Advances in EGFR-Positive Lung Cancer Treatment: 2023

Lung cancer is now understood not as a single disease but as a diverse collection of disease groups. With about 2 million new cases each year, it is one of the world's two most common cancers alongside breast cancer, yet it comprises many different subtypes. It therefore encompasses both common and rare diseases and requires a broad approach.

About 85% of lung cancers are non-small cell lung cancers (NSCLC). NSCLC itself includes dozens of subtypes, now classified by their genomic features. This makes precision oncology possible, allowing more targeted and personalized treatment approaches.

Lung cancers with EGFR genetic alterations form an important NSCLC subgroup, characterized by mutations in the epidermal growth factor receptor (EGFR) gene. These mutations play a critical role in cancer cell growth and spread and are more common in people of Asian ancestry and nonsmokers. The most frequent are exon 19 deletions and the exon 21 L858R point mutation. Their presence indicates sensitivity to EGFR tyrosine kinase inhibitors (TKIs), allowing good treatment responses.

Most patients with EGFR mutations eventually develop drug resistance, requiring continued development of treatment strategies. Secondary mutations such as T790M are among the most common causes and require different approaches. The diversity of EGFR mutations and their effects on treatment highlight the importance of individualizing care. Treatment of EGFR-mutated NSCLC therefore requires a personalized approach based on mutation type and overall health.

Notable Recent Studies

Several recent phase 3 trials have substantially updated approaches to EGFR-altered NSCLC, illustrating the continual evolution of treatment strategies and the growing importance of personalized medicine.

MARIPOSA positions amivantamab plus lazertinib as a new first-line standard for advanced EGFR-mutated NSCLC.

MARIPOSA-2 recommends considering amivantamab plus chemotherapy as a new standard for the same population after progression on osimertinib.

PAPILLON identifies amivantamab plus chemotherapy as a new first-line standard for NSCLC with EGFR exon 20 insertion mutations.

These studies were presented at ESMO Congress 2023.

MARIPOSA: Amivantamab Plus Lazertinib Versus Osimertinib

In MARIPOSA, amivantamab plus lazertinib significantly improved progression-free survival (PFS) over osimertinib monotherapy in previously untreated advanced EGFR-mutated NSCLC.

The study enrolled 1074 previously untreated patients with locally advanced or metastatic EGFR-mutated NSCLC. They were randomly assigned to amivantamab plus lazertinib (429 patients), osimertinib alone (429) or lazertinib alone (216).

Median follow-up was 22 months. The primary endpoint was progression-free survival (PFS) assessed by blinded independent central review.

Results

• Mean PFS was 23.7 months with amivantamab plus lazertinib versus 16.6 months with osimertinib (hazard ratio [HR], 0.70; 95% CI, 0.58-0.85; P <0.001).

• The 12-month PFS rates were 73% and 65%, respectively.
• The 24-month PFS rates were 48% and 34%, respectively.
• Mean extracranial PFS was 27.5 months with amivantamab plus lazertinib versus 18.5 months with osimertinib (HR, 0.68; 95% CI, 0.56-0.83; P <0.001). The 24-month extracranial PFS rates were 53% and 38%, respectively.
• Overall response rates were 86% with amivantamab plus lazertinib and 85% with osimertinib.
• Median response duration was 25.8 and 16.8 months, respectively.
• The 24-month PFS rate after first-line treatment (PFS2) was 72% with amivantamab plus lazertinib and 64% with osimertinib (HR, 0.75; 95% CI, 0.58-0.98; P =0.03).
• Although overall survival data were immature, there was a trend toward improvement with amivantamab plus lazertinib. The 24-month overall survival rates were 74% and 69%, respectively (HR, 0.80; 95% CI, 0.61-1.05; P =0.11).

These findings suggest that amivantamab plus lazertinib represents a new first-line standard for advanced EGFR-mutated NSCLC.

However, grade 3 or higher treatment-related adverse events (AEs) were more common with amivantamab–lazertinib than osimertinib: 75% versus 43%.

Treatment-related adverse events led to discontinuation in 10% of the combination group versus 3% with osimertinib. Diarrhea was more common with osimertinib, while paronychia, rash and hypoalbuminemia were more common with amivantamab plus lazertinib.

Venous thromboembolism (VTE) was an adverse event of special interest, occurring in 37% with amivantamab–lazertinib versus 9% with osimertinib. Discontinuation due to VTE occurred in 3% versus 0.5%, respectively.

Only 1% of patients receiving amivantamab–lazertinib used anticoagulants during the study, compared with none receiving osimertinib. Most VTE events with the combination occurred in the first four months. This led to a recommendation for prophylactic-dose anticoagulation during the first four months in ongoing combination trials.

The effect on quality of life needs better understanding, particularly given prolonged treatment. Amivantamab plus lazertinib nevertheless caused more treatment discontinuations, making it necessary to investigate how early amivantamab discontinuation affects outcomes. Continuing amivantamab throughout first-line treatment may importantly affect overall treatment success, so these factors require careful assessment and monitoring.

MARIPOSA-2: Amivantamab Plus Chemotherapy After Osimertinib

In MARIPOSA-2, amivantamab plus chemotherapy improved outcomes over chemotherapy alone in advanced EGFR-mutated NSCLC previously treated with osimertinib.

The study enrolled patients with locally advanced or metastatic EGFR-mutated NSCLC progressing after osimertinib monotherapy.

Patients were randomly assigned to:

• Carboplatin plus pemetrexed chemotherapy (263 patients),
• Amivantamab plus chemotherapy (131 patients), or
• Amivantamab plus lazertinib and chemotherapy (263 patients).

Initially, patients receiving amivantamab, lazertinib and chemotherapy took all treatments concurrently. Increased hematological toxicity prompted a regimen change, starting lazertinib after chemotherapy was completed. Of 263 patients in this arm, 166 received concurrent lazertinib and 97 received it after chemotherapy.

Results

• Median follow-up was 8.7 months. The dual primary endpoints were PFS with amivantamab–chemotherapy versus chemotherapy and with amivantamab–lazertinib–chemotherapy versus chemotherapy.
• Median PFS was 4.2 months with chemotherapy, 6.3 months with amivantamab–chemotherapy (HR, 0.48; 95% CI, 0.36-0.64; P <0.001) and 8.3 months with amivantamab–lazertinib–chemotherapy (HR, 0.44; 95% CI, 0.35-0.56; P <0.001).

• Median intracranial PFS was 8.3 months with chemotherapy, 12.5 months with amivantamab–chemotherapy (HR, 0.55; 95% CI, 0.38-0.79; P =0.001) and 12.8 months with amivantamab–lazertinib–chemotherapy (HR, 0.58; 95% CI, 0.44-0.78; P <0.001).
• Overall response rates were 36% with chemotherapy, 64% with amivantamab–chemotherapy (P <0.001) and 63% with amivantamab–lazertinib–chemotherapy (P <0.001). Median response durations were 5.6, 6.9 and 9.4 months, respectively.
• There was a trend toward improved overall survival with amivantamab–chemotherapy (HR, 0.77; 95% CI, 0.49-1.21), but not with amivantamab–lazertinib–chemotherapy (HR, 0.96; 95% CI, 0.67-1.35).

Grade 1 or higher treatment-related adverse events occurred in 92% with amivantamab–lazertinib–chemotherapy, 72% with amivantamab–chemotherapy and 48% with chemotherapy.

Patients receiving amivantamab–lazertinib–chemotherapy had higher rates of grade 3 or higher neutropenia (55%), thrombocytopenia (37%) and rash (15%) than those receiving amivantamab plus chemotherapy (45%, 15% and 10%, respectively) or chemotherapy alone (21%, 9% and 0%, respectively).

These findings suggest considering amivantamab plus chemotherapy as a new standard for EGFR-mutated NSCLC, particularly after progression on osimertinib. However, the toxicity observed argues against concurrent amivantamab, lazertinib and chemotherapy. Amivantamab–chemotherapy and amivantamab–lazertinib–chemotherapy offer new treatment options in this setting.

These approaches also bring challenges, particularly dermatological and hematological toxicity, making patient selection critical. Until the regimens receive FDA approval and overall survival data mature, chemotherapy will remain preferred for most patients with NSCLC progressing after osimertinib. This underscores the importance of continual development and evaluation in NSCLC care.

PAPILLON: Amivantamab Plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions

Amivantamab is approved for advanced NSCLC with EGFR exon 20 insertions progressing during or after platinum-based chemotherapy. Phase 1 data demonstrated the safety and antitumor activity of amivantamab plus carboplatin–pemetrexed chemotherapy. Additional data on this combination are needed.

The phase 3 international randomized PAPILLON trial assigned previously systemically untreated patients with advanced NSCLC and EGFR exon 20 insertion mutations 1:1 to intravenous amivantamab plus chemotherapy or chemotherapy alone. The primary outcome was PFS by blinded independent central review. Patients in the chemotherapy group could cross over to amivantamab monotherapy upon progression.

Results

• A total of 308 patients were randomized: 153 to amivantamab–chemotherapy and 155 to chemotherapy alone.
• PFS was significantly longer with amivantamab–chemotherapy than chemotherapy alone (median, 11.4 versus 6.7 months; hazard ratio for progression or death, 0.40; 95% confidence interval [CI], 0.30-0.53; P<0.001).

• At 18 months, 31% receiving amivantamab–chemotherapy and 3% receiving chemotherapy remained progression-free.
• In an interim overall survival analysis (33% maturity), the hazard ratio for death with amivantamab–chemotherapy versus chemotherapy was 0.67 (95% CI, 0.42-1.09; P=0.11).

The predominant adverse events associated with amivantamab–chemotherapy were reversible hematological and EGFR-related toxicities; 7% discontinued amivantamab because of adverse reactions.

In conclusion, amivantamab–chemotherapy showed superior effectiveness over chemotherapy as first-line treatment for advanced NSCLC with EGFR exon 20 insertions.

Osimertinib's Effect on Brain Metastases: FLAURA2

FLAURA2 evaluated osimertinib's first-line effectiveness against brain metastases in advanced EGFR-mutated NSCLC. It compared osimertinib plus chemotherapy with osimertinib alone, particularly among patients with brain metastases.

Patients were randomized to osimertinib plus platinum–pemetrexed (combination) or osimertinib alone (monotherapy). Treatment continued until progression or discontinuation. All patients had brain scans at baseline and progression, while those with brain metastases underwent regular assessment until progression.

Results

At baseline, 118 patients assigned to osimertinib plus chemotherapy and 104 assigned to osimertinib alone had at least one measurable or nonmeasurable brain metastasis, forming the full brain-metastasis analysis set (cFAS). Within this group, 40 combination patients and 38 monotherapy patients had at least one measurable target brain metastasis, forming the response-evaluable brain-metastasis set (cEFR).

• In cFAS, the hazard ratio (HR) for brain metastasis progression or death was 0.58 (95% confidence interval [CI], 0.33-1.01).
• In patients without brain metastases, the HR for brain metastasis progression or death was 0.67 (95% CI, 0.43-1.04).
• In cFAS, brain-metastasis objective response rates (ORR; 95% CI) were 73% (64-81) with the combination and 69% (59-78) with monotherapy. Complete brain-metastasis responses occurred in 59% and 43%, respectively.
• In cEFR, brain-metastasis objective response rates (ORR; 95% CI) were 88% (73-96) with the combination and 87% (72-96) with monotherapy. Complete brain-metastasis responses occurred in 48% and 16%, respectively.

In conclusion, osimertinib plus platinum–pemetrexed improved central nervous system (CNS) activity and delayed brain metastasis progression compared with osimertinib monotherapy, regardless of baseline brain metastases. The findings support this combination as a first-line option for advanced EGFR-mutated NSCLC, particularly with brain metastases. The results may mark a new milestone in treatment and offer an important option for these patients.

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