Is lazertinib (a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)) a consideration for a patient with metastatic lung adenocarcinoma, brain metastases, EGFR exon 19 deletion, and MET amplification who has progressed on osimertinib (Tagrisso)?

Lazertinib as Monotherapy Is Not Recommended After Osimertinib Progression

For a patient with metastatic lung adenocarcinoma, brain metastases, EGFR exon 19 deletion, and MET amplification who has progressed on osimertinib, lazertinib monotherapy is not the appropriate treatment—the recommended approach is amivantamab plus carboplatin-pemetrexed, with consideration of adding lazertinib to this regimen. 1, 2

Primary Treatment Recommendation

The ASCO 2024 guideline establishes amivantamab plus chemotherapy as the standard of care for patients who progress on osimertinib, based on the MARIPOSA-2 trial. 1 This combination achieved:

• Median PFS of 6.3 months versus 4.2 months with chemotherapy alone (HR 0.48, P < 0.001) 1, 3
• Objective response rate of 64% versus 36% with chemotherapy alone 1, 3
• Median intracranial PFS of 12.5 months versus 8.3 months with chemotherapy alone 3

The Role of Lazertinib in This Context

Lazertinib is only recommended in combination with amivantamab plus chemotherapy, not as monotherapy. 1, 3 The MARIPOSA-2 trial evaluated three arms:

• Amivantamab + chemotherapy
• Amivantamab + lazertinib + chemotherapy
• Chemotherapy alone

The triple combination (amivantamab + lazertinib + chemotherapy) showed median PFS of 8.3 months versus 4.2 months with chemotherapy alone (HR 0.44, P < 0.001). 1, 3 However, this regimen required modification during the trial due to increased hematologic toxicities, with lazertinib now started after carboplatin completion. 3

Critical Importance of MET Amplification

Your patient's MET amplification is one of the two most actionable resistance mechanisms after osimertinib progression. 1, 2 The ESMO guidelines specifically state that MET amplification may be treated with a combination of an EGFR and a MET TKI. 1

Amivantamab is a bispecific antibody targeting both EGFR and MET, making it particularly appropriate for this patient's resistance mechanism. 1 In the CHRYSALIS-2 cohort evaluating amivantamab plus lazertinib after osimertinib and chemotherapy failure, exploratory biomarker analyses showed responses in patients with MET-dependent resistance. 4

Treatment Algorithm for This Patient

1. Confirm MET amplification via tissue rebiopsy or liquid biopsy using next-generation sequencing 1, 2

2. Initiate amivantamab plus carboplatin-pemetrexed as the primary regimen 1, 2

3. Consider adding lazertinib to the regimen (starting after carboplatin completion to minimize hematologic toxicity) for potentially improved PFS, though this comes with increased toxicity 1, 3

4. Monitor with CT imaging every 6-12 weeks and brain MRI at each follow-up given baseline CNS involvement 2

Why Not Lazertinib Monotherapy?

Lazertinib as a single agent has never been studied or recommended after osimertinib progression. 1 While lazertinib is a third-generation EGFR TKI with preclinical data suggesting higher selectivity and improved blood-brain barrier penetration compared to osimertinib 5, it is only being evaluated:

• In treatment-naive patients as first-line therapy (MARIPOSA trial showed amivantamab + lazertinib superior to osimertinib monotherapy with median PFS 27.5 vs 18.5 months) 1
• In combination with amivantamab after osimertinib failure, not as monotherapy 1, 3, 4

Alternative Options If Amivantamab Is Unavailable

If amivantamab is not accessible, platinum-based chemotherapy (carboplatin-pemetrexed) remains the standard second-line option. 1 The ASCO guideline states that for patients who progress on osimertinib without emergent T790M or other targetable alterations, clinicians should offer platinum-based chemotherapy. 1

Combination strategies targeting MET amplification specifically include:

• Osimertinib plus savolitinib (30% response rate in MET-amplified patients) 1
• Osimertinib plus tepotinib (under investigation in INSIGHT 2 study) 1
• Osimertinib plus capmatinib (under investigation in GEOMETRY-E trial) 1

Critical Pitfalls to Avoid

Do not use PD-1/PD-L1 checkpoint inhibitors as monotherapy in this EGFR-mutant patient, as they show markedly inferior efficacy regardless of PD-L1 expression (response rate 12% vs 23% in EGFR wild-type). 1, 2 The IMMUNOTARGET registry demonstrated median PFS of only 2.1 months with single-agent ICIs in EGFR-mutant patients. 1

If considering immunotherapy at all, only use it in combination with chemotherapy and bevacizumab (atezolizumab + bevacizumab + carboplatin-paclitaxel), which showed median OS of 29.4 months in the IMpower150 subgroup analysis. 1, 6 However, this is not preferred over amivantamab-based regimens. 1, 2

Never sequence osimertinib within 3 months after immune checkpoint inhibitors due to significantly increased risk of pneumonitis (38% in the TATTON trial). 1, 6

Expected Toxicity Profile

The predominant adverse events with amivantamab-containing regimens are:

• Hematologic toxicities (higher with triple combination) 3
• EGFR-related toxicities: rash (81%, grade ≥3 in 10%), paronychia (52%) 4
• MET-related toxicities: hypoalbuminemia (grade ≥3 in 6%) 4
• Infusion-related reactions (68%, grade ≥3 in 9%) 4

Serious treatment-emergent adverse events occurred in 32% with amivantamab-chemotherapy versus 52% with amivantamab-lazertinib-chemotherapy versus 20% with chemotherapy alone. 1