Utility of Immunotherapy Keeps Evolving in Unresectable Stage III NSCLC

Many checkpoint inhibitors are currently under investigation in combination with concurrent radiotherapy in stage III non–small cell lung cancer, which experts propose could have practice-changing implications.

Enriqueta Felip, MD

Enriqueta Felip, MD

Although concurrent chemoradiotherapy (CRT) has historically been the standard of care for patients with unresectable stage IIIA and stage IIIB non–small cell lung cancer (NSCLC), the addition of immunotherapies to this setting, such as durvalumab (Imfinzi), have been linked with improvements in survival. Now, other checkpoint inhibitors are currently under investigation in combination with concurrent radiotherapy that experts propose could have practice-changing implications.

Concurrent Chemoradiation: A Historical Standard

Concurrent CRT has been identified as the treatment of choice for patients with unresectable stage IIIA and IIIB NSCLC, although sequential chemotherapy followed by radiotherapy stands as a valid alternative treatment option, according to Enriqueta Felip, MD, head of the Lung Cancer Unit, Oncology Department at Vall d’Hebron University Hospital, in a presentation during the 22nd Annual International Lung Cancer Congress.1 The recommended dose is 60 Gy to 66 Gy in 30 to 33 daily fractions.

Several studies have examined the optimal use of concurrent and sequential CRT strategies in this setting.

A meta-analysis by the NSCLC Collaborative Group of concomitant vs sequential chemotherapy in patients with locally advanced NSCLC identified that treatment with sequential chemotherapy plus radiation was linked with a 5-year overall survival (OS) rate of 10.6%; the 5-year OS rate with concurrent therapy was 15.1%.2

Additionally, the randomized phase 3 PROCLAIM trial (NCT00686959), examined the use of concurrent pemetrexed/cisplatin plus thoracic radiation therapy (TRT) followed by pemetrexed consolidation or standard etoposide/cisplatin plus TRT followed by consolidation platinum-based doublet chemotherapy in those with stage IIIA/B unresectable nonsquamous NSCLC. However, data showed that the median OS with concurrent therapy was 25.0 months vs 26.8 months in the etoposide/cisplatin arm (HR, 0.98; 95% CI, 0.79-1.20; P = .831).3

The phase 3 RTOG 0617 trial (NCT00533949) examined standard-dose vs high-dose conformal radiotherapy with concurrent chemotherapy with or without cetuximab (Erbitux) in patients with unresectable stage IIIA or IIIB NSCLC. Here, data revealed that radiotherapy at the standard dose elicited a median OS of 28.7 months vs 20.3 months for the high-dose arm (HR, 1.38; 95% CI, 1.09-1.76; P = .004).4

Felip noted past efforts to try and build upon these treatment approaches. However, induction chemotherapy, consolidation chemotherapy, targeted therapies in non–biomarker-driven patients, twice-daily irradiation, and increased radiotherapy dosage have not yielded positive results, Felip explained.

Breakthrough With Durvalumab in Stage III NSCLC

The addition of durvalumab has notably improved the benefit of CRT, as documented in the phase 3 PACIFIC study (NCT02125461).5 The trial comprised 713 patients with unresectable stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT who were randomized 2:1 to receive either durvalumab (n = 476) or placebo (n = 237) for up to 1 year.

In a 3-year OS update of the trial, data indicated that the addition of durvalumab led to a significant improvement in progression-free survival (PFS)vs placebo (HR, 0.52; 95% CI, 0.42-0.65; P < .0001). The updated OS data remained consistent with previously reported results (stratified HR, 0.69; 95% CI, 0.55-0.86); the median OS was not reached with durvalumab vs 29.1 months with placebo. Moreover the 12-, 24-, and 36-month OS rates for the durvalumab cohort vs placebo were 83.1% vs 74.6%, 66.3% vs 55.3%, and 57.0% vs 43.5%, respectively.

Pneumonitis was a notable concern associated with the consolidation immunotherapy, Felip explained; all-grade and grade 3/4 pneumonitis occurred in 33.9% and 3.6% of durvalumab-treated patients, respectively.

Findings from the study led to the February 2018 FDA approval of durvalumab as a treatment for patients with locally advanced, unresectable stage III NSCLC who have not progressed following CRT.

Five-year survival findings of PACIFIC were recently presented at the 2021 ASCO Annual Meeting. At a median follow-up of 34.2 months, the updated median 5-year OS was 47.5 months with durvalumab and 29.1 months with placebo (HR, 0.72; 95% CI, 0.59-0.89).6 The median 5-year PFS in the durvalumab arm was 16.9 months compared with 5.6 months with placebo (HR, 0.55; 95% CI, 0.45-0.68).

Additionally, the 60-month OS rate was 42.9% with durvalumab vs 33.4% with placebo. The 60-month PFS rates were 33.1% and 19.0%, respectively.

Assessing Other Immunotherapy Agents Plus Concurrent CRT

Researchers have explored other checkpoint inhibitor approaches in this setting beyond durvalumab.

In the phase 2 KEYNOTE-799 study (NCT0363178), pembrolizumab (Keytruda) plus concurrent CRT was found to induce antitumor effects in patients with unresectable, locally advanced, stage III NSCLC irrespective of PD-L1 expression or tumor histology.7 In cohort A, which comprises both patients of nonsquamous and squamous histology, the ORR was 70.5%.

The phase 2 NICOLAS trial (NCT02434081), which assessed concurrent radiotherapy along with nivolumab (Opdivo), and followed by consolidation nivolumab for up to 1 year, identified the regimen’s feasibility with no unexpected adverse effects or increased risk of severe pneumonitis.8

Additionally, the phase 2 DETERRED study (NCT02525757) was a 2-part trial assessing concurrent radiotherapy plus atezolizumab (Tecentriq) in patients with unresectable NSCLC. Findings from part 1, which had conventionally fractionated CRT followed by consolidation atezolizumab, showed that the median PFS was 18.6 months and the median OS was 22.8 months at a median follow-up of 22.5 months.9 In part 2, which had a median follow up of 15.3 months and involved concurrent CRT with atezolizumab and the same consolidation and maintenance therapies as in part 1, the median PFS was 13.2 months and the median OS was not reached.

Ongoing clinical trials are currently examining the efficacy of immunotherapy agents within this patient population. For example, the phase 2 COAST study (NCT03822351) is examining durvalumab, durvalumab/oleclumab, and durvalumab/monalizumab; the phase 2 LUN14-179 (NCT02343952) trial is assessing pembrolizumab, and the phase 2 BTCRC-LUN16-081 trial (NCT03285321) is evaluating nivolumab vs nivolumab/ipilimumab (Yervoy) following concurrent radiotherapy.

Other ongoing studies include the randomized phase 3 PACIFIC 2 trial (NCT03519971), which is assessing concurrent radiotherapy plus durvalumab in locally advanced unresectable stage III NSCLC, as well as the phase 3 CheckMate 73L trial (NCT04026412), which will evaluate the use of nivolumab plus concurrent CRT followed by nivolumab with or without ipilimumab in previously untreated, locally advanced stage III NSCLC. Another arm is looking at durvalumab plus CCRT.

Remaining Questions and Other Potential Avenues Up Ahead

“One important question now is [whether] we should give chemoradiotherapy first…or if it is better to start up front with chemotherapy, radiotherapy, and immunotherapy,” Felipe explained.

In hopes of answering this question, researchers are enrolling patients on the phase 3 EA5181 trial (NCT04092283), which is assessing the value of durvalumab as concurrent and consolidative therapy alone for patients with unresectable stage III disease.

Some patients are ineligible to receive radiation or may not be able to have chemotherapy-free regimens. A radiotherapy-free treatment with durvalumab is currently being assessed through the phase 3 BRIDGE trial (NCT04765709), which will determine whether chemoimmunotherapy can enhance tumor shrinkage in a population of patients who are not eligible for radiotherapy or surgery. The goal is to achieve radiotherapy eligibility within this population and possibly move on to an immunotherapy combination and consolidation immunotherapy, Felip noted.

Patients will receive durvalumab and chemotherapy induction followed by durvalumab and radiotherapy, followed by 1 year of consolidation durvalumab.

Other chemotherapy-free options are being tested in the phase 1 ARCHON-1 NRG-LU004 trial (NCT03801902) of durvalumab plus radiotherapy in patients with stage II to III NSCLC with a PD-L1 status of 50% or greater; a single-center phase 1 pilot trial (NCT04013542) examining ipilimumab plus nivolumab and radiotherapy in patients with stage II to III NSCLC; and the phase 2 SPRINT trial (NCT03523702) of pembrolizumab and radiotherapy in patients with a PD-L1 status of 50% or more.


  1. Enriqueta F. Updates for immunotherapy for unresectable stage III disease. Presented at 22nd Annual International Lung Cancer Congress; July 29-31, 2021; Huntington Beach, CA. Accessed July 30, 2021.
  2. Aupérin A, Péchoux CL, Rolland E, et al. Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol. 2010;28(13):2181-2190. doi:10.1200/JCO.2009.26.2543.
  3. Senan S, Brade A, Wang LH, et al. PROCLAIM: randomized phase III trial of pemetrexed-Ccsplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34(9):953-962. doi:10.1200/JCO.2015.64.8824
  4. Bradley JS, Paulus R, Komaki R, et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol. 2015;16(2):187-199. doi:10.1016/S1470-2045(14)71207-0
  5. Gray JE, Villegas A, Daniel D, et al. Three-year overall survival with durvalumab after chemoradiotherapy in stage III NSCLC—update from PACIFIC. J Thoracic Oncol. 2020;15(2):288-292. doi:10.1016/j.jtho.2019.10.002
  6. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin Oncol. 2021;39(suppl 15):8511-8511. doi:10.1200/JCO.2021.39.15_suppl.8511
  7. Jabbour SK, Lee KH, Frost N, et al. KEYNOTE-799: phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC. J Clin Oncol. 2021;39(suppl 15):8512. doi:10.1200/JCO.2021.39.15_suppl.8512
  8. Peters S, Felip E, Dafni U, et al. Progression-free and overall survival for concurrent nivolumab with standard concurrent chemoradiotherapy in locally advanced stage IIIA-B NSCLC: results from the European Thoracic Oncology platform NICOLAS phase II trial (European Thoracic Oncology Platform 6-14). J Thor Oncol. 2021;16(2):278-288. doi:10.1016/j.jtho.2020.10.129
  9. Lin SH, Lin Y, Yao L, et al. Phase II trial of concurrent atezolizumab with chemoradiation for unresectable NSCLC. J Thorac Oncol. 2020;15(2):248-257. doi:10.1016/j.jtho.2019.10.024.
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