Happy Upheavals Are Unveiled in Early-Stage Lung Cancer

Although advances in metastatic non–small cell lung cancer treatment have dramatically impacted cancer mortality, the translation of these approaches to earlier-stage NSCLC has just begun to bear fruit.

Although advances in metastatic non–small cell lung cancer (NSCLC) treatment have dramatically impacted cancer mortality,1 the translation of these approaches to earlier-stage NSCLC has just begun to bear fruit. The recent publications of the ADAURA (NCT02511106) and IMpower010 (NCT02486718) trials suggest that the incorporation of adjuvant targeted therapy and immunotherapy, respectively, may improve disease-free survival (DFS) following definitive surgery in selected populations with stage IB to IIIA NSCLC.2,3 Although many questions remain, including whether DFS is an appropriate end point in earlier-stage NSCLC,4 early adopters have found the option of additional treatment reassuring to those patients who want to be sure they have done “everything” and for those with unfavorable features who are not willing or healthy enough to receive chemotherapy.

Happily, it is only going to get more complicated from here. CheckMate 816 (NCT02998528), which combines neoadjuvant nivolumab (Opdivo) with chemotherapy, and KEYNOTE-091 (NCT02504372), evaluating adjuvant pembrolizumab (Keytruda), have been reported as positive trials with the promise of upcoming survival data this year, and dozens of other neoadjuvant and adjuvant trials exploring permutations of drugs, timing, and biomarkers are ongoing (Table). As we prepare to rethink how we manage earlier-stage NSCLC, a quick review of the history and unique features of neoadjuvant and adjuvant treatment may be helpful for context.

Table. Selected ongoing neoadjuvant and adjuvant clinical trials in earlier-stage NSCLC.

Platinum-based adjuvant chemotherapy changed standard-of-care practice in early-stage NSCLC approximately 15 years ago. Meta-analyses combining the results of JBR.10 (NCT00002583), ALPI, ANITA, IALT, and BLT suggested that 4 to 6 cycles of platinum-based doublet chemotherapy lead to a 4% to 5% improvement in overall survival (OS) at 5 years in those with stage IB to IIIA NSCLC, which is associated with a DFS HR of approximately 0.8.5,6 There are nuances regarding patient selection beyond the scope of this discussion–namely, whether the CALGB 9633 (NCT00002852) exploratory analysis that showed a benefit for stage IB patients with tumors greater than 4 cm should lead to a recommendation for adjuvant chemotherapy based on primary tumor size7 and whether all stage II patients should be offered adjuvant chemotherapy as the American Joint Committee on Cancer (AJCC) staging has changed since the original trials (i.e., nearly all patients considered stage II in the 1990 to 2000s had N1 lymph node involvement, while current AJCC stage IIA precludes lymph node involvement).8 Conservatively, it is thought that for every 20 patients with lymph node involvement treated with adjuvant chemotherapy, one patient who would have recurred and passed away from lung cancer in 5 years does not. A meta-analysis of platinum-based neoadjuvant chemotherapy trials including SWOG S9900 (NCT00004011), ChEST, NATCH, and others showed an almost identical benefit,9 and receiving this chemotherapy treatment before or after surgery is considered acceptable.

The associated risks of neoadjuvant and adjuvant platinum-based chemotherapy include less than 1% treatment-associated death and approximately 50% hematologic toxicities, which represent the majority of high grade complications.5,9,10 Approximately one-third of patients experience kidney dysfunction as a result of cisplatin11 and 5% endure some degree of permanent hearing loss.12 Salazar and colleagues note a significant proportion of patients with NSCLC start adjuvant chemotherapy outside of the recommended 8-to-12 week timeframe following surgery,13 1 out of 3 patients with NSCLC who are appropriate for adjuvant chemotherapy never receive it,14 and many fail to complete 4 cycles adjuvantly due to treatment-related symptoms.15 Long delays to surgery with neoadjuvant chemotherapy also associate with increased mortality.16 And, perhaps most importantly, the probability of 5-year OS by stage in NSCLC remains 36% for stage IIIA and 68% for stage IB NSCLC.8

What we take away from this history is that the rapid drug development in this space is on point. Updated approaches to neoadjuvant and adjuvant treatment in early-stage NSCLC could have tremendous impact, and the use of consistently applied biomarkers beyond stage could be helpful for improved patient selection. As waiting a decade or longer for survival end points can lead to challenges in application, it is appropriate to consider alternative end points, and many in our field are working on benchmarking these features.17 To date, an acceptable risk-benefit profile is profound benefit in few at the cost of limited toxicities in many, which may be reflected in the proportion of patients able to adhere to appropriately timed therapy. Questions regarding how to select an optimal approach with conflicting biomarkers and what to do upon relapse, especially if combination therapy becomes standard of care, will be problems of tomorrow. But for today, updating our routines to ensure molecular profiling and PD-L1 assessments are part of every NSCLC case and setting our own personal thresholds for acceptable risk-benefit may be the best way to prepare for the upheavals ahead.


  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30. doi:10.3322/caac.21590
  2. Planchard D. Adjuvant osimertinib in EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1780-1782. doi:10.1056/NEJMe2029532
  3. Felip E, Altorki N, Zhou C, 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;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5
  4. Zhong WZ, Wang Q, Mao WM, et al. Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(1):139-148. doi:10.1016/S1470-2045(17)30729-5
  5. Pignon JP, Tribodet H, Scagliotti GV, et al. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008;26(21):3552-3559. doi:10.1200/JCO.2007.13.9030
  6. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ. 1995;311(7010):899-909.
  7. Strauss GM, Herndon JE, Maddaus MA, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol. 2008;26(31):5043-5051. doi:10.1200/JCO.2008.16.4855
  8. Amin MB, Greene FL, Edge SB, et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA Cancer J Clin. 2017;67(2):93-99. doi:10.3322/caac.21388
  9. NSCLC Meta-analysis Collaborative Group. Preoperative chemotherapy for non-small-cell lung cancer: a systematic review and meta-analysis of individual participant data. Lancet. 2014;383(9928):1561-1571. doi:10.1016/S0140-6736(13)62159-5
  10. Postmus PE, Kerr KM, Oudkerk M, et al. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl 4):iv1-iv21. doi:10.1093/annonc/mdx222
  11. Taguchi T, Nazneen A, Abid MR, et al. Cisplatin-associated nephrotoxicity and pathological events. Contrib Nephrol. 2005;148:107-121. doi:10.1159/000086055
  12. Gandara DR, Crowley J, Livingston RB, et al. Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: a phase III study of the Southwest Oncology Group. J Clin Oncol. 1993;11(5):873-878. doi:10.1200/JCO.1993.11.5.873
  13. Salazar MC, Rosen JE, Wang Z, et al. Association of delayed adjuvant chemotherapy with survival after lung cancer surgery. JAMA Oncol. 2017;3(5):610-619. doi:10.1001/jamaoncol.2016.5829
  14. Felip E, Rosell R, Maestre JA, et al. Preoperative chemotherapy plus surgery versus surgery plus adjuvant chemotherapy versus surgery alone in early-stage non-small-cell lung cancer. J Clin Oncol. 2010;28(19):3138-3145. doi:10.1200/JCO.2009.27.6204
  15. Azzoli CG, Krug LM, Miller VA, et al. A phase II tolerability study of cisplatin plus docetaxel as adjuvant chemotherapy for resected non-small cell lung cancer. J Thorac Oncol. 2007;2(7):638-644. doi:10.1097/JTO.0b013e318074bbd0
  16. Rice JD, Heidel J, Trivedi JR, et al. Optimal surgical timing after neoadjuvant therapy for stage IIIa non-small cell lung cancer. Ann Thorac Surg. 2020;109(3):842-847. doi:10.1016/j.athoracsur.2019.09.076
  17. Lee JM, Kim AW, Marjanski T, et al. Important surgical and clinical end points in neoadjuvant immunotherapy trials in resectable NSCLC. JTO Clin Res Rep. 2021;2(10):100221. doi:10.1016/j.jtocrr.2021.100221