14.8 months (95% CI, 12.1-NE).

Among those who previously received osimertinib followed by platinum-based chemotherapy (n = 39), the doublet elicited an BICR-assessed ORR of 21% (95% CI, 9%-37%) and an investigator-assessed ORR of 26% (95% CI, 13%-42%). In those who received prior first- or second-generation EGFR TKI followed by osimertinib and then platinum-based chemotherapy (n = 67), the BICR-assessed ORR with the regimen was 36% (95% CI, 25%-49%) and the investigator-assessed ORR was 30% (95% CI, 19%-42%). In the group of patients who were heavily pretreated or out of sequence (n = 56), the BICR-assessed ORR was 39% (95% CI, 27%-53%) and the investigator-assessed ORR was 29% (95% CI, 17%-42%).

At a data cutoff of March 15, 2022, 30 of the 54 responders were still on treatment; 27 of the patients responded to treatment for at least 6 months. For the 69 patients with a best response of disease stability, 8 were still on treatment and 15 had stable disease for at least 6 months.

Moreover, 64 patients received treatment beyond investigator-assessed progression. The median treatment duration following progressive disease was 0.4 months (range, 0.1-10.5).

Of the patients with baseline brain metastases (n = 66), 30 were untreated in that they did not receive radiation or surgery; 27 patients completed at least 1 brain scan following baseline. Of those 27 patients, 26% achieved complete clearance of their central nervous system lesions and 64% still had these lesions present. Five patients had documented non-target intracranial progression at cutoff.

The most common EGFR-related treatment-emergent AEs (TEAEs) were rash (all-grade, 44%; grade 3 or higher, 2%), dermatitis acneiform (34%; 5%), paronychia (52%; 4%), stomatitis (39%; 1%), diarrhea (22%; 1%), and pruritus (19%; 1%). The MET-related TEAEs reported with the combination were hypoalbuminemia (42%; 7%) and peripheral edema (27%; 1%).

Other TEAEs reported with the doublet included infusion-related reactions (67%; 8%), increased alanine aminotransferase (28%; 3%), nausea (25%; 2%), decreased appetite (24%; 1%), constipation (23%; 0%), asthenia (23%; 4%), dry skin (23%; 0%), vomiting (22%; 1%), increased aspartate aminotransferase (22%; 2%), dyspnea (20%; 8%), thrombocytopenia (20%; 1%), fatigue (20%; 2%), headache (18%; 1%), anemia (17%; 2%), and hypocalcemia (16%; 1%).

Thirty-five percent of patients required dose interruptions, 9% needed dose reductions, and 7% discontinued treatment. Pneumonitis/interstitial lung disease (ILD) was reported in 7% of patients; 4% of these cases were grade 3 or higher. No grade 5 pneumonitis/ILD was observed. Cumulative grouped rash-associated toxicities were reported in 80% of patients, 10% of which were grade 3 or higher in severity.

CHRYSALIS-2 is ongoing and information regarding underlying resistance mechanisms will be shared at a future medical meeting.

Reference

Shu CA, Goto K, Ohe Y, et al. Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung (NSCLC) after progression on osimertinib and platinum-based chemotherapy: updated results from CHRYSALIS-2. J Clin Oncol. 2022;40(suppl 16):9006. doi:10.1200/JCO.2022.40.16_suppl.9006