Amivantamab is one of the most promising new treatments available for people with advanced non–small cell lung cancer (NSCLC) who carry atypical or uncommon EGFR mutations. While treatments for common EGFR mutations have advanced significantly in recent years, patients with rare EGFR alterations have historically had fewer effective options and often face shorter periods of disease control. The CHRYSALIS-2 Cohort C study has changed this conversation by demonstrating that amivantamab combined with lazertinib may offer meaningful and durable benefit for this patient population.
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Understanding Atypical EGFR Mutations
EGFR mutations help drive the growth of many lung cancers. Most patients have “common” EGFR mutations such as exon 19 deletion or L858R, but about 5–10% have atypical mutations, including G719X, S768I, and L861Q. These mutations often do not respond as well to older EGFR-targeting drugs, which is why new therapies are urgently needed. Atypical mutations may occur alone or in combination, and patients with compound mutations often experience even poorer outcomes.
What Is Amivantamab, and Why Is It Different?
Amivantamab is a bispecific antibody, meaning it targets two cancer-driving pathways—EGFR and MET—at the same time. By attaching to the surface of cancer cells, it blocks signals that help tumors grow and also helps the immune system recognize and attack the cancer. Lazertinib, taken as a daily pill, targets EGFR from inside the cancer cell. Together, these two medicines block cancer growth from different angles and may overcome resistance to earlier EGFR therapies.
This dual approach is particularly important for patients with atypical EGFR mutations, which do not always respond to older drugs such as gefitinib, erlotinib, or afatinib.
Who Was Included in the CHRYSALIS-2 Study?
The study enrolled 105 patients with advanced or metastatic NSCLC carrying atypical EGFR mutations. Participants were either newly diagnosed or had received up to two prior treatments, including first- or second-generation EGFR tyrosine kinase inhibitors. Patients with common EGFR mutations were not included, so the results specifically apply to rare EGFR mutation types.
How Well Did the Treatment Work?
Across all 105 patients, 52% experienced tumor shrinkage, and many others achieved disease stabilization. The median duration of response was more than a year, and the median progression-free survival—how long the cancer stayed under control—was 11.1 months. These results are considered clinically meaningful for a group of patients who often have limited treatment opportunities and historically shorter survival times.
The benefits were even more striking in patients who received the treatment as first-line therapy. In this group, 57% responded, and the median progression-free survival reached 19.5 months, nearly double what has been reported for older EGFR-targeted treatments in patients with these rare mutations. Many patients in this group remained alive and doing well at two years.
Even patients who had already received previous therapies benefited. The response rate was 48%, and the cancer remained controlled for a median of 7.8 months, showing that the combination may be helpful even after other treatments stop working.
Importantly, amivantamab combined with lazertinib worked across all major atypical mutation types and showed similar activity whether the mutation occurred alone or in combination with another atypical mutation. The presence of a TP53 co-mutation, which often signals more aggressive disease, did not meaningfully reduce the likelihood of response.
What Side Effects Should Patients Be Aware Of?
The safety profile of amivantamab plus lazertinib was consistent with what has been seen in earlier studies. Many patients experienced skin-related effects such as rash or nail inflammation, mild swelling, or temporary changes in blood test results. Most side effects were mild to moderate and manageable with supportive care.
Infusion-related reactions were common during the first amivantamab infusion, but nearly all were mild and rarely led to treatment discontinuation. The first dose is intentionally split over two days to help reduce this reaction.
One important finding is the occurrence of blood clots (venous thromboembolism) in about 30% of patients, mostly during the first four months of treatment. Because of this, preventive blood-thinning medication is now recommended for patients starting amivantamab-based therapy.
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How Is the Treatment Given?
Amivantamab is given by intravenous infusion once a week during the first month and then every two weeks afterward. Lazertinib is a pill taken once daily at home. Treatment continues as long as the cancer remains under control and the side effects remain manageable.
Why This Treatment Matters
Patients with atypical EGFR mutations have waited many years for more effective options. Older EGFR-targeted drugs offer limited benefit for mutations such as G719X, S768I, and L861Q, and outcomes have historically been worse compared with patients who have common mutations. The CHRYSALIS-2 results show that combining amivantamab with lazertinib may finally offer a treatment capable of producing deeper and more durable responses across this entire group of rare EGFR mutations.
The combination’s ability to work even in patients who previously received older EGFR inhibitors highlights its potential as both a first-line treatment and an option for patients who have already tried other therapies.
What This Means for Patients
For anyone diagnosed with an atypical EGFR-mutated lung cancer, discussing amivantamab plus lazertinib with your oncology team may be an important step. This treatment has shown promising results, with many patients experiencing meaningful tumor shrinkage and long-lasting control of their disease. Because each EGFR mutation is different, genetic testing is essential to determine whether this treatment is appropriate.
As research continues and more data become available, amivantamab-based combinations may play an increasingly central role in treating rare EGFR-mutated lung cancer.
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Written by Armen Gevorgyan, MD