CHRYSALIS, CHRYSALIS-2 Updates Add Support For Amivantamab Use In Specific NSCLC Populations

Author: By Lynda Williams, medwireNews Reporter 

medwireNews: Amivantamab is active against non-small-cell lung cancer (NSCLC) when given as a monotherapy to patients with a primary MET exon 14 skipping mutation (METex14), and when given alongside lazertinib to those with treatment-resistant, EGFR-mutated tumours, research shows. 

These updated results from the phase I CHRYSALIS and CHRYSALIS-2 trials, respectively, were reported to delegates attending the 2022 ASCO Annual Meeting in Chicago, Illinois, USA. 

CHRYSALIS presenting author Matthew Krebs, from The University of Manchester and The Christie NHS Foundation Trust in the UK, explained that as the bispecific antibody amivantamab has a higher affinity for MET than EGFR, it is important to investigate the agent in primary MET-driven tumours, especially as most patients given the MET tyrosine kinase inhibitors (TKIs) capmatinib or tepotinib develop acquired resistance to the treatment. 

Of the 55 patients with measurable, advanced METex14 NSCLC recruited to this arm of the trial so far, nine were treatment-naïve, 18 had previously received treatment excluding a MET TKI (median prior lines of therapy=1.5) and 28 had been given prior treatment including a MET TKI (median prior lines of therapy=3.0). 

The patients were aged a median of 70 years and 58% were women, which the presenter said was representative of the approximately 3% of NSCLC patients with a METex14 mutation. In addition, 53% were nonsmokers, 51% were Asian, and 18% had a history of brain metastases. 

Patients were given a weekly dose of amivantamab 1050 mg (bodyweight <80 kg) or 1400 mg (≥80 kg) in the first 4-week cycle and every 2 weeks thereafter, the presenter said. 

Of the 46 evaluable patients, the objective response rate (ORR) was 33% and this response rate ranged from 57% for the treatment-naïve individuals to 47% for those previously treated without a MET inhibitor and 17% for patients who had prior therapy including a MET inhibitor.  

The corresponding rates of clinical benefit – defined as a confirmed response or stable disease for at least 11 weeks – were 59%, 71%, 53% and 58%, and the median progression-free survival (PFS) durations were 6.7, unreached, 8.3 and 4.2 months, respectively. 

Amivantamab achieved responses “early”, after a median of 1.6 months, and these responses were “durable”, the presenter said. The median duration of response was unreached with ongoing responses in 11 of the 15 responding patients, including a response lasting at least 6 months in 10 cases. 

Matthew Krebs said the safety profile for patients with METex14 was “consistent” with that of the overall CHRYSALIS trial findings, with the majority of adverse events (AEs) associated with “on-target MET or EGFR activity” and occurring at grade 1–2. Discontinuations due to toxicity occurred in just 5% of patients. 

He added that, although infusion-related AEs were common, affecting 69% of patients at any grade, these were manageable and “very rarely occurred” after the first day of treatment, with just 5% of patients experiencing this AE at grade 3 or worse. 

When considered alongside the earlier CHRYSALIS findings for patients with EGFR-driven exon 20 insertion mutations given amivantamab, the METex14 results “confirm the independent, targeting action of each arm of the bispecific antibody”, concluded Matthew Krebs, adding that enrolment is ongoing for this arm in the CHRYSALIS trial. 

The CHRYSALIS-2 update was presented by Catherine Shu, from Columbia University Medical Center in New York, USA, who reported findings for the fully-accrued cohort of patients who had EGFR-mutated NSCLC that had progressed after osimertinib and platinum-based chemotherapy. 

She explained that 162 participants with an exon 19 deletion or the exon 21 L858R mutation were given amivantamab at the same dosage as the CHRYSALIS trial in combination with the third-generation, brain-penetrant EGFR TKI lazertinib at a dose of 240 mg/day. 

These patients were aged a median 61.5 years, 65% were women, 61% Asian and 69% nonsmokers. Brain metastases affected 41% at baseline, and the patients had previously received a median of three lines of therapy. These included frontline osimertinib followed by chemotherapy (23%) and osimertinib after an earlier generation EGFR TKI and then chemotherapy (42%), while the remaining 35% of patients were heavily pretreated or received a different sequence of therapy. 

Catherine Shu reported that the ORR was 33% including a complete response in 1%, a partial response in 32% and stable disease in 43%, giving a clinical benefit rate of 57%. The median duration of response was 9.6 months and after a median 10.0 months of follow-up, the median PFS was 5.1 months and overall survival 14.8 months. 

Overall, 30 of the 54 responding patients remained on treatment at the time of data cutoff and 27 had responses lasting at least 6 months, she noted, while eight of the 69 patients who achieved stable disease as their best response remained on treatment, and 15 did so for at least 6 months. 

The presenter also said that the forest plot showed “consistent” responses across the patient subgroups, including heavily pretreated patients and those with exon 19 deletion versus exon 21 L858R alterations. When looking at patients by prior therapy, the ORR was 21% for patients given front-line osimertinib, 36% for those with an earlier EGFR TKI before osimertinib and 39% for those given other sequences. 

Further assessment of the 27 patients who had untreated brain metastases at baseline and at least one scan after beginning treatment showed that 26% achieved complete clearance of central nervous system lesions on the combination treatment and 74% did not achieve a response, but none of the patients had progressive disease. 

Discussing the safety profile, Catherine Shu said that treatment interruptions, reductions and discontinuations of either treatment due to toxicity occurred in 35%, 9% and 7% of patients, respectively. Side effects included pneumonitis or interstitial lung disease in 7%, including at grade 3 or more severe in 4%. 

The presenter said that the “durable antitumor activity” in this group of patients who had received osimertinib plus platinum-based chemotherapy was comparable to that reported for individuals previously treated only with osimertinib, suggesting that “intervening chemotherapy does not impact amivantamab plus lazertinib activity”. 

Catherine Shu emphasized that the combination of amivantamab plus lazertinib “represents a chemotherapy-free regimen” for this patient population. 

She concluded that the CHRYSALIS-2 trial is ongoing and that the phase III MARIPOSA and MARIPOSA-2 trials are now evaluating amivantamab plus lazertinib as a first-line combination and alongside carboplatin and pemetrexed after osimertinib therapy. 

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2022 Springer Healthcare Ltd, part of the Springer Nature Group 

References 

• Krebs M, Spira AI, Cho BC, et al. Amivantamab in patients with NSCLC with MET exon 14 skipping mutation: Updated results from the CHRYSALIS study. J Clin Oncol 2022;40:(suppl 16; abstract 9008). Doi: 10.1200/JCO.2022.40.16_suppl.9008 
• Shu CA, Goto K, Ohe Y, et al. Amivantamab and lazertinib in patients with EGFR-mutant non-small cell lung cancer (NSCLC) after progression on osimertinib and platinum-based chemotherapy: Updated results from CHRYSALIS-2. J Clin Oncol 2022;40:(suppl 16; abstract 9006). Doi: 10.1200/JCO.2022.40.16_suppl.9006