The New Era of Perioperative Therapy in Non–Small Cell Lung Cancer

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Recent developments in surgery and therapeutics are changing the perioperative approach to non–small cell lung cancer (NSCLC). These advances were discussed at the 2023 Debates and Didactics in Hematology and Oncology conference, sponsored by Emory University, by Jennifer W. Carlisle, MD, Assistant Professor of Medicine at Emory’s Winship Cancer Institute.1

Lobectomy vs Limited Resection

“For decades, the standard for even very early–stage lung cancer has been lobectomy, if patients’ lung function would tolerate it,” Dr. Carlisle noted. This standard was based on a clinical trial of 247 patients with T1 N0 disease in which patients undergoing limited resection, as compared with lobectomy, experienced a marked increase in recurrences and deaths.2

We now have more support for surgeons who want to perform sublobar resection on patients with small [2 cm] peripheral tumors.
— Jennifer W. Carlisle, MD

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However, in March 2023, an international phase III study of 697 patients with 2-cm tumors, reported in The New England Journal of Medicine,3 found disease-free survival to be similar and pulmonary function to be improved for patients undergoing sublobar resection, as compared with lobectomy. “It makes sense that if you remove less lung, you’ll have better lung function. We now have more support for surgeons who want to perform sublobar resection on patients with these small peripheral tumors,” she commented.

Perioperative Therapy for Driver-Mutated Tumors

With the emergence of new adjuvant approaches, especially the approval of the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib, perioperative treatment has become more complex. The efficacy of this agent has heightened the importance of determining driver mutations early in the disease course rather than in the metastatic setting. In particular, clinicians need to be aware that up to 15% of patients with early-stage disease have an EGFR mutation, so treatment can be optimized, Dr. Carlisle explained.

Patients with EGFR-mutant tumors treated with osimertinib in the ADAURA trial had an 80% reduction in disease recurrence (P < .001).4 The drug’s efficacy in preventing relapse in the central nervous system (CNS)—as a result of its penetration of the blood-brain barrier—was clear; patients experienced a 76% improvement in CNS disease–free survival. Additionally, osimertinib conveyed a survival benefit regardless of tumor stage and prior chemotherapy.5

However, although many clinicians have adopted the use of osimertinib, questions remain.

  • Are these patients being cured with adjuvant osimertinib, or is early treatment simply delaying recurrence (and preventing CNS relapse) at a greater financial cost?
  • How can therapy be optimized: What is the optimal duration, and is chemotherapy also necessary?
  • Can osimertinib be beneficial in the neoadjuvant setting? NEO-ADAURA seeks to answer this question.
  • Which patients benefit most from osimertinib?
  • Does the benefit of osimertinib extend to patients with very early–stage disease? ADAURA2 is evaluating adjuvant osimertinib in patients with resected stage IA2 and IA3 disease.
  • What is the role of circulating tumor DNA (ctDNA) in assessing benefit?
  • What happens to tumors after relapse? Do they retain sensitivity to anti-EGFR agents?

Dr. Carlisle described her “take-aways” from the ADAURA trial: molecular testing of early-stage cancer is mandatory; next-generation sequencing is preferred over piecemeal testing; given the approval for neoadjuvant chemotherapy plus immunotherapy, next-generation sequencing is needed at diagnosis to avoid chemotherapy in patients with EGFR mutations.

Beyond EGFR Mutations

Although osimertinib is a treatment advance for EGFR-mutant tumors, other mutations lack such effective treatments. “What do we do now with all the other drivers that are much smaller pieces of the pie,” asked Dr. Carlisle. Early-stage trials, for instance, in ALK-mutated disease are “languishing,” she noted, and several studies have completion dates that are still years away. “With the much smaller populations of other targetable mutations, it’s going to be harder to get the same level of data [as for osimertinib].”

Nevertheless, therapeutics for other molecular targets are being explored in clinical trials in the neoadjuvant and adjuvant settings. They include (but are not limited to) the following agents:

  • Alectinib (ALK): ALNEO
  • Capmatinib (MET): Geometry-N
  • Divarasib (KRASG12): NAUTIKA-1
  • Entrectinib (ROS1, NTRK): NAUTIKA-1
  • Vemurafenib/cobimetinib (BRAF): NAUTIKA-1
  • Pralsetinib (RET): NAUTIKA-1.

It remains unknown whether a perioperative approach pairing chemotherapy with immunotherapy can be effective in patients with driver mutations, although this has been demonstrated in small subsets of patients with EGFR-mutant tumors in the neoadjuvant KEYNOTE-671 trial6 and the adjuvant KEYNOTE-091 trial.7 Hazard ratios in those studies, for pembrolizumab plus chemotherapy, were 0.09 and 0.44, respectively.

The question of the benefit of perioperative immunotherapy for the 30% or so of patients with KRAS mutations is also being explored. In one small study, neoadjuvant nivolumab resulted in benefit among patients with KRAS and other targetable mutations.8 Furthermore, in a subset analysis of IMpower010, atezolizumab plus chemotherapy yielded a disease-free survival benefit over chemotherapy alone, regardless of KRAS status.9

Molecular testing of earlystage [non–small cell lung] cancer is mandatory, and next-generation sequencing is preferred over piecemeal testing.
— Jennifer W. Carlisle, MD

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Dr. Carlisle commented on pathologic complete responses to immunotherapy. “I am encouraged that they are fairly consistent across the various approaches [agents],” in the 20% range and even higher with some agents. However, she said, patient selection may have been a factor.

“For patients with resectable, driver-negative disease, we need to consider a neoadjuvant approach unless there are surgical considerations or patient characteristics that push us toward the adjuvant route. We really want to give chemotherapy and immunotherapy together, and maybe PD-L1 levels would help sway us in this case. I also think there’s a role for adjuvant chemotherapy and immunotherapy together, rather than sequentially, which is not our current standard of care,” Dr. Carlisle stated.

Optimal Treatment Duration Unknown

Following neoadjuvant chemotherapy or immunotherapy, does adjuvant immunotherapy need to be given for 12 months, or will a shorter duration be sufficient? This question was explored by the phase II NADIM II trial in which 86 patients with stage IIIA–B disease lacking EGFR and ALK mutations received 6 months of adjuvant nivolumab after the neoadjuvant regimen of paclitaxel, carboplatin, and nivolumab.10 Preoperative checkpoint inhibition improved response, and the addition of 6 months of nivolumab to adjuvant chemotherapy led to a 53% reduction in disease progression and a 57% reduction in death.

“But we really don’t know how long patients need immunotherapy,” Dr. Carlisle emphasized. “Even in the metastatic setting, we lack clear data as to which patients require longer treatment. And many patients are afraid to stop treatment when it’s working, so they often continue beyond what the trial results suggest. With the limited data available, having this discussion with patients is difficult. No oncologist sitting across from a patient can say, ‘It will be fine if we stop this now,’ so we have more work to do to determine how much adjuvant treatment patients need. I think the answer will be in the prospective use of ctDNA.”

Need for Prompt Multidisciplinary Evaluation

Patients with a suspicious lung mass on biopsy should promptly undergo reflex next-generation sequencing and PD-L1 testing, regardless of disease stage, and positron-emission tomography, with or without brain magnetic resonance imaging. Although there may be some reimbursement challenges, acknowledged Dr. Carlisle, clinicians should “think outside the box” to get these tests done promptly. “Patients shouldn’t have to wait for these tests,” she added.

Testing should be followed by multidisciplinary clinical review, involving pulmonologists, surgeons, radiation oncologists, and medical oncologists according to the disease stage. Treatment should be determined by disease stage. 

DISCLOSURE: Dr. Carlisle has served on the advisory board of Sanofi and has received institutional grants from AstraZeneca, Amgen, Parexel, and Hutchison MediPharma.


1. Carlisle JW: New era of perioperative therapy in non–small cell lung cancer. 2023 Debates and Didactics in Hematology and Oncology Conference. Presented July 22, 2023.

2. Ginsberg RJ, Rubinstein LV: Randomized trial of lobectomy versus limited resection for T1 N0 non–small cell lung cancer. Lung Cancer Study Group. Ann Thorac Surg 60:615-623, 1995.

3. Altorki N, Wang X, Kozono D, et al: Lobar or sublobar resection for peripheral stage IA non-small-cell lung cancer. N Engl J Med 388:489-498, 2023.

4. Wu YL, Tsuboi M, He J, et al: Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med 383:1711-1723, 2020.

5. Tsuboi M, Herbst RS, John T, et al: Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 389:137-147, 2023.

6. Wakelee H, Liberman M, Kato T, et al: Perioperative pembrolizumab for early-stage non-small-cell lung cancer. N Engl J Med 389:491-503, 2023.

7. O’Brien M, Paz-Ares L, Marreaud S, et al: Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091): An interim analysis of a randomised, triple-blind, phase 3 trial. Lancet Oncol 23:1274-1286, 2022.

8. Rosner S, Sivapalan L, Zahurak M, et al: Response to neoadjuvant immune checkpoint inhibitor (ICI)-based therapy in oncogene-driven resectable non-small cell lung cancer. 2023 ASCO Annual Meeting. Abstract 8523.

9. Reck M, Srivastava MK, Wakelee HA, et al: IMpower010: Exploratory analysis of disease-free survival by KRAS status in patients with stage II-IIIA NSCLC treated with adjuvant atezolizumab vs best supportive care. 2023 ASCO Annual Meeting. Abstract 8522.

10. Provencio M, Nadal E, González-Larriba JL, et al: Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer. N Engl J Med 389:504-513, 2023.