Investigators Set Sights Beyond the PACIFIC Regimen in Unresectable Stage III NSCLC

Russell Kenneth Hales, MD

Concurrent chemoradiation followed by durvalumab (Imfinzi) has become the standard of care for patients with unresectable stage III non–small cell lung cancer (NSCLC) based on the results of the phase 3 PACIFIC trial (NCT02125461). However, several strategies are under clinical evaluation to push the paradigm beyond the PACIFIC regimen, said Russell Kenneth Hales, MD, during a presentation at the 19th Annual Winter Lung Cancer Conference^®, a program hosted by the Physicians’ Education Resource^®, LLC.¹

“Just as immunotherapy has transformed the management of stage IV [NSCLC], it is also transforming the management of stage III unresectable disease,” said Hales, director of the Thoracic Oncology Multidisciplinary Program and an assistant professor of radiation oncology and molecular radiation sciences at the Sidney Kimmel Comprehensive Cancer Center of Johns Hopkins Medicine. “We will see more neoadjuvant immunotherapy and chemoimmunotherapy, concurrent immunotherapy, and novel adjuvant immunotherapy, PARP inhibitors and other novel therapies as more studies read out in the next 5 years.”

Looking Back on the PACIFIC Trial

In February 2018, the FDA approved durvalumab for use in patients with unresectable stage III NSCLC whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.²

The regulatory decision was based on findings from the PACIFIC trial. The 5-year updated data from PACIFIC demonstrated a median progression-free survival (PFS) of 16.9 months (95% CI, 13-23.9) with durvalumab compared with 5.6 months (95% CI, 4.8-7.7) with placebo (HR, 0.55; 95% CI, 0.45-0.68).³ The median overall survival (OS) was 47.5 months (95% CI, 38.1-52.9) vs 29.1 months (95% CI, 22.1-35.1), respectively (HR, 0.72; 95% CI, 0.59-0.89).

“[The PACIFIC trial] is one of the great success stories in stage III lung cancer and something that has caused me and other providers to change how we council patients about prognosis and outcomes,” Hales said. “It also led to the National Comprehensive Cancer Network guidelines advocating for immunotherapy after chemoradiotherapy in selected [patients with- IIIA, IIIB, and IIIC NSCLC.”

Expanding Beyond the PACIFIC Regimen

The practice-changing data from the PACIFIC trial have jumpstarted new research efforts to further improve outcomes for patients with stage III NSCLC. Hales highlighted 4 areas of ongoing study: improving treatment options for patients with limited Karnofsky Performance Status (KPS), using concurrent immunotherapy and chemoradiation, giving neoadjuvant chemoimmunotherapy prior to chemoradiation, and capitalizing on novel adjuvant therapies.

Patients With Limited KPS

“Far too often we talk about advances in the field without taking a real gut check of the patients we care for. Many of these patients are not patients that would be eligible for the rigorous clinical trial therapies that we give,” Hales said.

The ongoing phase 2 PACIFIC-6 trial (NCT03693300) is assessing the safety of durvalumab after sequential chemotherapy and radiation in patients with unresectable stage III NSCLC, which could be better tolerated among patients compared with concurrent chemoradiation therapy.⁴

Additionally, the ongoing phase 2 DUART trial (NCT04249362) is evaluating durvalumab following radiation therapy in patients with stage III unresectable NSCLC who are ineligible for chemotherapy.⁵

“This is an important direction we need to go because plenty of our patients may not be eligible [for standard of care therapy]. If giving immunotherapy as a single-agent therapy is a way to help our patients who otherwise have nonmetastatic disease get systemic therapy, it may be an exciting option for them,” Hales said.

Concurrent Immunotherapy With Chemoradiation

Rather than waiting until patients respond to chemoradiation, studies are evaluating the utility of giving concurrent immunotherapy with chemoradiation in patients with stage III NSCLC.

For example, the results of the phase 2 NICOLAS trial (NCT02434081) demonstrated that at a median follow up of 21 months, the median PFS was 12.7 months (95% CI, 10.1-22.8) with concurrent nivolumab (Opdivo) plus chemoradiation followed by nivolumab in 79 patients with locally advanced stage IIIA to IIIB NSCLC.⁶ At an extended follow-up of 32.6 months, the median OS was 38.8 months (95% CI, 26.8-not estimable) and the 2-year OS rate was 63.7% (95% CI, 51.9%-73.4%).

“The importance of this study was more that it established the safety of this regimen for patients. This of course will need to be validated in a randomized, phase 3 trial,” Hales said.

Other ongoing studies are also evaluating the potential role of concurrent chemoradiation plus immunotherapy in patients with unresectable NSCLC, such as the phase 3 PACIFIC-2 trial (NCT03519971) with durvalumab, a phase 3 trial (NCT04092283) with durvalumab, and the phase 3 CheckMate73L trial (NCT04026412) with nivolumab with or without ipilimumab (Yervoy).^7-9

Neoadjuvant Chemoimmunotherapy Prior to Chemoradiation

Given the success of adding immunotherapy after chemoradiation, studies are ongoing to evaluate its utility before chemoradiation, Hales explained.

For example, the nonrandomized phase 2 KEYNOTE-799 trial (NCT03631784) evaluated neoadjuvant pembrolizumab (Keytruda) plus chemotherapy followed by pembrolizumab plus chemoradiation followed by pembrolizumab in patients with unresectable stage III NSCLC.¹⁰ Cohort A received carboplatin plus paclitaxel and cohort B received cisplatin plus pemetrexed.

The results of the study showed that patients in cohort A had an objective response rate (ORR) of 70.5% (95% CI, 61.2%-78.8%). The median ORR was 70.6% (95% CI, 60.7%-79.2%) in cohort B. The median duration of response was not reached in either group, but 79.7% of cohort A and 75.6% of cohort B had responses lasting at least 12 months.

Regarding safety, the rate of grade 3 to 5 pneumonitis, which was a key end point of the study, was 6.3% in cohort A and 5.9% in cohort B.

“With a primary outcome of safety and tolerability, this study does seem to show safety with an exciting response rate that will need to be validated with future studies,” Hales said.

A randomized phase 2 trial (NCT04085250) is ongoing evaluating nivolumab/chemotherapy (docetaxel plus cisplatin) followed by chemoradiation followed by nivolumab or observation in patients with stage III NSCLC.¹¹

Novel Adjuvant Therapies

The final area of study involves evaluating novel adjuvant therapies to move beyond traditional immunotherapy regimens, Hales explained.

For example, the phase 2 COAST trial (NCT03822351) is ongoing evaluating durvalumab alone or in combination with novel agents, including oleclumab or monalizumab, in patients with stage III NSCLC who have not progressed after concurrent chemoradiation.¹²

The phase 3 KEYLYNK-012 trial (NCT04380636) is evaluating pembrolizumab with concurrent chemoradiation followed by pembrolizumab with or without the PARP inhibitor olaparib (Lynparza) in patients with stage III NSCLC.¹³

Additionally, to potentially expand upon the results of the phase 3 ADAURA trial (NCT02511106), the phase 3 LAURA trial (NCT03521154) is ongoing to evaluate the utility of osimertinib (Tagrisso) following chemoradiation in patients with EGFR-mutated stage III unresectable NSCLC.¹⁴

Redefining Resectability?

Hales concluded the presentation by discussing whether resectability will be redefined as the paradigm continues to evolve. Prior to the PACIFIC trial, most patients with stage III disease received concurrent chemoradiation followed by resection. Then, the field shifted to make chemoradiation therapy followed by durvalumab standard. As such, utilizing chemoimmunotherapy followed by resection may have a role in stage III NSCLC and could redefine the definition of resectability.

“Resectable disease should be thought of as a function of technical operability and medical operability,” Hales said. “Technical operability [asks]: If a resection is done, can we completely remove all tumor in an oncologic fashion, including mediastinal disease? Medical operability [asks]: Will the patient simply tolerate the risks of the resection?”

A press release stated that the results of a prespecified interim analysis of the phase 3 CheckMate 816 trial (NCT02998528) were positive, indicating that nivolumab plus chemotherapy led to a clinically meaningful improvement in event-free survival vs chemotherapy alone when given before surgery in patients with resectable stage IB to IIIA NSCLC.¹⁵

However, as neoadjuvant therapy has not been found to improve medical resectability, unresectable patients are unlikely to tolerate surgery following neoadjuvant therapy, Hales explained.

Although evaluation of induction chemoimmunotherapy is needed to determine whether it can render patients with bulky, mediastinal disease resectable, these patients should be considered unresectable outside of a clinical trial and most should continue to be treated with concurrent chemoradiation therapy followed by immunotherapy, Hales continued.

“The use of additional therapies will need to be balanced with a reality check [for] the average patient that we care for, and while the definition of unresectability is in my opinion unlikely to dramatically change, we will find that more patients have unresectable but curable disease in the future,” Hales concluded.

References

1. Hales R. Unresectable stage III non-small cell lung cancer: beyond PACIFIC. Presented at: 19th Annual Winter Lung Cancer Conference. February 4-6, 2022; Miami Beach, FL.
2. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. News release. FDA. February 16, 2018. Accessed February 7, 2022. https://bit.ly/3EFpXO3
3. 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. doi:10.1200/JCO.2021.39.15_suppl.8511
4. A study to determine safety of durvalumab after sequential chemo radiation in patients with unresectable stage III non-small cell lung cancer. ClinicalTrials.gov. Updated February 2, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03693300
5. Study of durvalumab following radiation therapy in patients with stage 3 unresectable NSCLC ineligible for chemotherapy (DUART). ClinicalTrials.gov. Updated February 1, 2022. Accessed February 7, 2022. https://www.clinicaltrials.gov/ct2/show/NCT04249362
6. 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 Thorac Oncol. 2021;16(2):278-288. doi:10.1016/j.jtho.2020.10.129
7. Study of durvalumab given with chemoradiation therapy in patients with unresectable non-small cell lung cancer. ClinicalTrials.gov. Updated November 22, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03519971
8. Testing the addition of an antibody to standard chemoradiation followed by the antibody for one year to standard chemoradiation followed by one year of the antibody in patients with unresectable stage III non-small cell lung cancer. ClinicalTrials.gov. Updated February 4, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04092283
9. A study of nivolumab and ipilimumab in untreated participants with stage 3 non-small cell lung cancer (NSCLC) that is unable or not planned to be removed by surgery (CheckMate73L). ClinicalTrials.gov. Updated January 14, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04026412
10. Jabbour SK, Lee KH, Frost N, et al. Pembrolizumab plus concurrent chemoradiation therapy in patients with unresectable, locally advanced, stage III non-small cell lung cancer: the phase 2 KEYNOTE-799 nonrandomized trial. JAMA Oncol. 2021;7(9):1351-1359. doi:10.1001/jamaoncol.2021.2301
11. Study of nivolumab for non-small cell lung cancer (stage III) following neoadjuvant chemotherapy plus nivolumab and definitive concurrent chemoradiation therapy. ClinicalTrials.gov. Updated February 15, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04085250
12. Durvalumab alone or in combination with novel agents in subjects with NSCLC (COAST). ClinicalTrials.gov. Updated November 19, 2021. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03822351
13. Study of pembrolizumab with concurrent chemoradiation therapy followed by pembrolizumab with or without olaparib in stage III non-small cell lung cancer (NSCLC) (MK-7339-012/KEYLYNK-012). ClinicalTrials.gov. Updated February 4, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04380636
14. A global study to assess the effects of osimertinib following chemoradiation in patients with stage III unresectable non-small cell lung cancer (LAURA) (LAURA). ClinicalTrials.gov. Updated January 19, 2022. Accessed February 7, 2022. https://clinicaltrials.gov/ct2/show/NCT03521154
15. Neoadjuvant Opdivo (nivolumab) plus chemotherapy significantly improves event-free survival in patients with resectable non-small cell lung cancer in phase 3 CheckMate-816 trial. News release. Bristol Myers Squibb. November 8, 2021. Accessed February 7, 2022. https://bit.ly/3GxT2KQ