Amivantamab Shows Continued Efficacy Following Platinum Treatment in Patients With EGFR Exon 20 Insertion+ NSCLC

Article

Patients with non-small cell lung cancer harboring exon 20 insertion mutations whose disease progressed after platinum-based chemotherapy continued to show responses to amivantamab in a long-term analysis of the CHRYSALIS trial.

Pilar Garrido López, MD, PhD

Pilar Garrido López, MD, PhD

Long-term data from the phase 1 CHRYSALIS trial (NCT02609776) demonstrated continued efficacy with amivantamab-vmjw (Rybrevant) among patients with non–small cell lung cancer (NSCLC) harboring EGFR exon 20 insertion mutations whose disease progressed on platinum-based chemotherapy. Data were presented during the 2023 European Lung Cancer Congress.1 According to investigators, the agent also showed continued tolerability.

At a median follow-up of 19.2 months, the median progression-free survival (PFS) with amivantamab was 6.9 months (95% CI, 5.6-8.8), with a 2-year PFS rate of 13.7%. The median overall survival (OS) with the drug was 23 months (95% CI, 18.5-29.5), and the 2-year landmark OS rate was 47.2%.

Moreover, amivantamab elicited an objective response rate (ORR) of 37% (95% CI, 28%-46%) per investigator assessment, with a median duration of response (DOR) of 12.5 months (95% CI, 6.9-19.3). Notably, the agent’s efficacy proved to be consistent, irrespective of previous therapies received or response to prior platinum chemotherapy.

Forty-two percent of patients (n = 48/114) were reported to have sustained clinical benefit with amivantamab, having received the agent of 12 or more cycles. Thirteen percent of these patients were still receiving amivantamab, and they had been receiving it for a median of 2.6 years. At the data cutoff of September 12, 2022, 7 of these patients were progression free and 8 were receiving treatment beyond disease progression.

“Sustained clinical benefit with [amivantamab], meaning to receive [the agent] for 12 cycles [or more], was associated with having a good performance status, [namely an] ECOG [performance status of 0]; having a response according to RECIST criteria; and not having a baseline alteration in the RAS/RAF/MEK pathway,” said Pilar Garrido López, MD, PhD, lead study author and associate professor of medical oncology at Universidad de Alcalá, in Madrid, Spain, in a presentation of the data.

In May 2021, the FDA granted an accelerated approval to amivantamab for use in adult patients with NSCLC whose tumor harbor EGFR exon 20 insertion mutations and whose disease progressed on platinum-based chemotherapy.2 The regulatory decision was based on earlier data from CHRYSALIS, in which the agent induced an ORR of 40% (95% CI, 29%-51%) by independent central review and RECIST v1.1 criteria, with a median DOR of 11.1 months (95% CI, 6.9-not evaluable) in this group of patients (n = 81).

The first-in-human, open-label, multicenter, two-part, phase 1 study enrolled patients with metastatic or unresectable NSCLC who had an ECOG performance status of 0 or 1 and who had progressed on or were not able to receive standard treatment.3 For the dose-expansion phase of the trial, patients were required to have measurable disease by RECIST v1.1 criteria and qualifying EGFR or MET mutations via next-generation sequencing. Those with untreated or active brain metastases were excluded.

The trial is examining the use of amivantamab alone and in combination with other agents in patients with advanced NSCLC. For the EGFR exon 20 insertion–positive cohort, the agent was evaluated as a monotherapy, and was administered at the recommended phase 2 dose (RP2D) of 1050 mg in those who weighed less than 80 kg, and of 1400 mg in those who weighed at least 80 kg.

The primary objective of the dose-escalation portion of the research was to identify the maximum tolerated dose and the RP2D of amivantamab. In the expansion phase, investigators examined the safety, tolerability, and antitumor activity of the agent when given at the RP2D.

At the meeting, Garrido López, who is also head of the Thoracic Tumours Section in the Medical Oncology Department at the University Hospital Ramón y Cajal, in Madrid, Spain, reported long-term results from the study for this patient population.

Among the 114 patients included in the analysis, the median age was 62 years (range, 36-84). More than half of patients were female (61%) and Asian (52%). Fifty-seven percent of patients were nonsmokers, and 43% were smokers. Twenty-five percent of patients had brain metastases at baseline.

Regarding ECOG performance status, 29% of patients had a status of 0, 70% had a status of 1, and 1% had a status of 2. This was a heavily pretreated population who had received a median of 2 prior lines of therapy (range, 1-7). All patients previously received platinum-based chemotherapy, 44% had prior immunotherapy, and 20% previously received an EGFR TKI.

As previously presented, no differences in ORRs were observed for the subgroups of age, sex, race, ECOG performance status at baseline, number of prior lines of treatment, smoking history, or presence of brain metastases.

Investigators conducted a univariate analysis in which they examined potential demographic predictors of sustained clinical benefit with amivantamab. To do this, they considered age, sex, race, body mass index category, performance status, brain metastases, smoking status, and previous treatment. “Only an ECOG performance status of 0 was associated with sustained clinical benefit,” Garrido López noted. There was also a trend linking underweight patients with shorter treatment with the agent.

All patients were required to submit a plasma sample at baseline to undergo circulating tumor DNA analysis, Garrido López added. “Patients with baseline alterations in the RAS/RAF/MEK pathway were only seen in the group [of patients who received] less than 12 treatment cycles,” she noted. “None of [these alterations] occurred in the group [of patients who received the agent for] 12 cycles or more.” Achieving a partial response to treatment with amivantamab was also noted to be associated with sustained clinical benefit.

No new safety signals were observed with longer follow-up. In the group of patients with EGFR exon 20 insertion–positive disease, the most common EGFR-related toxicities were paronychia (total, 58%; grade ≥3, 4%), dermatitis acneiform (47%; 1%), rash (43%; 2%), stomatitis (25%; 1%), pruritus (20%; 0%), and diarrhea (18%; 4%). The most common MET-related adverse effects (AEs) were hypoalbuminemia (39%; 4%) and peripheral edema (27%; 1%).

Other toxicities reported with the agent included infusion-related reactions (67%; 3%), nausea (28%; 1%), constipation (26%; 0%), fatigue (26%; 4%), dyspnea (25%; 5%), cough (21%; 0%), arthralgia (21%; 0%), back pain (20%; 1%), decreased appetite (20%; 1%), increased alanine aminotransferase (18%; 4%), dry skin (17%; 0%), and vomiting (17%; 1%).

Toxicities of special interest included rash (89%; 4%), interstitial lung disease (7%; 0%), and venous thromboembolism (11%; 6%).

Treatment-related dose interruptions occurred in 29% of patients. Amivantamab-related dose reductions were required by 18% of patients.

“[There were] low rates of treatment-related discontinuations [7%],” Garrido López said. “Cumulative grouped rash and infusion-related reactions remained the most frequent toxicities.”

Amivantamab is now being explored in combination with chemotherapy for use as a first-line treatment in patients with NSCLC harboring EGFR exon 20 insertion mutations, as part of the phase 3 PAPILLON trial (NCT04538664).4

Dr Garrido López's personal financial interests include consultancy/honoraria from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi, and Takeda. She has received direct funding from Medscape and Touch Medical. Institutional funding has been received from Amgen, AstraZeneca, Blueprint, Bristol Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Janssen, IO Biotech, Lilly, MSD, Novartis, Pharmamar, Pfizer, Roche, Sanofi, Takeda, and Theradex Oncology.

References

  1. Garrido P, Girard N, Cho BC, et al. Long-term efficacy, safety and predictors of response to amivantamab among patients with post-platinum EGFR Ex20ins-mutated advanced NSCLC. Presented at: 2023 European Lung Cancer Congress; March 29-April 1, 2023; Copenhagen, Denmark. Abstract 30.
  2. FDA grants accelerated approval to amivantamab-vmjw for metastatic non-small cell lung cancer. FDA. May 21, 2021. Accessed March 29, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
  3. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J Clin Oncol. 2021;39(30):3391-3402. doi:10.1200/JCO.21.00662
  4. A study of combination amivantamab and carboplatin-pemetrexed therapy, compared with carboplatin-pemetrexed, in participants with advanced or metastatic non-small cell lung cancer characterized by Epidermal Growth Factor Receptor (EGFR) exon 20 insertions (PAPILLON). ClinicalTrials.gov. Updated March 2, 2023. Accessed March 29, 2023. https://clinicaltrials.gov/ct2/show/NCT04538664
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