Implications of the PACIFIC Trial in 2020

Approximately one-third of patients with NSCLC are diagnosed with stage III disease.¹ Concurrent platinum-based chemotherapy with thoracic radiation (CRT) has been considered the cornerstone of treatment for patients with inoperable stage III disease. Consolidation immunotherapy with the PD-L1 inhibitor durvalumab following CRT has revolutionized the treatment paradigm for patients with locally advanced NSCLC and is now widely adopted as the standard-of-care therapy based on results from the PACIFIC trial.^2,3

In the PACIFIC trial, a multicenter phase III study, patients with unresectable stage III NSCLC without evidence of disease progression following CRT were randomly assigned to treatment with durvalumab (10 mg/kg) or matching placebo every 2 weeks in a 2:1 ratio. The co-primary endpoints of the study were PFS and OS. In 2017, the first interim analyses showed an impressive benefit with consolidation durvalumab compared with placebo, with a near tripling of PFS (from 5.6 to 16.8 months; HR 0.52, 95% CI [0.42, 065]; p < 0.001).² As a result of the observed improvement in PFS, in February 2018, the U.S. Food and Drug Administration approved durvalumab for patients with unresectable stage III NSCLC irrespective of tumor PD-L1 status.4 The improvement in PFS persisted (17.2 vs 5.6 months; HR 0.51, 95% CI [0.41, 0.63]) and translated into an improvement in OS (from median OS not reached to 28.7 months; HR 0.68, 99.73% CI [0.47, 0.997]; p = 0.0025) in all predefined subgroups at the time of the final study analysis reported in 2018.

The PACIFIC study reported that durvalumab following CRT was well tolerated, with less than 2% of patients experiencing grade 3 or 4 pneumonitis in the durvalumab arm. When grade 3 or 4 toxicities from any cause were compared, rates were 30.5% in the durvalumab arm versus 26.1% in the placebo arm, with only 15.4% versus 9.8% of patients, respectively, discontinuing treatment.3 Moreover, the addition of durvalumab did not compromise patient reported symptom, functioning, or global health status.⁵ In the recently released 3-year survival update, durvalumab following CRT resulted in a 31% reduction in risk of death (OS HR 0.69, 95% CI [0.55, 0.86]), thus confirming the long-term safety and durability of cure achieved with durvalumab compared with placebo.⁶

The PACIFIC trial established the benefit of immune checkpoint inhibitors in the treatment of unresectable locally advanced NSCLC, but several questions have remained unanswered. Positron emission tomography, which is performed routinely as a standard-of-care staging procedure for stage III NSCLC in the United States, was not required for screening in the global PACIFIC trial, raising the possibility of an underestimation of patients with metastatic disease. On the other hand, since the trial accrued a geographically diverse population of patients, the results from the study can be easily adapted as a global standard of care. Furthermore, random selection within the trial aims to distribute risks related to uniform staging procedures across both arms allows for fair comparisons. Additionally, at first glance, the lower survival rate in the placebo arm compared with historical control appears as a concern.^7,8 However, there are limitations to cross-trial comparisons, and more specifically, in the historical trials of CRT in locally advanced NSCLC, randomization occurred prior to initiation of CRT, whereas in the PACIFIC trial, randomization occurred after completion of CRT. 

Results in the PACIFIC trial’s post-hoc analysis also raised questions. The analysis showed lack of improved survival with consolidation durvalumab in patients with EGFR-mutant or PD-L1–negative tumors (tumor proportion score [TPS] < 1%; HR 1.14, 95% CI [0.7, 1.84]). However, these results need to be interpreted with caution, as biomarker testing was not mandatory for trial accrual. Among the patients who were tested, few patients had EGFR-mutant disease (6% [43 patients]) or PD-L1–negative disease (10% [74 patients]), and the study was not powered to make definitive clinical conclusions about the benefit of durvalumab or lack thereof in these smaller patient subsets. In addition, the role of consolidation durvalumab needs to be ascertained in certain patient populations with stage III NSCLC that were not included as part of the PACIFIC trial, for example, patients who are unable to tolerate CRT, treatment with sequential chemotherapy, and radiation. Future studies are needed to address these and other questions. 

In the initial versions of the protocol, it was mandated that patients initiate durvalumab within 14 days of completion of CRT. Following an amendment, the trial criteria was loosened to expand the window of enrollment to up to 42 days post completion of concurrent treatment. It is unclear whether the improved survival in patients who were started on durvalumab closer to the completion of CRT ( 2 weeks vs. > 2 weeks after completion of CRT; HR 0.43, 95% CI [0.28, 0.66]) was solely due to a time-dependent synergy between immunotherapy and radiation therapy or whether it was also due to a better overall status in those who were able to start on durvalumab earlier after standard CRT treatment.⁶ 

Success shown in the PACIFIC trial has set the stage for future studies aimed at optimizing the integration of immunotherapy in the management of locally advanced, unresectable NSCLC. Several clinical trials are currently underway, and their results would ultimately help to define the optimal duration and sequencing of consolidation immunotherapy (induction, concurrent, or consolidation immunotherapy with CRT) for treatment of locally advanced NSCLC. In the phase III PACIFIC-2 study, investigators are evaluating concurrent administration of durvalumab with CRT (NCT03519971). The results of this trial would be clinically relevant but challenging to incorporate in the current treatment paradigm due to the lack of consolidation immunotherapy in the control arm.

Concurrent immunotherapy and CRT has been evaluated in several early-phase trials (NICOLAS, DETERRED, and KEYNOTE-799).9-11 In the phase II NICOLAS and KEYNOTE-799 studies, concurrent CRT with nivolumab and pembrolizumab therapy, respectively, have shown promising antitumor activity but were associated with a higher-than-expected rate of pneumonitis.9,10 The phase II DETERRED study assessed the safety and efficacy of adding atezolizumab to CRT in two parts: as sequential (part 1) or as concurrent (part 2) treatment. In initial results, concurrent administration of atezolizumab was overall well tolerated.¹¹

Other trials are evaluating alternative sequential immunotherapy strategies as monotherapy or in combination. Initial data from the phase II LUN14-179 trial have hinted toward a similar efficacy, albeit with a slightly higher risk of pulmonary toxicity with consolidation pembrolizumab.¹² The RTOG 3505, a phase III trial of consolidative nivolumab similar to the PACIFIC trial, was terminated due to a change in the treatment landscape (NCT02768558). The phase II COAST study (NCT03822351), a three-armed, randomized control design using consolidation durvalumab alone as the control arm, is evaluating the combination of consolidation durvalumab with novel immunotherapy agents (anti-CD73 agent oleclumab or anti-NKG2A agent monalizumab).

Other studies are working to evaluate biomarker-driven strategies to optimize treatment in PD-L1–high tumors. In the phase II SPRINT study (selective personalized radioimmunotherapy for locally advanced NSCLC trial), a PD-L1 TPS of 50% or greater is being used as a cutoff to enroll patients to treatment with induction pembrolizumab followed by radiation therapy alone and consolidation pembrolizumab. Patients with PD-L1–low (TPS < 50%) tumors will receive CRT alone.¹³ On the other hand, the phase I NRG-LU004 study (NCT03801902) is evaluating an alternative radiation treatment schedule in PD-L1–high tumors (TPS  50%) and comparing accelerated hypofractionated radiation (60 Gy in 15 fractions) to conventional radiation therapy (60 Gy in 15 fractions). 

The practice-changing results of the PACIFIC trial represent the first impressive improvement in the management of locally advanced NSCLC in several decades. Ultimately, the clinical benefits observed in ongoing immunotherapy trials for patients with locally advanced NSCLC would need to be compared with the standard-of-care PACIFIC regimen in larger phase III studies. The effects of different radiation therapy techniques on immunotherapy-related toxicities should also be investigated. Additionally, it would be extremely valuable to evaluate the efficacy of the PACIFIC regimen alone or in combination with novel agents in a dedicated study for patients with targetable mutations and PD-L1–negative tumors.

 
References: 

1.    2009-2015 S. Cancer Stat Facts: Lung and Bronchus. National Cancer Institute. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed 11 November 2019, 2019.
2.    Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919-1929.
3.    Antonia SJ, Villegas A, Daniel D, et al. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. New England Journal of Medicine. 2018;379(24):2342-2350.
4.    FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm597248.htm. Published 2018. Accessed 4/15/2018.
5.    Hui R, Özgüroğlu M, Villegas A, et al. Patient-reported outcomes with durvalumab after chemoradiotherapy in stage III, unresectable non-small-cell lung cancer (PACIFIC): a randomised, controlled, phase 3 study. The Lancet Oncology. 2019;20(12):1670-1680.
6.    Gray JE, Villegas A, Daniel D, et al. Three-Year Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC—Update from PACIFIC. Journal of Thoracic Oncology. 2020;15(2):288-293.
7.    Senan S, Brade A, Wang LH, et al. PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin 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.
8.    Bradley JD, 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.
9.    Peters S, Felip E, Dafni U, et al. Safety evaluation of nivolumab added concurrently to radiotherapy in a standard first line chemo-radiotherapy regimen in stage III non-small cell lung cancer-The ETOP NICOLAS trial. Lung cancer. 2019;133:83-87.
10.    Jabbour SK, Park K, Cohn D, Liu H, Keller SM, Kowalski DM. Phase 2 trial of first-line pembrolizumab with platinum doublet chemotherapy and radiotherapy in patients (pts) with unresectable, locally advanced stage III non–small-cell lung cancer (NSCLC): KEYNOTE-799. Journal of Clinical Oncology. 2019;37(15_suppl):TPS8575-TPS8575.
11.    Lin SH, Lin Y, Mok I, et al. Phase II trial combining atezolizumab concurrently with chemoradiation therapy in locally advanced non-small cell lung cancer. Journal of Clinical Oncology. 2019;37(15_suppl):8512-8512.
12.    Durm GA, Althouse SK, Sadiq AA, et al. Phase II trial of concurrent chemoradiation with consolidation pembrolizumab in patients with unresectable stage III non-small cell lung cancer: Hoosier Cancer Research Network LUN 14-179. Journal of Clinical Oncology. 2018;36(15_suppl):8500-8500.
13.    Ohri N, Cheng H, Jolly S, et al. The selective personalized radioimmunotherapy for locally advanced NSCLC trial (SPRINT). Journal of Clinical Oncology. 2019;37(15_suppl):TPS8571-TPS8571.
14.    Ross HJ, Kozono DE, Urbanic JJ, et al. Phase II trial of atezolizumab before and after definitive chemoradiation for unresectable stage III NSCLC. Journal of Clinical Oncology. 2018;36(15_suppl):TPS8585-TPS8585.

Table. Key Phase II and III Studies Evaluating Immunotherapy for Treatment of Locally Advanced Unresectable NSCLC

Abbreviations: CRT, concurrent platinum-based chemotherapy with thoracic radiation; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; TPS, tumor proportion score.

Trial information was obtained from ClinicalTrials.gov on March 5, 2020.