Akciğer kanserinde yeni tedavi seçeneği olarak Amivantamab ve Lazertinib kombinasyonu

Akciğer kanserinde yeni tedavi seçeneği olarak Amivantamab ve Lazertinib kombinasyonu

Evre IV akciğer kanserinde bireye özgü tedavide yüz güldüren sonuçlar mevcut.

Akciğer kanseri tedavisine başlamadan önce artık standart istenmesi gereken mutasyonlar mevcut. Akciğer kanseri tedavisine başlamadan önce bakılması gereken mutasyonlar EGFR, ALK, KRAS, ROS1, BRAF, NTRK1/2/3, METex14skipping, RET, ERBB2 (HER2) ve ayrıca PD-L1 düzeyi tedaviye karar vermede önemli bir belirteç.

EGFR mutasyonu yaklaşık %10-20 oranında akciğer adenokanserinde görülür. Sigara içmemiş ve kadın hastalarda bu oran daha yüksektir.

Osimertinib üçüncü kuşak EGFR mutasyonuna bağlı artmış Tirozin Kinaz aktivitesini inhibe eden oral alınan bir molekül. Yıllarca diğer tedavilere (kemoterapi ve diğer EGFR inhibitörleri) karşı üstünlüğünü korudu.

Son açıklanan çalışma c-MET ve EGFR reseptörlerine bağlanan antikor yapısındaki Amivantamab ve üçün kuşak EGFR Tirozin kinaz inhibitörü oral alınana Lazertinib kombinasyonu, EGFR ekzon 19 ve 21 mutasyonu olan hastalarda, hastalıksız süre, yanıt süresini belirgin artırdığı, hastaların yanıt oranın %86 çıktığı belirtildi. Aynı zamanda genel sağkalım yönünden artmış bir trend olduğu gözlendi.

Bu kombinasyonun en büyük dezavantajı maliyet toksisite olduğu belirtildi.

Ayrıca Amivantamab, Lazertinib kemoterapi kombinasyonu Osimertinib sonrası hastalarda etkili olduğu belirtildi. Osimertinib sonrası progresyon gösteren EGFR ekzon 19 ve 21 mutasyonu olan hastalarda Amivantamab, Lazertinib ve kemoterapi(karboplatin+ pemetrexet kombinasyonu ile %64 oranında yanıt alındığı gösterildi.

Bu kombinasyonun etkili olduğu diğer bir grup hasta, yaklaşık %4 oranında görülen ve kötü seyreden exon 20 insertion mutasyonu olan hastalar.

Amivantamab Karboplatin+ pemetrexet kombinasyonu ile bu grup hastaların %73 oranında yanıt alındı görüldü.

Amivantamab intravenöz formunda sık görülen yan etkiler, bu ilacın kulanımı için kaygılar oluşturuyordu. Son Amerika Onkoloji kongresinde  Amivantamab subcutan formu ile yan etkilerin belirgin az görüldüğü belritildi. Bu son veriye göre subcutan form ile yan etkilerin %66’dan, %13 geriledi etkinliğin benzer olduğu saptandı.

Bu çalışmayla EGFR mutasyonu olan hastalarda subcutan Amivantamab ve oral Lazertinib önemli bir tedavi seçeneği oldu

Kaynak

ESMO 2023

Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, plus lazertinib (laz), a CNS-penetrant, 3rd-generation EGFR TKI, have demonstrated antitumor activity in phase 1 studies. MARIPOSA (NCT04487080) evaluated ami+laz vs osimertinib (osi) in the first-line setting.

Methods

Patients (pts) with treatment-naïve, EGFR-mutated (Ex19del or L858R) locally advanced or metastatic NSCLC were randomized 2:2:1 to ami+laz, osi, or laz. Primary endpoint was progression-free survival (PFS) of ami+laz vs osi by blinded independent central review. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), PFS after first subsequent therapy (PFS2), and safety. CNS monitoring was required.

Results

1074 pts were randomized (ami+laz, 429; osi, 429; laz, 216). Baseline characteristics were balanced; median age was 63 years, 62% were female, 59% Asian, and 41% had a history of brain metastases. At a median follow-up of 22.0 months (mo), ami+laz showed a 30% reduction in the risk for disease progression or death vs osi (HR, 0.70; 95% CI, 0.58–0.85; P<0.001), with median PFS of 23.7 mo (95% CI, 19.1–27.7) vs 16.6 mo (95% CI, 14.8–18.5), respectively. ORR was 86% (95% CI, 83–89) for ami+laz vs 85% (95% CI, 81–88) for osi, with median DoR among confirmed responders of 25.8 mo (95% CI, 20.1–NE) vs 16.8 mo (95% CI, 14.8–18.5), respectively. Early PFS2 data favored ami+laz vs osi (HR, 0.75; 95% CI, 0.58–0.98). At interim OS, there was a favorable trend for ami+laz over osi (HR, 0.80; 95% CI, 0.61 to 1.05; P=0.1). EGFR- and MET-related AEs were higher for ami+laz except diarrhea, which was higher for osi. VTEs were increased for ami+laz, mostly grade 1-2, occurred early, and effectively managed with anticoagulants. ILD rates were low and similar across arms.

Conclusions

Ami+laz was statistically superior to osi, providing clinically meaningful improvement in PFS, with higher DoR and a favorable OS trend. The safety profile of ami+laz was consistent with prior reports. MARIPOSA establishes ami+laz as a new first-line, standard of care for EGFR-mutated advanced NSCLC.

Clinical trial identification

NCT04487080.

Background

Amivantamab (ami) is an EGFR-MET bispecific antibody with immune cell–directing activity. Ami combined with carboplatin/pemetrexed (ami-chemo) demonstrated safety and antitumor activity in the phase 1 CHRYSALIS study. PAPILLON (NCT04538664) evaluated ami-chemo vs chemo in first-line EGFR Ex20ins advanced NSCLC.

Methods

Treatment-naïve pts were randomized 1:1 to ami-chemo or chemo. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Secondary endpoints included objective response rate (ORR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety. Crossover to ami monotherapy was allowed for the chemo arm upon progression.

Results

Overall, 308 pts were randomized (ami-chemo, 153; chemo, 155); median age was 61/62 years, 56/60% female, 64/59% Asian, and 23/23% with history of brain metastases for ami-chemo/chemo, respectively. At median follow-up of 14.9 months, the median PFS was 11.4 months (95% CI, 9.8–13.7) for ami-chemo vs 6.7 months (95% CI, 5.6–7.3) for chemo (hazard ratio [HR], 0.40; 95% CI, 0.30–0.53; P<0.001). The 18-month PFS rate was 31% for ami-chemo vs 3% for chemo. PFS benefit of ami-chemo was consistent across subgroups. ORR was 73% (95% CI, 65–80) for ami-chemo vs 47% (95% CI, 39–56) for chemo (odds ratio, 2.97; 95% CI, 1.84–4.79; P<0.001). Median PFS2 was not estimable for ami-chemo vs 17.2 months for chemo (HR, 0.49; 95% CI, 0.32–0.76; P=0.001). Interim OS analysis (33% maturity) showed a favorable trend for ami-chemo vs chemo (HR, 0.67; 95% CI, 0.42–1.09; P=0.106), despite 66%, of chemo-randomized pts whose disease had progressed, receiving second-line ami. The most common TEAEs (≥40%) for ami-chemo were neutropenia, paronychia, rash, anemia, infusion-related reactions, and hypoalbuminemia; no new safety signals. Discontinuation of ami due to treatment-related AEs was 7%.

Conclusions

Among pts with EGFR Ex20ins advanced NSCLC, ami-chemo achieved superior PFS vs chemo. Safety profile was consistent with that of each individual agent. PAPILLON establishes ami-chemo as the new first-line standard of care in EGFR Ex20ins advanced NSCLC.

Clinical trial identification

NCT04538664.

Background

Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, plus carboplatin-pemetrexed (chemo) with and without lazertinib (laz), a CNS-penetrant, 3rd-gen EGFR TKI, have demonstrated antitumor activity in phase 1 studies. MARIPOSA-2 (NCT04988295) evaluated these combinations in EGFR-mutated (Ex19del or L858R) advanced NSCLC after disease progression on osimertinib (osi).

Methods

Patients (pts) were randomized 2:2:1 to ami-laz-chemo, chemo, or ami-chemo. Dual primary endpoints were progression-free survival (PFS) of ami-chemo vs chemo and ami-laz-chemo vs chemo by blinded independent central review. Secondary endpoints included objective response rate (ORR), overall survival (OS), intracranial PFS, and safety. During the study, hematologic toxicities in the ami-laz-chemo arm necessitated a regimen change to start laz after carboplatin completion.

Results

In total, 657 pts were randomized (ami-chemo, 131; ami-laz-chemo, 263; chemo, 263). Baseline characteristics were balanced between arms, including the number of pts with a history of CNS metastases (44%–46%). At a median follow-up of 8.7 mo, PFS was significantly improved with ami-chemo (HR, 0.48; 95% CI, 0.36–0.64) and ami-laz-chemo (HR, 0.44; 95% CI, 0.35–0.56) vs chemo (median PFS, 6.3 and 8.3 vs 4.2 mo, respectively; P<0.001 for both). ORR was 64% for ami-chemo and 63% for ami-laz-chemo vs 36% for chemo (P<0.001 for both). Interim OS was immature; HR of 0.77 (95% CI, 0.49–1.21) for ami-chemo vs chemo and HR of 0.96 (95% CI, 0.67–1.35) for ami-laz-chemo vs chemo. Median intracranial PFS was 12.5 mo for ami-chemo and 12.8 mo for ami-laz-chemo vs 8.3 mo for chemo (HR, 0.55 and 0.58; P=0.001 and P<0.001, respectively). Predominant AEs in the ami-containing arms were hematologic, EGFR, and MET-related. Ami-chemo had lower rates of hematologic AEs than ami-laz-chemo. The impact of modifying the ami-laz-chemo regimen on safety and efficacy requires longer follow-up.

Conclusions

Ami-chemo and ami-laz-chemo improved PFS, ORR, and intracranial PFS vs chemo in EGFR-mutated advanced NSCLC after progression on osi and may represent a new standard of care.

Clinical trial identification

NCT04988295.