SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) mutations and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• CHRYSALIS (NCT02609776) is an ongoing phase 1, open-label, multicenter, dose escalation and dose expansion study evaluating the safety, efficacy, and pharmacokinetics of RYBREVANT as monotherapy and in combination with other therapies in adult patients with advanced NSCLC harboring EGFR or MET mutations who had disease progression during or after previous standard of care (SOC) treatment.^2,3
• Spira et al (2021)³ reported results for 19 patients with advanced NSCLC harboring MET Exon 14 skipping mutations (METex14) who received treatment with RYBREVANT as monotherapy at the recommended phase 2 dose (RP2D) from CHRYSALIS.
  • Among 19 patients treated in the METex14 cohort, 14 were considered response-evaluable. Partial responses (PRs) were observed in 9 patients (64%) with a median time to first confirmed response of 4.1 months (range, 1.6-9.9). The median treatment duration was 6.5 months (range, 4.3-12.2) and the median duration of response was not reached.
  • The safety profile of RYBREVANT in this subgroup of patients was consistent with previously reported experience of patients with EGFR-mutated NSCLC. Of all the patients who experienced infusion-related reactions (IRRs) in the METex14 cohort, 14 (74%) patients experienced a grade 1 or 2 reaction and 0 experienced a grade ≥3 reaction.
• Krebs et al (2022)⁴ presented updated results for 55 patients from the METex14 NSCLC cohort described above.
  • Among all patients and treatment-naïve patients, overall response rate (ORR) was 33% and 57%, respectively, and clinical benefit rate (CBR) was 59% and 71%, respectively. Among patients with and without prior MET therapy, ORR was 17% and 47%, respectively, and CBR was 58% and 53%, respectively. Overall, median progressionfree survival (PFS) was 6.7 months (95% confidence interval [CI], 2.915.3).
  • No new safety signals were observed. The safety profile for the METex14 subset was consistent with the larger CHRYSALIS safety population, with most events being grade 1-2.
• Leighl et al (2023)⁵ presented updated results for 97 patients from the METex14 NSCLC cohort described above.
  • Among all patients and treatment-naïve patients, respectively, ORR was 33% and 50%, and CBR was 70% and 88%. Among patients with and without prior MET therapy, respectively, ORR was 21% and 46%, and CBR was 68% and 64%. Overall, median PFS was 5.4 months (95% CI, 4.3-7.0), and median overall survival (OS) was 15.8 months (95% CI, 13.1-21.8).
  • No new safety signals were observed. The safety profile for the METex14 subset was consistent with prior reports.
• Haura et al (2019)⁶ reported preliminary data from the CHRYSALIS study from a cohort of patients (n=142) with advanced NSCLC who had been treated with RYBREVANT monotherapy.
  • Among 131 (92%) patients with primary EGFR mutations, 10 (8%) patients had secondary cMET amplification (≥6 copies). A best response of PR was observed in 32 of 108 (30%) patients with diverse EGFR mutations; 9 of these patients had concurrent cMET amplification.
  • Overall, the safety profile in the analyzed patient population was deemed manageable and consistent with EGFR inhibition.
    • Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 49 (35%) patients.
    • Treatment-related grade ≥3 adverse events (AEs) were reported in 12 (9%) patients.
    • AEs leading to treatment discontinuation and dose reduction occurred in 8% (4% treatment related) and 4% of patients, respectively.

clinical data

CHRYSALIS Study

Spira et al (2021)³ reported the preliminary efficacy and safety data of patients with METex14 NSCLC who received the RP2D of RYBREVANT in the METex14 dose expansion cohort (n=19).

Study Design/Methods

• Phase 1, ongoing, dose escalation and dose expansion study
  • The dose escalation cohort established the RP2D of RYBREVANT 1050 mg (<80 kg) and 1400 mg (≥80 kg) intravenously once weekly (QW) for Cycle 1 and every other week (Q2W) thereafter.
  • The dose expansion cohort is evaluating the safety and efficacy at the RP2D in patients with METex14. This cohort plans to enroll approximately 100 patients.
• Key eligibility criteria for METex14 cohort: metastatic/unresectable NSCLC; measurable disease; progressed after or declined SOC; primary METex14 mutation by next-generation sequencing (NGS) of tumor or circulating tumor deoxyribonucleic acid (ctDNA)

Results

Patient Characteristics

• Across the dose escalation and dose expansion of CHRYSALIS, 19 patients with METex14 were treated at the RP2D (safety population).
• Median age was 70 years (range, 55-75) and the median number of prior lines was 2 (range, 0-10) (Table: Demographics and Baseline Disease Characteristics).

Efficacy

• Of the 19 patients treated in the METex14 cohort, 14 were considered response-evaluable (patients who received ≥1 dose of study drug and have ≥1 postbaseline disease assessment or discontinued treatment prior to first disease assessment).
  • PRs were observed in 9 patients (64%), with 5 confirmed and 4 pending confirmation.
  • Antitumor activity was observed in treatment-naïve and previously-treated patients, including 4 of 7 patients previously treated with MET tyrosine kinase inhibitors (TKI).
    • Of 7 patients previously treated with MET TKIs, 2 had potential resistance mechanisms identified.
  • The median time to first confirmed response was 4.1 months (range, 1.6-9.9).
• Of the 14 response-evaluable patients, 11 remain on treatment, including 8 of 9 patients who have responded to treatment.
  • The median treatment duration was 6.5 months (range, 4.3-12.2).
  • The median duration of response was not reached.
• No patient demonstrated an increase in tumor assessment as defined by change in sum of diameters (SoD) of target lesions.

Safety

• The safety profile of RYBREVANT in this subgroup of patients with METex14 was consistent with previously reported experience of patients with EGFR-mutated NSCLC.
  • Treatment-related grade ≥3 AEs (16%): dyspnea, hypoalbuminemia, and rash (n=1, each)
  • Treatment-related: discontinuations in 5%, dose reductions in 11%, and dose interruptions in 32%
• Of the IRRs that occurred in the METex14 cohort, 14 patients (74%) experienced a grade 1 or 2 reaction and 0 experienced a grade ≥3 reaction (Table: Safety Profile).

Krebs et al (2022)⁴ presented the updated preliminary efficacy and safety data (as of April 11, 2022 [clinical cutoff]) for patients with METex14 NSCLC who received the RP2D of RYBREVANT in the METex14 dose expansion cohort (n=55).

Results

Patient Characteristics

• A total of 55 patients were enrolled as of the clinical cutoff date of April 11, 2022 (up to 100 planned) in the METex14 cohort, of which 28 received prior MET inhibitor therapy.
• Median age was 70 years (range, 43-88), and 10 patients had a history of brain metastases (Table: Demographics and Baseline Disease Characteristics).

Efficacy

• A total of 46 patients were evaluable for efficacy.
• ORR in the total population was 33% (Table: Responses to RYBREVANT Monotherapy).
• Median PFS in the total population was 6.7 months (95% CI, 2.9-15.3).
  • Median PFS in patients with and without prior MET inhibitor therapy was 4.2 months (95% CI, 2.9-not evaluable [NE]) and 8.3 months (95% CI, 1.5-15.3), respectively.
  • Median PFS in treatment-naïve patients was NE (95% CI, 2.6-NE).
• Median time to response was 1.6 months (range, 1.2-9.9).
• Median duration of response was not estimable as 11 of 15 patients who responded continued treatment.
  • Overall, 10 patients (67%) who responded had a response duration of ≥6 months.
  • The longest responder is at 76 weeks (ongoing).

Safety

• No new safety signals were observed. The safety profile of RYBREVANT in the METex14 subset was consistent with the overall safety profile of the larger CHRYSALIS safety population (Table: Safety Profile).
• Treatment modifications due to toxicity occurred in 425 patients: interruptions in 21%, reductions in 12%, and discontinuations in 5% of patients.
  • Rates of pneumonitis/interstitial lung disease (ILD) was 4%.
  • Cumulative grouped rash-related AEs occurred in 322 (76%) patients, of whom 16 (4%) had grade ≥3 events. For the METex14 subset, cumulative grouped rash-related AEs occurred in 39 (69%; grade ≥3, 2 [4%]) patients.
    • Rash-related terms included rash, dermatitis acneiform, acne, blister, dermatitis, dermatitis atopic, dermatitis exfoliative generalized, dermatitis infected, eczema asteatotic, erythema, erythema multiforme, folliculitis, hand dermatitis, macule, palmar-plantar erythrodysesthesia syndrome, perineal rash, perioral dermatitis, pustule, rash erythematous, rash macular, rash maculopapular, rash popular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin lesion, and toxic epidermal necrolysis.

Leighl et al (2023)⁵ presented the updated preliminary efficacy and safety data (as of June 19, 2023 [clinical cutoff]) for patients with METex14 NSCLC who received the RP2D of RYBREVANT in the METex14 dose-expansion cohort (n=97) at a median follow-up of 10 months.

Results

Patient Characteristics

• A total of 97 patients were enrolled as of the clinical cutoff date of June 19, 2023, in the METex14 cohort, of whom, 53 received prior MET therapy.
• Median age was 70 years (range, 43-88), and 14 patients had a history of brain metastases (Table: Demographics and Baseline Disease Characteristics).

Efficacy

• ORR in the total population was 33% (Table: Responses to RYBREVANT Monotherapy).
• Median PFS in the total population was 5.4 months (95% CI, 4.3-7.0).
  • PFS rate at 6 and 12 months was 44% and 30%, respectively.
• Median OS in the total population was 15.8 months (95% CI, 13.1-21.8).
  • OS rate at 6 and 12 months was 89% and 66%, respectively.
• Among the 32 evaluable patients, median time to response was 1.5 months (range, 1.29.9), median duration of response was 11.2 months (95% CI, 5.3-19.0), and median duration of exposure was 8.6 months (range, 1.9-31.4).
  • Overall, 15 patients (47%) who responded had a response duration of ≥6 months.
    • Durable responses at 12, 18, and 24 months were observed in 10, 6, and 3 patients, respectively.
  • At the time of data cutoff, 12 (38%) patients who responded remained on treatment.

Safety

• No new safety signals were observed. The safety profile for the METex14 subset was consistent with prior reports (Table: Safety Profile).
• Treatment-related dose interruptions, reductions, and discontinuations were seen in 24 (24.7%), 12 (12.4%), and 9 (9.3%) patients, respectively.
  • Rate of pneumonitis/ILD was 4.1%.
  • Cumulative grouped rash-related AEs occurred in 76 (78.4%) patients, of whom, 3 (3.1%) had grade ≥3 events.
  • Cumulative-grouped treatment-emergent venous thromboembolism (VTE) events occurred in 8 (8.2%) patients, of whom 2 (2.1%) had grade ≥3 events (none were grade 5).

Haura et al (2019)⁶ reported preliminary data from a cohort of patients (n=142) with advanced NSCLC in the CHRYSALIS study who had been treated with RYBREVANT monotherapy.

• Among 131 (92%) patients with primary EGFR mutations, 10 (8%) patients had secondary cMET amplification (≥6 copies), defined per central NGS or local fluorescence in situ hybridization findings of tumor biopsy samples.
• A best response of PR was observed in 32 of 108 (30%) patients with diverse EGFR mutations; 9 of these patients had concurrent cMET amplification.
• RYBREVANT activity was observed in 58 patients with post third-generation TKI disease.
  • Overall, 16 of 58 (28%) patients had a best response of PR (8 confirmed):
    • Eight patients with C797S
    • Three patients with cMET amplification (≥6 copies)
    • Five patients without identified EGFR- or cMET-based resistance
• The safety profile in the analyzed patient population was deemed manageable and consistent with EGFR inhibition.
  • Grade ≥3 TEAEs were reported in 49 (35%) patients.
  • Treatment-related grade ≥3 AEs were reported in 12 (9%) patients.
  • AEs leading to treatment discontinuation and dose reduction occurred in 8% (4% treatment related) and 4% of patients, respectively.
  • The most frequently observed TEAEs (≥20%) were IRR (62%), rash (56%), paronychia (26%), and constipation (22%).
  • IRRs were primarily limited to the first infusion (Cycle 1 Day 1).
  • No specific details on safety outcomes in patients with cMET amplifications were reported.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 24 October 2024.