MET status may predict benefit of amivantamab-lazertinib therapy in lung cancer subset
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Key takeaways:
- MET-positive status via immunohistochemistry may help predict response to the combination.
- Researchers reported improved response rates and longer PFS among those with MET-positive disease.
CHICAGO — MET status by immunohistochemistry may predict how patients with osimertinib-treated EGFR-mutated non-small lung cancer will respond to subsequent combination therapy, according to findings presented at ASCO Annual Meeting.
Patients with MET-positive status appeared five times as likely as those with MET-negative status to respond to amivantamab (Rybrevant, Janssen) plus lazertinib (Leclaza; Yuhan, Janssen) in the post-osimertinib setting.
They also achieved a nearly threefold increase in PFS, results showed.
“One of the strongest points of the design of this study is that biopsy was mandatory after osimertinib but before treatment with the combination,” Benjamin Besse, MD, PhD, director of clinical research at Institute Gustave Roussy in France, told Healio. “We don’t know if this overexpression is related to osimertinib, but it is present after osimertinib. When we have the biomarker and give the treatment right away, it works. The numbers really are convincing, and the science behind it is convincing.”
Background
Amivantamab is a bispecific antibody that targets EGFR and MET with immune cell-directing activity. Lazertinib is a third-generation EGFR tyrosine kinase inhibitor.
A prior study showed 36% of chemotherapy-naive patients treated with osimertinib (Tagrisso, AstraZeneca) — an irreversible EGFR TKI — responded to subsequent therapy with the amivantamab-lazertinib combination. Responses lasted a median 9.6 months.
Findings from exploratory analyses suggested EGFR/MET immunohistochemistry staining may predict response to the combination.
Methods
The ongoing phase 1/phase 1B CHRYSALIS-2 study is designed to assess lazertinib as monotherapy and in combination with amivantamab for patients with advanced EGFR-mutated NSCLC.
One of the four cohorts included 108 patients (median age, 65 years; range, 32-84; 69% women; 54% white; 43% Asian) who relapsed after osimertinib treatment.
All patients in the cohort were chemotherapy naive and had EGFR exon 19 deletion or L858R-mutated advanced NSCLC.
Patients had received a median one (range, 1-3) prior lines of therapy; 70% received osimertinib as first-line therapy and 30% received it in the second-ln the setting.
Besse and colleagues used this cohort to prospectively validate whether immunohistochemistry or circulating tumor DNA-based next-generation sequencing biomarkers may predict response to amivantamab plus lazertinib.
Investigators collected plasma and tissue after osimertinib treatment but prior to treatment with the combination.
Researchers established a training subset to identify biomarker criteria and a validation subset to identify predictive potential.
Results
The analysis included 101 response-evaluable patients.
Researchers reported an ORR of 30% (95% CI, 21-40), with a median response duration of 10.8 months (95% CI, 5.5 to not estimable) and median PFS of 5.7 months (95% CI, 4-8.2). Median OS had not been reached.
The majority of patients in the cohort were evaluable for MET immunohistochemistry (n = 77) and/or had detectable baseline circulating tumor DNA (n = 87).
Analyses from the training set (n = 50) identified MET-positive status — defined as immunohistochemistry-based MET expression of 3+ staining on at least 25% of tumor cells — as predictive of response to the amivantamab-lazertinib combination.
Researchers confirmed this observation through analyses in the validation set (n = 27).
Besse and colleagues determined 28 (36%) of the 77 patients had MET3+ staining on at least 25% of tumor cells.
Researchers reported overall response rates of 61% (95% CI, 41-79) for the MET-positive group and 14% (6-27) for the MET-negative group.
Median PFS was 12.2 months (95% CI, 8 to not estimable) in the MET-positive group and 4.2 months (95% CI, 2.8-6.4) in the MET-negative group.
Results also showed longer median duration of response (10.8 months vs. 6.8 months) and a higher clinical benefit rate (86% vs. 61%) in the MET-positive group.
MET-positive status on immunohistochemistry appeared predictive of response regardless of molecular resistance mechanism, Besse said.
Baseline next-generation sequencing of circulating tumor DNA did not predict response to the amivantamab-lazertinib combination. This finding is not surprising given amivantamab targets a protein on the surface of cancer cells, Besse said.
The safety profile of the combination appeared consistent with prior reports, Besse said.
The most common adverse events included paronychia (all grade, 48%; grade 3 or higher, 4%), rash (all grade, 48%; grade 3 or higher, 5%) and stomatitis (all grade, 30%; grade 3 or higher 1%).
Twenty-four patients (22%) required dose interruptions, six (6%) required dose reductions and five (5%) discontinued both amivantamab and lazertinib.
Twenty-nine patients (27%) developed treatment-emergent venous thromboembolism events, including 11 (10%) grade 3 or grade 4 events. No patients discontinued treatment due to VTE. Two patients (2%) developed pneumonitis, but no grade 3 or higher cases occurred.
“It is important to note this combination has a certain degree of toxicity — mostly skin toxicity, but it also increases rates of VTE,” Besse said. “Prophylactic anticoagulation may be something important to give to patients.”
Next steps
Besse and colleagues plan to confirm the predictive value of MET overexpression in two new cohorts in CHRYSALIS-2. One cohort will receive the amivantamab-lazertinib combination and the other will receive amivantamab monotherapy.
“Amivantamab plus lazertinib is a promising combination for patients with EGFR mutation-positive non-small cell lung cancer,” Besse told Healio. “The field of EGFR-mutated non-small cell lung cancer is moving quite fast. We have good data in the adjuvant setting, and the landscape in the first-line metastatic setting could change with the new FLAURA2 data. We may have many options in the first line, and any predictive biomarkers will help us determine the best treatments for the best patients.”
Perspective
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Vamsidhar Velcheti, MD
The study reveals that the combination of amivantamab and lazertinib is a promising treatment option for patients with EGFR-mutated advanced NSCLC who relapsed after osimertinib treatment.
Particularly interesting is the identification of immunohistochemistry-based MET expression as a potential predictive biomarker for response. Patients with strong MET expression demonstrated a notably higher ORR and PFS. This finding is pivotal, as it can guide the selection of patients more likely to benefit from the amivantamab-lazertinib combination.
In contrast, the study showed that circulating tumor DNA-based, next-generation sequencing was less successful at finding predictive biomarkers. Despite its usefulness in revealing genomic alterations, in this context it failed to identify a subgroup more likely to benefit from the treatment.
This research advances our understanding of the role of bispecific antibodies and EGFR inhibitors in treating NSCLC. It emphasizes the importance of considering the patient’s unique molecular profile — in this case, MET status determined by immunohistochemistry — in personalized cancer treatment strategies.
Overall, the study strengthens the argument for the amivantamab-lazertinib combination as a potential chemotherapy-free option for a specific subset of patients with NSCLC.
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Besse B, et al. Abstract 9013. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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