Interplay between surgery and pharmacotherapy in multimodality treatment of NSCLC
25 Apr 2025
byDr Alan Sihoe, Consultant in Cardio-Thoracic Surgery, CUHK Medical Centre, Hong Kong
At the 28th Congress of the Asian Pacific Society of Respirology, Dr Alan Sihoe, Consultant in Cardio-Thoracic Surgery, CUHK Medical Centre, Hong Kong, discussed the interplay between pharmacotherapy and surgery in treatment of non-small-cell lung cancer (NSCLC), and emphasized the importance of immunotherapy (IO) timing for maximizing curative surgery rates. Dr Sihoe also shared a case of a patient with stage IVA NSCLC who received surgery in 2017 followed by two lines of tyrosine kinase inhibitor (TKI) treatment and remained well as of November 2024.
Maximizing curative surgery rates
“For many years, surgeons have focused on stage I disease, but as operability is being redefined, surgery is now included as an option for stage II and III patients in international treatment guidelines,” said Dr Sihoe. [NCCN Clinical Practice Guidelines in Oncology, Non-Small-Cell Lung Cancer, version 3.2025] “However, as some of these operations are challenging, the risk-benefit ratio is at the forefront of a surgeon’s mind. If the benefit can be increased with very effective adjuvant IO or TKI therapy, while the risk remains the same, surgery becomes more worthwhile.”
IMpower010 – a breakthrough for multimodality treatment
“Impower010 was the first breakthrough study to show a statistically significant separation of survival curves with multimodality treatment,” Dr Sihoe remarked.
The phase III IMpower010 trial included 1,005 patients with completely resected stage IB (tumours ≥4 cm)–IIIA NSCLC who were randomized 1:1 to receive adjuvant intravenous (IV) atezolizumab 1,200 mg Q3W for 16 cycles or best supportive care (BSC) after ≤4 cycles of cisplatin-based chemotherapy. In stage II–IIIA patients with high PD-L1 expression (tumour cell [TC] expression, ≥50 percent), adjuvant atezolizumab significantly reduced the risk of recurrence or death by 57 percent vs BSC (median disease-free survival [DFS], not estimable vs 35.7 months; hazard ratio [HR], 0.43; 95 percent confidence interval [CI], 0.27–0.68) after a median follow-up of 32.2 months. [Lancet 2021;398:1344-1357]
“At final analysis, with ≥5 years of follow-up, among patients with high PD-L1 expression and without EGFR or ALK alterations, 5-year DFS was in the region of 70 percent for stage III NSCLC,” Dr Sihoe reported. [Felip E, et al, WCLC 2024, abstract OA01.04] (Figure)
Why worry about preoperative attrition with perioperative/neoadjuvant IO?
Surgery is potentially the most curative therapeutic option for NSCLC. [Non-Small Cell Lung Cancer Treatment (PDQ®): Health Professional Version, 2025] “While multimodality therapy has helped us redefine operability, neoadjuvant or perioperative use of IO in stage IB/II disease makes me anxious due to preoperative attrition,” shared Dr Sihoe. "Although many patients achieve great results with perioperative and neoadjuvant IO, the results of trials published to date consistently suggest that 20 percent of them never get surgery."
In the KEYNOTE-671 study (n=797) of perioperative pembrolizumab for early-stage NSCLC, 17.9 percent of patients did not undergo planned surgery following neoadjuvant pembrolizumab. [N Engl J Med 2023;389:491-503] Similarly, 16.8 percent of patients in the CheckMate 816 study (n=358) in resectable stage IB–IIIA disease did not receive definitive surgery following neoadjuvant nivolumab, and 19.4 percent of patients with stage II–IIIB disease who received neoadjuvant durvalumab in the AEGEAN trial (n=802) did not subsequently have surgery. [N Engl J Med 2022;386:1973-1985; N Engl J Med 2023;389:1672-1684]
“What is the consequence of not having surgery?” Dr Sihoe asked. “In CheckMate 816, among patients who only had neoadjuvant nivolumab plus chemotherapy but did not have surgery, the median event-free survival was 6.7 months.” [Spicer J, et al, ASCO 2024, abstract LBA8010]
Type and timing of surgery matter
“The standard of care for early-stage resectable NSCLC is minimally invasive video-assisted thorascopic surgery [VATS], which leaves a small wound,” said Dr Sihoe. “Yet, 58–67 percent of patients with stage IB/II disease who received neoadjuvant chemotherapy [with or without nivolumab] in CheckMate 816 needed thoracotomy, which leaves a big wound. Another 16 percent of patients had pneumonectomy – not an acceptable practice for early-stage lung cancer due to resulting life-long morbidity as well as short-term complications.” [Spicer J, et al, ASCO 2021, abstract 8503]
“In addition, patients who undergo thoracotomy instead of VATS have a significantly higher number of circulating cancer-associated cells, while VATS minimizes the shedding of circulating tumour DNA [ctDNA] into the bloodstream,” he pointed out. [BMJ Open Respir Res 2021;8:e000917] Of note, ctDNA negativity after surgery was associated with better prognosis among stage II–IIIA patients in IMpower010. [Ann Oncol 2021;32:S1374]
Another prognostic factor is the interval between surgery and adjuvant treatment. A retrospective data analysis of 1,522 patients with stage IB–IIIA lung cancer found the poorest survival rate in cases where chemotherapy was delayed beyond 60 days after surgical resection. [PLoS ONE 2016;11:e0163809] “Modern minimally invasive surgery can safely reduce the interval between surgery and adjuvant treatment and also facilitate completion of adjuvant therapy,” Dr Sihoe highlighted. [J Thorac Dis 2013;5:578-584]
What about patients with driver mutations?
“Most studies on multimodality therapy have been conducted in Caucasian patients, most of whom do not have driver mutations. However, here in East Asia, the high prevalence of oncogene mutations makes treatment with TKIs particularly relevant,” explained Dr Sihoe. [Curr Oncol 2022;29:2154-2164]
In the phase III ALINA trial (n=257) in patients with completely resected, ALK-positive NSCLC, the proportion of stage IB–IIIA patients alive and disease-free at 3 years was 88.7 vs 54.0 percent in the alectinib vs chemotherapy group (HR, 0.24; 95 percent CI, 0.13–0.43; p<0.001). Respective central nervous system–specific 3-year DFS rates were 95.5 and 79.7 percent (HR, 0.22; 95 percent CI, 0.08–0.58). [N Engl J Med 2024;390:1265-1276]
“But to me, the most impressive are the 2- and 3-year DFS rates of 92.7 and 90.3 percent in patients with stage IIIA disease [vs 60.7 and 48.6 percent, respectively, with chemotherapy], which is as good as what we could achieve after the best possible surgery for stage I disease 10 years ago. For a surgeon, this effectively means that even patients with stage III disease may be potential candidates for curative surgery and should not be denied consideration for curative multi-modality therapy. The key message is that these breakthroughs bring hope of cure [surgery] to patients previously assumed inoperable,” said Dr Sihoe. [N Engl J Med 2024;390:1265-1276] Historically, 2-year overall survival rates with platinum-based combination therapy for stage IIIA disease have been 55–65 percent. [J Thorac Oncol 2016;11:39-51]
