MA06.06 Treatment Recommendations for Stage III NSCLC by 3 Dutch Multidisciplinary Tumor Boards Prior To, and Following the PACIFIC Trial

8511 Background: In the placebo-controlled Phase III PACIFIC trial of patients with unresectable Stage III NSCLC whose disease had not progressed after platinum-based concurrent chemoradiotherapy (cCRT), durvalumab improved overall survival (OS) (stratified hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.53–0.87; p=0.0025; data cutoff [DCO] Mar 22, 2018) and progression-free survival (PFS) (stratified HR 0.52, 95% CI 0.42–0.65; p<0.0001; DCO Feb 13, 2017) based on the DCOs used for the primary analyses, and the degree of benefit remained consistent in subsequent updates. Durvalumab was associated with a manageable safety profile, and did not detrimentally affect patient-reported outcomes, compared with placebo. These findings established consolidation durvalumab after CRT (the ‘PACIFIC regimen’) as the standard of care in this setting. We report updated, exploratory analyses of OS and PFS, assessed approximately 5 years after the last patient was randomized. Methods: Patients with WHO PS 0/1 (and any tumor PD-L1 status) whose disease did not progress after cCRT (≥2 overlapping cycles) were randomized (2:1) 1–42 days following cCRT (total prescription radiotherapy dose typically 60–66 Gy in 30–33 fractions) to receive 12 months’ durvalumab (10 mg/kg IV every 2 weeks) or placebo, stratified by age (<65 vs ≥65 years), sex, and smoking history (current/former smoker vs never smoked). The primary endpoints were OS and PFS (blinded independent central review; RECIST v1.1) in the intent-to-treat (ITT) population. HRs and 95% CIs were estimated using stratified log-rank tests in the ITT population. Medians and OS/PFS rates at 60 months were estimated with the Kaplan–Meier method. Results: Overall, 709/713 randomized patients received treatment in either the durvalumab (n/N=473/476) or placebo (n/N=236/237) arms. The last patient had completed study treatment in May 2017. As of Jan 11, 2021 (median follow-up duration of 34.2 months in all patients; range, 0.2–74.7 months), updated OS (stratified HR 0.72, 95% CI 0.59–0.89; median 47.5 vs 29.1 months) and PFS (stratified HR 0.55, 95% CI 0.45–0.68; median 16.9 vs 5.6 months) remained consistent with the results from the primary analyses. The 60-month OS rates were 42.9% and 33.4% with durvalumab and placebo, respectively, and 60-month PFS rates were 33.1% and 19.0%, respectively. Updated treatment effect estimates for patient subgroups will be presented. Conclusions: These updated survival analyses, based on 5-year data from PACIFIC, demonstrate robust and sustained OS plus durable PFS benefit with the PACIFIC regimen. An estimated 42.9% of patients randomized to durvalumab remain alive at 5 years and approximately a third remain both alive and free of disease progression. Clinical trial information: NCT02125461.

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Observed survival benefit with limited exposure of durvalumab in unresectable stage III non-small cell lung cancer at a large community-based institution.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20539 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20539-e20539

Author(s):

Deepak Vadehra ◽

Christopher R Pallas ◽

Donald Moore ◽

Jeryl Jean Villadolid ◽

Myra M. Robinson ◽

...

Keyword(s):

Lung Cancer ◽

Survival Benefit ◽

Locally Advanced ◽

Small Cell ◽

Stage Iii ◽

Advanced Stage ◽

Small Cell Lung ◽

Fda Approval ◽

The Pacific ◽

Stage Iii Nsclc

e20539 Background: The PACIFIC trial ushered in a paradigm shift in the management of unresectable, non-metastatic non-small cell lung cancer (NSCLC), demonstrating improvement in 12,24,36-month overall survival (OS) and leading to the 2018 FDA approval for durvalumab in unresectable or locally advanced stage III NSCLC. With almost 3 years of FDA approval, we performed a retrospective analysis of patient experiences and outcomes at Levine Cancer Institute analyzing patient data to assess survival and potential points of clinical significance. Methods: Patients over the age of 18, who met criteria similar to the PACIFIC trial (i.e. unresectable or locally advanced stage III NSCLC) from February 2018 through September 2020 were analyzed. Those who were receiving active treatment at the data cutoff were excluded. Patient characteristics, prior treatment, durvalumab administration, immune-related adverse events (irAEs), and efficacy data were summarized and evaluated. OS and progression free survival (PFS) were evaluated with Kaplan Meier methods. Results: A total of 159 patients were evaluated. 40.9% were female and 59.1% were male. The median age was 67 (range 38-83 years). Of note, 86.8% of patients were white, whereas 13.2% were nonwhite. 50.3% patients experienced an irAE. The most common reasons for discontinuation of durvalumab were completion (at least 24 doses), progressive disease, or toxicity (33.3%, 30.8%, 26.4%, respectively). The median number of doses of durvalumab received was 14 (range 1-26 doses). The median PFS was 15.3 months with 12-and 24-month PFS being 54% and 41.1 %, respectively. Median OS was 42 months with 12-and 24-month OS being 78.1% and 67.8%, respectively. Our analysis compared outcomes in those who completed adjuvant durvalumab versus those who did not complete adjuvant therapy (Table). Conclusions: Data shows the best survival in those who completed durvalumab (comparable to historic values) and novel data shows a perceived survival benefit in those completing 12 doses compared to those who did not. Thus, partial treatment may provide a survival advantage. Further multivariate analysis will look for possible correlations to increased immune events and inability to complete therapy. Further investigation will delve into this cohort’s small proportion of non-white patients, evaluating for possible barriers to care that may lead to more patients being diagnosed with stage IV NSCLC.[Table: see text]

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Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.8546 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 8546-8546

Author(s):

Kamya Sankar ◽

Alex K. Bryant ◽

Michael Green ◽

Nithya Ramnath

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Median Number ◽

Small Cell ◽

Stage Iii ◽

Small Cell Lung ◽

The Pacific ◽

Stage Iii Nsclc

8546 Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p < 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.

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The Evolving Role of Immunotherapy in Stage III Non-Small Cell Lung Cancer

Current Oncology ◽

10.3390/curroncol28060451 ◽

2021 ◽

Vol 28 (6) ◽

pp. 5408-5421

Author(s):

Kirstin Perdrizet ◽

Parneet K. Cheema

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Concurrent Chemotherapy ◽

Small Cell ◽

Stage Iii ◽

Small Cell Lung ◽

The Pacific ◽

Stage Iii Nsclc

The management of Stage III non-small cell lung cancer (NSCLC) is complex and requires multidisciplinary input. Since the publication of the PACIFIC trial (consolidative durvalumab post concurrent chemotherapy and radiation in Stage III disease) which showed improved survival for patients in the immunotherapy arm, there has been much interest in the use of immunotherapy in the Stage III setting. In this review, we explore the biologic and clinical rationale for the use of immunotherapy in Stage III NSCLC, present previously published and upcoming data in the neoadjuvant, adjuvant, and concurrent realms of Stage III management, and discuss unanswered questions and challenges moving forward.

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Prospective phase I multi-institutional trial of PD-1 blockade with pembrolizumab during concurrent chemoradiation for locally advanced, unresectable non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.8511 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 8511-8511 ◽

Cited By ~ 5

Author(s):

Salma K. Jabbour ◽

Abigail T. Berman ◽

Roy H. Decker ◽

Yong Lin ◽

Steven J. Feigenberg ◽

...

Keyword(s):

Clinical Trial ◽

Phase I ◽

Combined Treatment ◽

Locally Advanced ◽

Stage Iii ◽

The Pacific ◽

Increased Risk ◽

Prospective Phase ◽

Stage Iii Nsclc ◽

Grade 3

8511 Background: The PACIFIC study showed that consolidative Programmed Death Ligand 1 inhibition (PD-L1i) after chemoradiation therapy (CRT) improves PFS and OS in patients with Stage IIII NSCLC (Antonia et al. NEJM 2017, 2018). Limited data, however, exist regarding the incorporation of PD-L1i concurrently during CRT. We sought to assess the safety and toxicity of PD-1i using pembrolizumab (pembro) during definitive CRT for Stage III NSCLC. Methods: In this multi-center prospective Phase I clinical trial using a 3+3 design, we evaluated the timing and dosing of pembro combined with chemotherapy (carboplatin + paclitaxel weekly) and definitive RT (60 Gy in 2 Gy/day x 30 fractions) for unresectable, locally advanced Stage III NSCLC (AJCC 7thEd). Dose Cohorts (C) evaluated were--C1: full dose (FD) pembro (200 mg IV Q3 weeks) 2-6 weeks after CRT; C2: reduced dose (RD) pembro (100 mg IV Q3 weeks) starting Day 29 of CRT; C3: FD pembro starting Day 29 of CRT; C4: RD pembro starting on Day 1 of CRT; C5: FD pembro starting on Day 1 of CRT. For each cohort, pembro was continued Q3 weeks for up to 18 cycles (as monotherapy after CRT in either RD or FD based on initial dose assignment). Dose Limiting Toxicity (DLT) was defined as Grade ≥4 pneumonitis within 21 days of cycle 1 of pembro. Results: We enrolled 23 subjects from 8/2016-11/2018; median follow up (f/u) was 11.4 mo (range, 3.1 mo- 25.2 mo). Median age was 69 yrs (range 53-85); 52% were women. No DLTs were observed in any of the cohorts (C1 to C5). Grade ≥3 immune-related adverse events (irAE) occurred in 4 patients (18%). irAE’s included: Grade 5 (bilateral), 3, 2 pneumonitis (n=1, 1, 4, respectively (6 total)); Grade 3 hyperglycemia (n=1); Grade 3 interstitial nephritis (n=1); Grade 2 thyroiditis (n=4); Grade 2 myositis (n=1); Grade 1-2 transaminitis (n=3). Median PFS for patients who received ≥2 doses (n=18) of pembro was 20.3 mo. Conclusions: Combined treatment with PD-Li and CRT for stage III NSCLC was well tolerated with promising PFS to date but showed an increased risk for irAEs, particularly pneumonitis. Based on these encouraging results, further prospective study of PD-1i and CRT for Stage III NSCLC is warranted. Clinical trial information: NCT02621398.

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DUART: durvalumab after radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy

Future Oncology ◽

10.2217/fon-2021-0952 ◽

2021 ◽

Author(s):

Andrea R Filippi ◽

Rafał Dziadziuszko ◽

Maria Rosario García Campelo ◽

Jean-Baptiste Paoli ◽

William Sawyer ◽

...

Keyword(s):

Performance Status ◽

Poor Performance ◽

Standard Of Care ◽

Stage Iii ◽

Poor Performance Status ◽

Open Label ◽

Unresectable Stage ◽

The Pacific ◽

Radiotherapy Alone ◽

Stage Iii Nsclc

Consolidation durvalumab is standard of care in patients with unresectable, stage III non-small-cell lung cancer (NSCLC) without disease progression following chemoradiotherapy (the ‘PACIFIC regimen’). However, many patients with poor performance status, older age or comorbidities may be ineligible for chemotherapy due to expected high toxicity. These patients typically receive radiotherapy alone, with poor survival outcomes. Based on the PACIFIC trial data, and the strong biological rationale for combining radiotherapy with anti-programmed cell death ligand-1 therapy, durvalumab following radiotherapy could provide additional survival benefit versus radiotherapy alone. Here, we describe the DUART trial, a Phase II, open-label, single-arm study assessing the safety and tolerability of durvalumab following radiotherapy in patients with unresectable, stage III NSCLC who are ineligible for chemotherapy (ClinicalTrials.gov Identifier: NCT04249362 ).

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Durvalumab consolidation therapy following chemoradiotherapy among patients with unresectable stage III non-small cell lung cancer (NSCLC) treated in a U.S. community oncology network.

Journal of Clinical Oncology ◽

10.1200/jco.2020.39.28_suppl.295 ◽

2021 ◽

Vol 39 (28_suppl) ◽

pp. 295-295

Author(s):

David Michael Waterhouse ◽

Candice Yong ◽

Nicholas J. Robert ◽

Kathleen M. Aguilar ◽

Juliet Ndukum ◽

...

Keyword(s):

Real World ◽

Chart Review ◽

Stage Iii ◽

Consolidation Therapy ◽

Unresectable Stage ◽

The Pacific ◽

The Mean ◽

Stage Iii Nsclc ◽

Ecog Ps ◽

Observation Period

295 Background: While the introduction of durvalumab consolidation therapy shifted the treatment paradigm for unresectable stage III NSCLC, few studies have examined real-world use of durvalumab in this patient population. Methods: This was a retrospective study of adult patients diagnosed with unresectable Stage III NSCLC between 8/1/2017-2/29/2020 who received chemoradiotherapy (CRT) followed by durvalumab consolidation therapy in The US Oncology Network. Structured electronic health record (EHR) data was used to screen for potentially eligible patients who received durvalumab consolidation. Through a targeted chart review, patients’ eligibility was verified. Study variables on patient demographics, clinical characteristics, CRT and durvalumab treatment patterns were sourced from structured and unstructured EHR data. Results: Among 1,626 patients who received CRT during the study observation period and were screened through structured records, 851 (52.3%) of these patients received durvalumab. Through chart review, 528 patients were verified to be eligible for this analysis (median age 70 years, 51.5% male, 18% Eastern Cooperative Oncology Group performance status [ECOG PS] score of 0, 59% with an ECOG PS score of 1). Across the study population, 73.9% received a total radiation dose between 54 and 66 Gy, with the rest receiving higher doses (6.5%), lower doses (3.2%) or doses not documented (15.8%). The mean and median time from end of radiation to post-CRT scan were 41 and 36 days, respectively; the mean and median time from end of radiation to durvalumab initiation were 58 and 47 days, respectively, with 57% of patients initiating durvalumab > 42 days. At the end of study observation period (median follow-up duration of 46.9 weeks), 173 of 528 patients (32.7%) were still actively receiving durvalumab treatment, 98 (18.6%) had completed planned treatment and 257 (48.7%) had discontinued treatment due to progression (18.2%), adverse events (17.2%), death (5.3%) or other reasons (8%). Conclusions: These results provide insights into real-world use of the PACIFIC regimen in a community setting with an older and more fragile population. Radiation therapy doses administered during CRT were largely consistent with the PACIFIC trial. There were delays in time to post-CRT scan and durvalumab initiation, with more than half of patients starting durvalumab > 42 days after CRT. These findings highlight opportunities for quality improvement measures in this population.

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