Polling Data Show Updates in Treatment of mNSCLC With EGFR Mutations

Edward S. Kim, MD, MBA, FACP, FASCO

Non-small cell lung cancer (NSCLC) accounts for apNon–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases,¹ with a high percentage harboring actionable mutations that can be identified via molecular testing including PD-L1, EGFR, ALK, ROS1, BRAF, NTRK1/2/3, MET exon 14 skipping, RET, KRAS, and HER2.² A broad molecular panel–based testing approach is recommended regardless of disease stage and should be done at the time of diagnosis to minimize tissue use, identify rare driver mutations, counsel patients for potential clinical trials, and allow for improved personalized patient care.^2,3 In addition, RNA next-generation sequencing should be considered for patients without driver mutations to identify possible fusion events.² 

EGFR mutations are largely made up of EGFR exon 21 L858R point mutations (~40%) and EGFR exon 19 deletions (~45%).^1,4 These 2 mutations are known as activating or sensitizing mutations, as they make the tumor more responsive to tyrosine kinase inhibitors (TKIs). Although patients with these EGFR mutations tend to show improved response and survival rates to EGFR TKIs, acquired resistance often develops leading to disease progression. The most common resistance mechanism is development of the T790M mutation, which alters the EGFR protein to reduce the binding affinity of early-generation EGFR TKIs. This secondary mutation develops in approximately 50% of patients with NSCLC who initially respond well to EGFR TKIs.^3,5

Approved EGFR NSCLC Therapies

First-generation reversible EGFR TKIs were FDA approved in the early 2000s for targeted treatment of common EGFR exon 19 deletions and exon 21 L858R point mutations in advanced NSCLC.⁶ Second-generation irreversible EGFR TKIs (afatinib [Gilotrif] and dacomitinib [Vizimpro]) offered broader coverage but came with increased adverse events. To address frequently acquired resistance mutations to early-generation TKIs, osimertinib (Tagrisso), a third-generation irreversible TKI, was FDA approved.^3,6 Improved response rates and central nervous system penetration resulted in osimertinib becoming the preferred first-line therapy for advanced NSCLC. The FDA-approved therapies for NSCLC at each stage of disease are summarized in the Table.⁷ 

Table. FDA-Approved EGFR Inhibitors for Exon 19 Deletions and Exon 21 L858R in NSCLC^7,a

^aAs of November 2024.

Recently, 2 new combination therapies have been FDA approved. First, amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) was approved for first-line treatment of locally advanced or metastatic NSCLC (mNSCLC) harboring EGFR exon 19 deletions or exon 21 L858R mutations based on findings from the phase 3 MARIPOSA trial (NCT04487080).⁸ Trial results showed a 7.1-month improvement in median progression-free survival and a 30% reduction in the risk of progression or death with the combination vs patients treated with osimertinib.⁸ Second, based on findings from the phase 3 MARIPOSA-2 trial (NCT04988295), the FDA approved amivantamab plus chemotherapy (carboplatin and pemetrexed [Alimta]) for patients with locally advanced or mNSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations with disease progression post EGFR TKI therapy.⁹ This trial showed a 2.1-month improvement in progression-free survival and a 28% increase in objective response rate with the combination vs chemotherapy alone.⁹

Future Direction for EGFR NSCLC Therapies

Amivantamab’s recent approvals by the FDA were for intravenous (IV) administration only, not subcutaneous (SC). However, the phase 3 PALOMA-3 trial (NCT01942135) showed SC administration improved overall survival and reduced infusion-related reactions compared with IV administration of amivantamab, both administered with lazertinib, in participants with advanced or EGFR-mutated mNSCLC after progression on osimertinib and chemotherapy.¹⁰ In addition, a phase 2 study (COPERNICUS; NCT06667076) is ongoing at City of Hope of SC amivantamab in combination with lazertinib for first-line treatment or SC amivantamab in combination with chemotherapy for second-line therapy of locally advanced or mNSCLC harboring EGFR exon 19 deletions or exon 21 mutations. This study will be the first to investigate SC amivantamab, venous thromboembolism events, prophylactic-dose anticoagulation, and enhanced dermatologic adverse event management.

Improving survival and quality of life for patients with NSCLC is of the utmost importance in the exploration of novel treatment strategies that may lead to the development of new EGFR TKIs and combination therapies.

Survey Results From Case-Based Roundtables

When participants in the Case-Based Roundtable events were asked what they are most likely to offer their patients with an EGFR exon 21 L858R mutation as a first-line therapy, the overwhelming majority responded “osimertinib single agent” (POLL 1).

POLLING QUESTION 1.

What are you most likely to offer a patient with NSCLC and a classical EGFR driver mutation of exon 21 L858R as first-line therapy, assuming that a clinical trial is not an option?

When asked what they would select as second-line therapy for a patient with disease progression and an ECOG performance status of 1, the majority responded “amivantamab plus carboplatin plus pemetrexed” with “continue osimertinib and add chemotherapy” as the next highest response (POLL 2).

POLLING QUESTION 2.

At this stage of disease progression with an ECOG performance status of 1, what would you select as second-line therapy?

After further discussion, the group was asked to consider what they were most likely to offer a patient with mNSCLC with a classical EGFR mutation who progressed on or after osimertinib. Seventy-one percent responded they would treat with “amivantamab plus carboplatin plus pemetrexed” (POLL 3).

POLLING QUESTION 3.

After the discussion this evening, what are you most likely to offer a patient with a classical EGFR mutation such as exon 21 L858R–mutated mNSCLC with disease progression on or after osimertinib?

Conclusions

Given the success of SC amivantamab in combination with lazertinib or carboplatin and pemetrexed, ongoing studies are exploring the safety and effectiveness of these combinations in other EGFR-mutated NSCLC populations. A recent phase 1 study, CHRYSALIS-2 (NCT04077463), showed clinically significant antitumor activity with amivantamab in combination with lazertinib in patients with NSCLC with EGFR exon 19 deletion or exon 21 L858R mutation who progressed on or after osimertinib and chemotherapy.¹¹ The phase 2 SKIPPirr study (NCT05663866) showed that in a similar patient population, adding an oral dexamethasone twice-daily regimen to IV amivantamab plus lazertinib reduced the rate of infusion-related reactions by 3-fold.¹²

Survey results from the Case-Based Roundtables indicate that amivantamab in combination with carboplatin and pemetrexed is now being utilized for the treatment of patients with advanced NSCLC with common EGFR mutations who progressed on or after osimertinib. Although most adverse events of these 2 amivantamab combination therapies are generally manageable, as with any new treatment, clinicians must continue to monitor their patients closely to address any potential serious adverse events including infusion reactions.

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