Outcomes with durvalumab after chemoradiotherapy in stage IIIA-N2 non-small-cell lung cancer: an exploratory analysis from the PACIFIC trial

Background The phase III PACIFIC trial (NCT02125461) established consolidation durvalumab as standard of care for patients with unresectable, stage III non-small-cell lung cancer (NSCLC) and no disease progression following chemoradiotherapy (CRT). In some cases, patients with stage IIIA-N2 NSCLC are considered operable, but the relative benefit of surgery is unclear. We report a post hoc, exploratory analysis of clinical outcomes in the PACIFIC trial, in patients with or without stage IIIA-N2 NSCLC. Materials and methods Patients with unresectable, stage III NSCLC and no disease progression after ≥2 cycles of platinum-based, concurrent CRT were randomized 2 : 1 to receive durvalumab (10 mg/kg intravenously; once every 2 weeks for up to 12 months) or placebo, 1-42 days after CRT. The primary endpoints were progression-free survival (PFS; assessed by blinded independent central review according to RECIST version 1.1) and overall survival (OS). Treatment effects within subgroups were estimated by hazard ratios (HRs) from unstratified Cox proportional hazards models. Results Of 713 randomized patients, 287 (40%) had stage IIIA-N2 disease. Baseline characteristics were similar between patients with and without stage IIIA-N2 NSCLC. With a median follow-up of 14.5 months (range: 0.2-29.9 months), PFS was improved with durvalumab versus placebo in both patients with [HR = 0.46; 95% confidence interval (CI), 0.33-0.65] and without (HR = 0.62; 95% CI 0.48-0.80) stage IIIA-N2 disease. Similarly, with a median follow-up of 25.2 months (range: 0.2-43.1 months), OS was improved with durvalumab versus placebo in patients with (HR = 0.56; 95% CI 0.39-0.79) or without (HR = 0.78; 95% CI 0.57-1.06) stage IIIA-N2 disease. Durvalumab had a manageable safety profile irrespective of stage IIIA-N2 status. Conclusions Consistent with the intent-to-treat population, treatment benefits with durvalumab were confirmed in patients with stage IIIA-N2, unresectable NSCLC. Prospective studies are needed to determine the optimal treatment approach for patients who are deemed operable.

Stage IIIA-N2 NSCLC represents a heterogeneous disease group, with some patients being potentially eligible for thoracic surgery. 5,6 Before the approval of durvalumab, the recommended therapeutic approach for patients with stage IIIA-N2 disease comprised multimodality treatment with chemotherapy, radiotherapy, and (in patients deemed operable) a surgical resection. [7][8][9][10] Given the clinically meaningful improvements demonstrated with the PACIFIC regimen across a wide population of patients with unresectable, stage III NSCLC, the potential utility of immunotherapy in this setting warrants further evaluation in patients with stage IIIA-N2 disease who are deemed operable. Here we report a post hoc, exploratory analysis of clinical outcomes with durvalumab in patients from the PACIFIC trial with or without stage IIIA-N2, unresectable NSCLC.

Study design
The eligibility criteria and study design for PACIFIC (NCT02125461), a randomized, double-blind, international, multicenter trial, have been described previously. 2,3 Briefly, eligible patients had histologically or cytologically documented stage III, unresectable NSCLC, (according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology, version 7) and had not progressed after at least two cycles of platinum-based, cCRT. Enrolled patients were randomized in a 2 : 1 ratio to receive either durvalumab (10 mg/kg bodyweight; AstraZeneca, Gaithersburg, MD) or placebo intravenously once every 2 weeks for 12 months, or until confirmed disease progression, initiation of an alternative anticancer therapy, development of unacceptable toxicities, or withdrawal of consent. All patients provided written informed consent for participation in the trial, which was approved by relevant ethics committees and carried out in accordance with the International Conference on Harmonization Guidelines on Good Clinical Practice and the Declaration of Helsinki.

Endpoints and assessments
The primary endpoints were PFS [by blinded independent central review as per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1] and OS. Secondary efficacy endpoints included time to death or distant metastasis (TTDM), objective response rate (ORR), and safety (graded as per Common Terminology Criteria for Adverse Events version 4.03).
A post hoc, exploratory analysis of these endpoints was conducted in subgroups comprising patients with or without stage IIIA-N2 NSCLC; the subgroup without stage IIIA-N2 disease included patients with all other stages [i.e. stage IIIA non-N2 (T3N1, T4N0, and T4N1) and stage IIIB].

Statistical analyses
Analysis of RECIST-assessed endpoints (PFS, TTDM, and ORR) was based on the data cut-off (DCO) used for the primary analysis of PFS (13 February 2017). OS and safety were analyzed based on the DCO used for the primary analysis of OS (22 March 2018).
Treatment effects (HRs) for time-to-event endpoints were estimated using unstratified Cox proportional hazards models, with treatment being the only covariate. Medians and associated 95% CIs were estimated with the Kaplane Meier method. Adverse events (AEs), all-cause pneumonitis (i.e. pneumonitis/radiation pneumonitis), and ORR were summarized descriptively. All data were summarized based on the ITT population except for safety data, which were summarized based on the as-treated population. At the DCO for its primary analysis, PFS favored durvalumab compared with placebo in both patients with (HR ¼ 0.46; 95% CI 0.33-0.65) and without (HR  Table 2).

Of
The incidences of any-grade, grade 3/4, and serious AEs were broadly similar between patients with and without stage IIIA-N2 disease irrespective of study treatment ( of cytotoxic chemotherapy was higher among patients with stage IIIA-N2 disease, relative to those without.

DISCUSSION
In the PACIFIC trial, observed treatment benefits (in terms of PFS, OS, and TTDM) favored durvalumab versus placebo, with a manageable safety profile, irrespective of stage IIIA-N2 status. These findings were consistent with results for the ITT population. [1][2][3] Stage IIIA-N2 NSCLC is a heterogeneous disease, with patients varying in terms of their fitness to undergo curative-intent treatment. Consequently, current treatment guidelines are somewhat complex, comprising multimodality regimens of chemotherapy with radiotherapy and/ or surgical resection, with the combination and sequence of modalities tailored according to the disease characteristics of individual patients. 10 As such, the optimal treatment sequence for this population has not been identified. Surgical treatment may be more appropriate in some patient subsets (e.g. those with minimal N2 disease) compared with others (e.g. those presenting with bulky or multilevel N2 disease). 8,11 Importantly, there is, currently, no uniform definition of 'resectable N2 disease' and definitions can differ according to local practice and expertise. 6 At present, the relative benefit of surgery has not been established definitively, with prospective randomized trials generally showing no significant differences in OS between patients with stage IIIA-N2 disease who did and who did not undergo surgical resection as part of a multimodality regimen. [12][13][14][15][16][17][18] However, as much of the available data were generated before the current era of minimally invasive staging procedures/surgical resections and modern radiotherapy techniques (enabling improved tissue sparing), 19,20 and as some key studies did not mandate histological confirmation of N2 disease, results of these older studies may not reflect the potential survival benefit in suitable subsets of patients with stage IIIA-N2 disease.
The findings of the present study (albeit carried out in patients with unresectable disease) emphasize the need to better define operability in the stage IIIA-N2 disease setting in order to demarcate patients who are more likely to benefit from surgery following chemotherapy/CRT. Future studies should seek to assess the impact of the PACIFIC regimen on progression patterns in patients with stage IIIA-N2 disease, as this information will help inform discussions regarding the optimum multimodal treatment approach for patients (given that surgery is expected to improve locoregional control). We did not analyze locoregional failure for the present study as radiotherapy planning parameters were not collected as part of the PACIFIC protocol. This is an important limitation of the study as it was not possible to correlate disease progression with prior radiation fields in all cases.
The treatment landscape for patients with resectable NSCLC is evolving rapidly. Recently, the US Food and Drug Administration approved use of adjuvant (anti-PD-L1) immunotherapy following resection and platinum-based chemotherapy for patients with stage II-IIIA NSCLC (and whose tumors have PD-L1 expression on 1% of tumor cells). 21 In addition, several ongoing phase III trials are assessing neoadjuvant chemoimmunotherapy followed by surgery (e.g. NCT03800134, NCT02998528, and NCT03425643). The utility of immunotherapy in patients with stage IIIA-N2 NSCLC, including in patients who are deemed resectable (either in combination with or instead of surgery), remains unclear. 9,15,18 Multiple early-phase clinical trials are evaluating neoadjuvant/adjuvant immunotherapy in patients with resectable, stage IIIA-N2 NSCLC. 22,23 For example, data from a single-arm phase II study demonstrated a 1-year event-free survival rate of 73% (90% CI 63-82) with neoadjuvant/adjuvant durvalumab in this setting. 23 However, larger comparative trials of surgical and non-surgical strategies for these patients are warranted.
The analyses reported in the present study are limited by their post hoc, exploratory nature. The PACIFIC trial was not designed to assess clinical outcomes with durvalumab according to specific disease stage, and complete details of mediastinal lymph node site involvement and gross tumor volumes were unavailable. In addition, details underlying the decision to deem each patient unresectable were not collected (with decision making at the discretion of the local  Pneumonitis/radiation pneumonitis is a composite term that includes events of acute interstitial pneumonitis, interstitial lung disease, pneumonitis, pulmonary fibrosis, and radiation pneumonitis (alveolitis and diffuse alveolar damage were also included, but no events were found).

ESMO Open
principal investigator and associated multidisciplinary team), and study enrollment was not stratified according to TNM (tumorenodeemetastasis) classification. Therefore, while clinical benefit with durvalumab (versus placebo) was observed irrespective of stage IIIA-N2 status, robust conclusions cannot be drawn due to the inherent lack of sufficient statistical power and imbalances in potentially prognostic baseline factors.

Conclusions
In the PACIFIC trial, treatment benefit was observed with durvalumab versus placebo in patients with stage IIIA-N2, unresectable NSCLC. In the era of immune checkpoint inhibitors, prospective clinical studies comparing surgical and non-surgical strategies are warranted to establish the optimal treatment approach for patients with stage IIIA-N2 NSCLC who are potentially operable. Furthermore, improved and uniform definitions of patients who may or may not be suitable for surgery will be essential in this setting.