Data Support Resection in cT4, Stage IIIB Non–Small Cell Lung Cancer

“In this era of modern systemic therapy, it’s critical to evaluate patients in a multidisciplinary fashion to see what’s going to be the best [treatment option],” according to Neel Chudgar, MD.

Surgical input is necessary for determining resectability in patients with non–small cell lung cancer (NSCLC) who have clinical T4 (cT4) or stage IIIB (N2) disease, and treatment with neoadjuvant therapies may transform the patient’s disease from unresectable to resectable, according to Neel Chudgar, MD in a presentation at the 21st Annual Winter Lung Cancer Conference hosted by Physician’s Education Resource^®.¹

Defining Resectability

Chudgar, a thoracic surgeon at Montefiore Einstein Comprehensive Cancer Center, highlighted the challenge of determining resectability in patients with lung cancer based on the continuous evolution of thoracic and cardiovascular surgical techniques in the field. He referred to an excerpt from Eugene E. Clifton, MD, which was originally published in JAMA in 1966, to illustrate his point about the everchanging standards in lung cancer surgery.

“What would have been well-accepted criteria of inoperability 15 to 20 years ago no longer hold, and those of today may be in doubt in a few years,” Clifton wrote.² “Criteria also vary from group to group, among individual surgeons, and, indeed, for the same surgeon from time to time depending on his recent experience.”

Moreover, Chudgar focused on resectability with respect to stage III NSCLC. Data highlighted 2-year and 5-year survival rates, respectively, of 55% and 36% in those with stage IIIA disease and 44% and 26% for those with stage IIIB disease. He also addressed some considerations that practices may have when managing NSCLC, such as appropriately staging tumors as stage IIIA, IIIB, or IIIC disease; determining whether resectability is technically possible in cT4 invasive disease; and the alternative efficacy and safety of administering radiotherapy to patients.

“The National Comprehensive Cancer Network [NCCN] guidelines are very familiar to us….When we get to stage III [disease], we have the designation of unresectable vs potentially resectable [disease]. There’s no clear designation in the guidelines as to what qualifies one vs the other,” Chudgar said.

According to the current NCCN guidelines for managing NSCLC, it is recommended that those with stage IIIA (T4, N0-1) resectable disease receive systemic therapy or concurrent chemoradiation followed by a surgical reevaluation including a chest CT with or without PET/CT.³ Following surgery, the subsequent recommended course of treatment is observation or adjuvant systemic therapy in the case of an R0 resection; in the event of an R1 or R2 resection, reresection and/or radiotherapy boost followed by adjuvant systemic therapy is recommended. Additionally, it is advised that patients with stage IIIA unresectable disease receive definitive concurrent chemoradiotherapy followed by durvalumab (Imfinzi).

To help further define the subsets of patients with NSCLC whose disease could be considered resectable, Chudgar aimed to answer 3 primary questions in his presentation. First, could surgery be considered in those with cT4 disease? Next, would patients with stage IIIB/N2 disease derive benefit from surgery? Finally, to what extent could immunotherapy influence whether disease could be resected?

Resection in cT4 Disease

With respect to defining resectability in those with cT4 disease, Chudgar highlighted findings from a study published in European Journal of Cardio-Thoracic Surgery, which reviewed data from the National Cancer Database (NCDB) collected between 2010 and 2019 on patients with cT4N0-1 disease.⁴ Investigators assessed the trends of minimally invasive surgical resections, perioperative outcomes, and survival among this patient population.

Data from the study highlighted that the rates of minimally-invasive resection for cT4 disease increased from 17.2% in 2010 to 47.9% in 2019. However, Chudgar noted that 32.5% of patients were overstaged.

When comparing outcomes between those who received open surgery and those who underwent minimally invasive surgery, respectively, the median length of hospital stay was 6 days and 5 days in each group (P <.001). Additionally, 30-day readmission rates were 5.3% vs 4.6% (P = .34), and the 30-day mortality rates were 3.4% vs 2.9% in each respective group (P = .38). Patients who received open surgery had a 90-day mortality rate of 6.2% compared with 4.9% among those who underwent minimally invasive resection (P = .23).

Based on propensity-matched group analysis, the 5-year overall survival (OS) rate was 53.4% with minimally invasive surgery compared with 51.2% using open surgery (P = .487). The presentation noted that the study was limited due to its inability to specifically identify those with T4-invasive disease.

Given these data, Chudgar concluded that resection could be considered for those with cT4 disease. He stated that surgical resection could be safely performed in appropriately selected patients without compromising their perioperative survival and other outcomes.

Resection in Stage IIIB Disease

Chudgar spoke about findings from another NCDB study that focused on outcomes of patients with cT3-4N2 disease over time to illustrate the extent to which resection is suitable for those with stage IIIB NSCLC.

The study included 44,756 patients who were treated between 2010 and 2020.⁵ Of these patients, 91% received multimodality treatment alone, and 9% underwent surgery in combination with multimodality treatment. Additionally, 51% were diagnosed between 2010 and 2015, and 49% received a diagnosis from 2015 to 2020.

With a median follow-up of 14.6 months, a propensity-matched scoring analysis including 34,088 patients highlighted a median OS of 16.8 months for those diagnosed between 2015 and 2020 compared with 15.1 months for those diagnosed from 2010 to 2015. Additionally, the 3-year OS rate in each respective group was 31.1% vs 25.4% (HR, 0.90; 95% CI, 0.87-0.92; P <.001).

Among patients who had a diagnosis between 2010 and 2015 (n = 4492), the median OS was 16 months with multimodal therapy vs 44 months with the addition of surgery. The 3-year OS rate in each respective group was 25.4% vs 54.8% (HR, 0.46; 95% CI, 0.43-0.49; P <.001). Of those with a diagnosis between 2015 and 2020 (n = 3342), the median OS with each respective treatment was 19 months vs 60 months, with 3-year OS rates of 31.8% vs 63.5% (HR, 0.39; 95% CI, 0.36-0.43; P <.001).

According to Chudgar, the data supported the notion that those with stage IIIB disease could be eligible for surgical resection, noting that resection may confer a survival advantage in select patients.

“In this era of modern systemic therapy, it’s critical to evaluate patients in a multidisciplinary fashion to see what’s going to be the best [treatment option],” Chudgar said.

Immunotherapy in Resectable Disease

For patients with resectable disease, Chudgar highlighted a variety of immunotherapeutic options that may confer clinical benefits. These options included perioperative chemotherapy plus nivolumab (Opdivo) as assessed in the phase 3 CheckMate 816 trial (NCT02998528)⁶ and the phase 2 NADIM2 study (NCT03838159);⁷ chemotherapy plus durvalumab in the phase 3 AEGEAN trial (NCT03800134);⁸ chemotherapy plus toripalimab (Loqtorzi) in the phase 3 Neotorch trial (NCT04158440);⁹ and chemotherapy plus pembrolizumab (Keytruda) in the phase 3 KEYNOTE 671 trial (NCT03425643).¹⁰

Findings from these trials suggested that the addition of immunotherapy to chemotherapy improved outcomes for patients with resectable NSCLC. For instance, data from NADIM-2, in which 72% of patients had node-positive disease and 39% had multi-station N2 disease, indicated an improvement in OS with nivolumab plus chemotherapy compared with chemotherapy alone (HR, 0.43; 95% CI, 0.19-0.98).

Across the 5 aforementioned trials, anywhere from 80.6% to 93.0% of patients in the experimental treatment arms underwent surgical resection following neoadjuvant therapy compared with 69.0% to 80.7% in the control arms. Additionally, a R0 resection was achieved in anywhere from 83.2% to 95.8% of patients receiving experimental treatment compared with 77.8% to 92.6% in the control arms.

Of note, 17% of patients who received immunotherapy plus chemotherapy in the CheckMate 816 trial underwent pneumonectomy compared with 25% of those who received chemotherapy alone. Across all disease stages in the AEGEAN trial, thoracotomy was administered to 49% of patients in the durvalumab arm vs 51% of those in the placebo arm, and minimally-invasive surgery was given to 49% and 47% of patients, respectively.

In the CheckMate 816 trial, minimally invasive surgery was performed for 30% of patients who received nivolumab plus chemotherapy compared with 22% of those who received chemotherapy alone. Additionally, the rates of minimally invasive followed by open surgery were 11% and 16% in each respective arm.

“Neoadjuvant therapies may be able to convert unresectable disease to resectable,” Chudgar concluded.

References

1. Chudgar M. What is the definition of resectability? Redefining resectability in a new neoadjuvant landscape. Presented at the 21st Annual Winter Lung Cancer Conference. Miami, Florida; February 2-4, 2024.
2. Clifton EE. The criteria for operability and resectability in lung cancer. JAMA. 1996;195(12):1031-1032. doi:10.1001/jama.1966.03100120099025
3. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 1.2024. Accessed February 6, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
4. Rodriguez-Quintero JH, Elbahrawy MM, Montal AM, et al. “Minimally invasive surgery for clinical T4 non-small cell lung cancer: national trends and outcomes”: minimally invasive surgery for cT4 NSCLC. EJCTS. Published online January 23, 2024. doi:10.1093/ejcts/ezae009
5. Rodriguez-Quintero JH. Outcomes of patients with cT3-4N2 NSCLC in the era of modern systemic therapy. Is it time to redefine resectability? Presented at the 60th Society of Thoracic Surgeons Annual Meeting. January 27-29, 2024; San Antonio, TX.
6. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386:1973-1985. doi:10.1056/NEJMoa2202170
7. 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. 2023;389:504-513. doi:10.1056/NEJMoa2215530
8. Heymach JV, Harpole D, Mitsudomi T, et al. Perioperative durvalumab for resectable non–small-cell lung cancer. N Engl J Med. 2023;389:1672-1684. doi:10.1056/NEJMoa2304875
9. Lu S, Zhang W, Wu L, et al. Perioperative toripalimab plus chemotherapy for patients with resectable non-small cell lung cancer: the Neotorch randomized clinical trial. JAMA. 2024;331(3):201-211. doi:10.1001/jama.2023.24735
10. Wakelee H, Liberman M, Kato T, et al. Perioperative pembrolizumab for early-stage non–small-cell lung cancer. N Engl J Med. 2023;389:491-503. doi:10.1056/NEJMoa2302983