Non-Small Cell Lung Cancer


Developments in Targeted Therapy for Advanced Non–Small Cell Lung Cancer

clinical topic updates by Roy S. Herbst, MD, PhD

Advanced non–small cell lung cancer (NSCLC) research includes the exploration of strategies to overcome resistance, such as combinations that can improve long-term responses. Disease-free survival benefits are being reported with the use of targeted therapies in the adjuvant setting, which is likely to shift the targeted therapy landscape in the years to come.

Expert Commentary
“Whether you are targeting molecular alterations, such as EGFR or ALK, or immune checkpoints, such as PD-1 or PD-L1, one of the challenges relates to how to manage resistance. Most of the research interest is in the use of combinations to overcome resistance.”
— Roy S. Herbst, MD, PhD

One of the most exciting areas of research in NSCLC is in immune resistance or so-called cold tumors. This is when a tumor has no T-cell infiltrate, and—no matter how much you block PD-1 or PD-L1—there is not going to be a response because there are no T cells there. Figuring out why the T cells are missing and how to better get them inside the tumor is a major goal.


Adagrasib is a KRAS inhibitor that was recently approved by the US Food and Drug Administration for the treatment of patients with KRAS G12C–mutated, locally advanced or metastatic NSCLC after at least 1 prior systemic therapy. Going forward, a challenge lies in figuring out how to pair KRAS-targeted agents with immunotherapy. If progress occurs in this area, it may bring KRAS therapy to the frontline setting.


Improvements in targeted therapies have also come with the development of newer-generation agents that are more selective and have less toxicity and by studying the patterns of resistance. The third-generation EGFR inhibitor osimertinib targets the T790M mutation, which is a mechanism of resistance in 50% of patients with NSCLC.


Additionally, targeted therapies are being studied in patients with earlier disease. For instance, the phase 3 ADAURA trial evaluated adjuvant osimertinib in EGFR-mutated stages IB to IIIA NSCLC after complete tumor resection. This trial showed a significant disease-free survival benefit over placebo, a reduction in local and distant recurrence, and improved central nervous system disease-free survival. We await reports from several ongoing studies on the use of targeted therapies in the neoadjuvant/adjuvant setting and on more uncommon or rare mutations (eg, ALK and ROS), and there is a good deal of interest in early-stage NSCLC harboring actionable mutations.


Whether you are targeting molecular alterations, such as EGFR or ALK, or immune checkpoints, such as PD-1 or PD-L1, one of the challenges relates to how to manage resistance. Most of the research interest is in the use of combinations to overcome resistance. To do that, we are going to use biopsies to choose the right combination of therapeutics. We published data evaluating the combination of ramucirumab, a VEGFR2 inhibitor, plus pembrolizumab in immunotherapy-refractory patients. VEGF is involved in immune resistance, and blocking VEGF appears to be immune activating, improving tumor blood flow, which allows more T cells in. This is a promising strategy for some tumors; however, in lung cancer, it is more difficult. These are not VEGF-driven tumors, and, really, we are only getting a small immune effect. The anti-VEGF tyrosine kinase inhibitors are associated with toxicities. The antibodies might have more promise. The ongoing phase 3 Pragmatica-Lung study is comparing ramucirumab plus pembrolizumab with usual care for the treatment of stage IV or recurrent NSCLC following immunotherapy.


Bonaventura P, Shekarian T, Alcazer V, et al. Cold tumors: a therapeutic challenge for immunotherapy. Front Immunol. 2019;10:168. doi:10.3389/fimmu.2019.00168


ClinicalTrials.gov. Ramucirumab plus pembrolizumab vs usual care for treatment of stage IV or recurrent non-small cell lung cancer following immunotherapy, Pragmatica-Lung study. Updated September 14, 2023. Accessed October 27, 2023. https://clinicaltrials.gov/study/NCT05633602


Herbst RS, Arkenau H-T, Santana-Davila R, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial. Lancet Oncol. 2019;20(8):1109-1123. doi:10.1016/S1470-2045(19)30458-9


Herbst RS, Blanke CD, Sigal EV. Novel approach to accelerate lung cancer research: LungMap and the potential of public-private partnerships. Clin Cancer Res. 2023 Oct 30. doi:10.1158/1078-0432.CCR-23-2690


Herbst RS, Wu Y-L, John T, et al. Adjuvant osimertinib for resected EGFR-mutated stage IB-IIIA non-small-cell lung cancer: updated results from the phase III randomized ADAURA trial [published correction appears in J Clin Oncol. 2023;41(22):3877]. J Clin Oncol. 2023;41(10):1830-1840. doi:10.1200/JCO.22.02186


Jänne PA, Riely GJ, Gadgeel SM, et al. Adagrasib in non–small-cell lung cancer harboring a KRASG12C mutation. N Engl J Med. 2022;387(2):120-131. doi:10.1056/NEJMoa2204619


Liu J, Amini A, Govindarajan A, et al. Targeted therapies in early-stage resectable non-small-cell lung cancer: new kids on the block. JCO Precis Oncol. 2023;7:e2200445. doi:10.1200/PO.22.00445


Reckamp KL, Redman MW, Dragnev KH, et al. Phase II randomized study of ramucirumab and pembrolizumab versus standard of care in advanced non-small-cell lung cancer previously treated with immunotherapy-lung-MAP S1800A [published correction appears in J Clin Oncol. 2022;40(25):3002]. J Clin Oncol. 2022;40(21):2295-2306. doi:10.1200/JCO.22.00912


Tsuboi M, Herbst RS, John T, et al. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med. 2022;389(2):137-147. doi:10.1056/NEJMoa2304594


Zhou C, Tang K-J, Cho BC, et al; PAPILLON Investigators. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. 2023 Oct 21. doi:10.1056/NEJMoa2306441

Roy S. Herbst, MD, PhD

Deputy Director
Chief of Medical Oncology
Ensign Professor of Medicine
Yale Cancer Center
Smilow Cancer Hospital
Yale School of Medicine
New Haven, CT