Phase III KEYNOTE-789 Study of Pemetrexed and Platinum With or Without Pembrolizumab for Tyrosine Kinase Inhibitor‒Resistant, EGFR–Mutant, Metastatic Nonsquamous Non–Small Cell Lung Cancer

Author(s): James Chih-Hsin Yang, MD, PhD¹; Dae Ho Lee, MD, PhD²; Jong-Seok Lee, MD, PhD³; Yun Fan, MD⁴; Filippo de Marinis, MD, PhD⁵; Eiji Iwama, MD, PhD⁶; Takako Inoue, MD⁷; Jerónimo Rodríguez-Cid, MD⁸; Li Zhang, MD⁹; Cheng-Ta Yang, MD¹⁰; Emmanuel de la Mora Jimenez, MD¹¹; Jianying Zhou, MD¹²; Maurice Pérol, MD¹³; Ki Hyeong Lee, MD, PhD¹⁴; David Vicente, MD¹⁵; Eiki Ichihara, MD, PhD¹⁶; Gregory J. Riely, MD, PhD¹⁷; Yiwen Luo, PhD¹⁸; Diana Chirovsky, PhD¹⁸; M. Catherine Pietanza, MD¹⁸; Niyati Bhagwati, MD¹⁸; Shun Lu, MD, PhD¹⁹

Source: https://doi.org/10.1200/JCO.23.0274

Dr. Maen Hussein's Thoughts

Pembrolizumab in addition to chemotherapy DID NOT help, recall now we have new approval for those patients (datopotamab).

PURPOSE

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard first-line therapy for EGFR-mutant, metastatic non–small cell lung cancer (NSCLC); however, most patients experience disease progression. We report results from the randomized, double-blind, phase III KEYNOTE-789 study of pemetrexed and platinum–based chemotherapy with or without pembrolizumab for TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC (ClinicalTrials.gov identifier: NCT03515837).

METHODS

Adults with pathologically confirmed stage IV nonsquamous NSCLC, documented DEL19 or L858R EGFR mutation, and progression after EGFR-TKI treatment were randomly assigned 1:1 to 35 cycles of pembrolizumab 200 mg or placebo once every 3 weeks plus four cycles of pemetrexed and carboplatin or cisplatin once every 3 weeks and then maintenance pemetrexed. Dual primary end points were progression-free survival (PFS) and overall survival (OS). Final PFS testing was completed at the second interim analysis (IA2; data cutoff, December 3, 2021); OS was tested at final analysis (FA; data cutoff, January 17, 2023). Efficacy boundaries were one-sided P = .0117 for PFS and OS.

RESULTS

Four hundred ninety-two patients were randomly assigned to pembrolizumab plus chemotherapy (n = 245) or placebo plus chemotherapy (n = 247). At IA2, the median PFS was 5.6 months for pembrolizumab plus chemotherapy versus 5.5 months for placebo plus chemotherapy (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.97]; P = .0122). At FA, the median OS was 15.9 versus 14.7 months, respectively (HR, 0.84 [95% CI, 0.69 to 1.02]; P = .0362). Grade ≥3 treatment-related adverse events occurred in 43.7% of pembrolizumab plus chemotherapy recipients versus 38.6% of placebo plus chemotherapy recipients.

CONCLUSION

Addition of pembrolizumab to chemotherapy in patients with TKI-resistant, EGFR-mutant, metastatic nonsquamous NSCLC did not significantly prolong PFS or OS versus placebo plus chemotherapy in KEYNOTE-789.

Author Affiliations

¹National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; ²Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea; ³Seoul National University Bundang Hospital, Seoul, South Korea; ⁴Zhejiang Cancer Hospital, Hangzhou, China; ⁵Istituto Europeo di Oncologia, IRCCS, Milan, Italy; ⁶Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; ⁷Osaka International Cancer Institute, Osaka, Japan; ⁸Oncology Center, Medica Sur Hospital, Mexico City, Mexico; ⁹Peking Union Medical College Hospital, Beijing, China; ¹⁰Chang Gung Memorial Hospital, Taoyuan, Taiwan; ¹¹Instituto Jalisciense de Cancerología, Guadalajara, Mexico; ¹²The First Affiliated Hospital, Zhejiang University, Zhejiang, China; ¹³Centre Léon Bérard, Lyon, France; ¹⁴Chungbuk National University Hospital, Cheongju-si, South Korea; ¹⁵Hospital Universitario Virgen Macarena, Sevilla, Spain; ¹⁶Okayama University Hospital, Okayama, Japan; ¹⁷Memorial Sloan Kettering Cancer Center, New York, NY; ¹⁸Merck & Co, Inc, Rahway, NJ; ¹⁹Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China;

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.