In 2022, lung cancer remains one of the top causes of death in the United States and worldwide. In the U.S. alone, lung cancer is responsible for 25% of all cancer deaths. There are an estimated 236,740 new cases of lung cancer (117,910 in men and 118,830 in women) and an estimated 130,180 deaths from lung cancer (68,820 in men and 61,360 in women). According to the American Cancer Society, each year, more people die of lung cancer than of colon, breast and prostate cancers combined.1 Approximately 75% of lung cancers are advanced or metastatic at the time of diagnosis.
We have witnessed significant advances in cancer treatment in recent years. In lung cancer, in particular, new drugs are being approved by the Food and Drug Administration (FDA) every month and many more are in the pipeline.
In the treatment of advanced/metastatic non-small cell lung cancer (NSCLC), over the last decade, we have seen the addition of new tools in the form of targeted therapy and immunotherapy.
For targeted therapy, there are now nine actionable genomic alterations, for which all patients with advanced disease should be tested (EGFR, KRAS, ALK, ROS1, BRAF V600E, NTRK1/2/3, MET, RET, and ERBB1/HER2). For each of these alterations, there is at least one drug that can target it and, hence, could treat the cancer more effectively. In addition, we now test patients for markers such as programmed death ligand 1 (PD-L1) and tumor mutation burden (TMB), and patients with NSCLC with high PD-L1 or high TMB could effectively be treated with immunotherapy.
A large body of research, long in coming, also has changed the way we treat earlier (resectable) NSCLC. In 2020, ADAURA changed the way we treat early-stage NSCLC with EGFR alteration: the addition of osimertinib showed unprecedented survival benefits. ADAURA is a phase 3, international, randomized, double-blind, placebo-controlled trial, that enrolled 682 patients in the U.S., Europe, Australia, China and Korea. All patients were diagnosed with non-squamous NSCLC, stage 1b, 2, 3a, with EGFR alteration. All patients were treated with standard of care, i.e., surgery followed by adjuvant chemotherapy if indicated. Subsequently, patients were randomized to receive adjuvant OSIMERTINIB 80mg daily vs. placebo. The duration of treatment was three years or until disease progression or intolerable toxicities. The primary endpoints of the study were overall survival and disease-free survival (DFS). The three-year DFS rate in the overall population was 85% with osimertinib vs. 44% with placebo, HR was 0.27 (95% CI 0.21, 0.34; 305/682 events).2
One year later, the IMpower010 trial enrolled patients with stage 2-3a NSCLC who underwent surgery plus adjuvant therapy and were randomized to either maintenance atezolizumab or best supportive care (BSC). The results show a significant benefit of atezolizumab for patients with a PD-L1 >1%. At three years, DFS was 60% in the atezolizumab arm and 48% in the BSC arm. This trial led to the FDA approval of Atezolizumab maintenance for patients with resected NSCLC and PD-L1 >1%.3
After seeing remarkable results with using the new oncolytic agents in the adjuvant setting, the researchers asked the question: if we use these agents earlier, in the neo-adjuvant setting, would we see any additional benefit? In May 2022, the CheckMate816 study was reported and again, we have seen very encouraging results. This trial enrolled patients with stage 1b-3a, deemed resectable and randomized to either neoadjuvant chemo-immunotherapy (Nivolumab) or chemotherapy alone. Patients received three cycles of chemo-immunotherapy and then underwent surgery. The primary endpoints were pathologic complete response (pCR) and event-free survival (EFS), and secondary endpoints included overall survival. The study found that during a minimum follow-up of 21 months, median EFS was significantly longer with nivolumab+chemotherapy vs. chemotherapy alone. (63.8% vs. 45.3%). The percentage of patients with a pCR also favored nivolumab+chemotherapy (24% vs. 2.2%).4 As a result, we now have the option of using immunotherapy earlier, before the surgical intervention.
We are living in an era of unprecedented progress in the fight against cancer, and there is no sign this extraordinary progress will slow down. Each new discovery sets the basis for more questions, research, and answers in our quest to cure lung cancer.
- “About Lung Cancer.” American Cancer Society. https://www.cancer.org/content/dam/CRC/PDF/Public/8703.00.pdf. Accessed 15 November 2022.
- Yi-Long Wu, et al. Osimertinib in Resected EGFR-Mutated Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Oct 29;383(18):1711-1723.
- Enriquetta Felip, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021 Oct 9;398(10308):1344-1357.
- Forde Patrick, et al. Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer. N Engl J Med. 2022 May 26;386(21):1973-1985.