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;

Thoracic Radiotherapy Improves the Survival in Patients With EGFR-Mutated Oligo-Organ Metastatic Non–Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor–Tyrosine Kinase Inhibitors: A Multicenter, Randomized, Controlled, Phase III Trial

Patients were treated with thoracic and extrathoracic radiation to oligometastatic sites and it seems to help with improving survival, something to consider especially with SBRT now. Do our radiation oncologists have additional input?

A Multicenter Open-Label Randomized Phase II Study of Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor–Naïve EGFR-Mutant Metastatic Non–Small Cell Lung Cancer (RAMOSE trial)

Improved progression-free survival (PFS), now we have osimertinib and ramucirumab, amivantamab and Lazertinib (PFS 24.8 vs 23 months but NOT head to head).

De-Escalation Strategies With Immune Checkpoint Blockers in Non–Small Cell Lung Cancer: Do We Already Have Enough Evidence?

Very thought-provoking review of immune checkpoint blockade therapy and strategies to possibly de-escalate therapy in the future. Could we reduce doses, extend dose intervals or diminish the duration of treatment? There is some (low-level) data supporting these ideas. However, ongoing prospective studies, mostly being done in countries with nationalized systems, will be informative on these topics. Expect interest in this topic to increase in a couple of years.

Datopotamab Deruxtecan Versus Docetaxel for Previously Treated Advanced or Metastatic Non–Small Cell Lung Cancer: The Randomized, Open-Label Phase III TROPION-Lung01 Study

Positive trial for the newest ADC on the block, Dato-DXd, is an ADC that delivers a topoisomerase I inhibitor payload via a TROP2 antibody. PFS was not impressive but favored DDxd at 4.4 vs 3.7 months in the docetaxel arm. This drug is now approved in metastatic breast cancer.

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC

Superior to osi (23 vs 16 progression-free survival). This is more toxic though, but seems manageable. Could this be a new first line standard of care? Also, this includes brain penetration data.