Highlights
– Amivantamab plus lazertinib produced an investigator-assessed objective response rate (ORR) of 52% in 105 patients with atypical EGFR‑mutant advanced NSCLC (median follow‑up 16.1 months).
– Responses were durable (median duration of response 14.1 months) and deeper and longer in treatment‑naïve patients (ORR 57%; mPFS 19.5 months; mDoR 20.7 months).
– Safety findings were consistent with known profiles of the agents and were predominantly grade 1–2; no new safety signals were identified.
Background
EGFR mutations are well established as predictive biomarkers in non‑small cell lung cancer (NSCLC). The classical activating mutations — exon 19 deletions and exon 21 L858R — are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). However, a substantial minority of EGFR‑mutant NSCLC harbor atypical (uncommon) alterations such as G719X, S768I, and L861Q, alone or in combination. These uncommon variants are biologically heterogeneous and have variable sensitivity to approved TKIs. Clinical outcomes with existing agents (first‑, second‑, and third‑generation TKIs) are mixed across mutation subtypes, and optimal treatment strategies remain incompletely defined. There is therefore an unmet need for more effective, broadly active therapies for patients with atypical EGFR mutations.
Study design
CHRYSALIS‑2 is a multi‑cohort clinical study evaluating the combination of amivantamab and lazertinib in patients with advanced NSCLC. Cohort C specifically enrolled patients with atypical EGFR mutations (examples: G719X, L861Q, S768I) and allowed up to two prior lines of systemic therapy. Importantly, cases with coexisting exon 19 deletions, exon 21 L858R, or exon 20 insertions were excluded to focus on uncommon‑only genotypes.
Intervention: Intravenous amivantamab (1,050 mg; 1,400 mg if ≥80 kg) once weekly for 4 weeks then every 2 weeks, combined with oral lazertinib 240 mg daily. The primary endpoint for Cohort C was investigator‑assessed objective response rate (ORR). Key secondary endpoints included duration of response (DoR), progression‑free survival (PFS), overall survival (OS), and safety.
Key findings
As of the data cutoff (January 12, 2024), 105 participants received the amivantamab–lazertinib combination. Median follow‑up in the overall cohort was 16.1 months.
Overall efficacy
– ORR (investigator assessed): 52% (95% CI, 42–62).
– Median duration of response (mDoR): 14.1 months (95% CI, 9.5–26.2).
– Median progression‑free survival (mPFS): 11.1 months (95% CI, 7.8–17.8).
– Median overall survival (mOS): not estimable (NE; 95% CI, 22.8–NE) at the time of analysis.
Subgroup analyses
– Treatment‑naïve participants (no prior EGFR TKI or systemic therapy): ORR 57% (95% CI, 42–71); mPFS 19.5 months (95% CI, 11.2–NE); mDoR 20.7 months (95% CI, 9.9–NE); mOS NE (95% CI, 26.3–NE). These results suggest enhanced depth and durability of response when the combination is used up‑front.
– Mutation‑specific and structural subgroup results: The most common atypical genotypes were G719X (56%), L861X (26%), and S768I (23%); solitary versus compound atypical mutations did not appreciably change ORR. When grouped using a structure‑informed classification (P‑loop & αC‑helix compressing, classical‑like, and T790M‑like), ORRs were 45% (n = 38), 64% (n = 14), and 67% (n = 3), respectively — indicating variable but meaningful activity across mechanistic subclasses.
Safety
Adverse events were consistent with previously published safety profiles for amivantamab and lazertinib. Most events were grade 1–2; specific adverse events were not detailed in the summary but the investigators reported no new safety signals. The tolerability profile supports feasibility of the combination in this population, though infusion‑related reactions (with amivantamab), dermatologic and gastrointestinal toxicities (with TKIs), and class effects should be anticipated and monitored in practice.
Interpretation and clinical context
The combination of amivantamab (a bispecific antibody targeting EGFR and MET) and lazertinib (an oral third‑generation EGFR TKI) is mechanistically attractive for uncommon EGFR mutations. Amivantamab engages the extracellular receptor and can induce receptor downregulation and antibody‑dependent cellular cytotoxicity, while lazertinib inhibits intracellular kinase activity, including some resistance variants. This dual blockade may extend activity beyond what is seen with TKIs alone in structurally diverse atypical mutations.
In the context of historical treatments, published outcomes for atypical EGFR mutations have been heterogeneous. Second‑generation agents such as afatinib have demonstrated activity against several uncommon variants in pooled analyses, and osimertinib shows variable responses across mutation subtypes. Direct cross‑trial comparisons are limited by differences in patient selection, prior therapy, and response assessment, but the 52% ORR and prolonged responses reported with amivantamab–lazertinib are clinically meaningful and compare favorably with many historical benchmarks, particularly given the inclusion of previously treated patients and a heterogeneous mutation mix.
Expert commentary, limitations, and unanswered questions
These results are encouraging but should be viewed through the lens of study design and remaining evidence gaps. Cohort C is a single‑arm, nonrandomized cohort with investigator‑assessed responses; central blinded review and randomized comparisons would strengthen causal inference. The cohort intentionally excluded tumors with concurrent classical activating mutations or exon 20 insertions, which limits applicability to mixed‑mutation tumors that are encountered in practice.
Key limitations include heterogeneity of the atypical mutation group, modest subgroup sample sizes (some structural classes had very small numbers), and evolving follow‑up for overall survival. Intracranial activity of the combination was not described in the summary but is an important consideration in EGFR‑mutant NSCLC given the high incidence of brain metastases. Safety details were summarized as consistent with prior experience, but granular rates of specific grade ≥3 events, dose modifications, and discontinuations are necessary for clinical decision making.
Future directions should include: randomized comparisons against current standards (for example, afatinib or osimertinib in first‑line atypical EGFR mutations), detailed CNS efficacy reporting, translational biomarker analyses to identify which mutation subtypes or compound mutation patterns benefit most, and characterization of acquired resistance mechanisms to the dual therapy.
Conclusion
CHRYSALIS‑2 Cohort C provides important prospective evidence that amivantamab plus lazertinib yields clinically meaningful activity in patients with advanced NSCLC harboring atypical EGFR mutations. The combination produced a durable ORR of 52% overall and appeared particularly active in the treatment‑naïve subset, with an acceptable safety profile and no new safety signals. While data are encouraging, confirmatory randomized studies, detailed safety and CNS efficacy data, and mechanistic biomarker work will be key before this approach can be widely adopted as standard of care for atypical EGFR‑mutant NSCLC.
Funding and clinicaltrials.gov
CHRYSALIS‑2 is reported in the primary literature; details on study sponsorship and funding are provided in the original JCO publication (Tomasini et al.). For registry and protocol information, consult ClinicalTrials.gov and the published manuscript for the specific trial identifier and funding disclosures.
Selected references
1. Tomasini P, Wang Y, Li Y, et al; CHRYSALIS‑2 Cohort C. Amivantamab Plus Lazertinib in Atypical EGFR‑Mutated Advanced Non‑Small Cell Lung Cancer: Results From CHRYSALIS‑2. J Clin Oncol. 2025 Dec 1: JCO2402835. doi:10.1200/JCO-24-02835. PMID: 41325571.
2. Robichaux JP, Elamin YY, Tan Z, et al. Structure‑based classification predicts drug response in EGFR‑mutant non‑small‑cell lung cancer. Nat Med. 2021;27(11):1660–1669.
3. Yang JC, Sequist LV, Geater SL, et al. Afatinib for patients with lung adenocarcinoma harbouring uncommon EGFR mutations: a pooled analysis of LUX‑Lung 2, 3, and 6. Lancet Oncol. 2015;16(7):830–838.
4. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non–Small Cell Lung Cancer. Latest version. For recommended testing and treatment options, consult the NCCN guideline repository.
Clinical takeaways
– Amivantamab plus lazertinib is a promising therapeutic approach for atypical EGFR mutations, offering a clinically relevant ORR with meaningful durability, particularly as first‑line therapy.
– The combination’s mechanistic complementarity may overcome limitations of TKIs alone in structurally heterogeneous mutations, but randomized comparative data and deeper safety/CNS analyses are needed to define its role in treatment algorithms.
