Median overall survival doubled for veterans with stage 3 non-small cell lung cancer who received chemoradiotherapy plus durvalumab, as compared to those receiving chemoradiotherapy alone, according to a new study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, which was held virtually 4-10 June, 2021 [1]. Physician’s Weekly spoke with principle investigator Dr. Nithya Ramnath, Section Chief of Oncology at the University of Michigan.

Based on outcomes from the PACIFIC trial, the current standard of care for patients with unresectable stage 3 non-small-cell lung cancer (NSCLC) is chemoradiotherapy followed by durvalumab maintenance [2]. Veterans were not included in PACIFIC, but they are a unique population with significant co-morbidities, characterized by traditionally higher smoking rates. The researchers wanted to know what the impact of adding durvalumab to chemoradiation was on the survival of veterans with stage 3 NSCLC; therefore the study team used the VA’s Corporate Data Warehouse, selecting patients with stage 3 NSCLC who received chemoradiotherapy and at least one dose of durvalumab and compared disease outcomes with historical data from veterans who had received chemoradiation alone.

The median age of the veterans meeting inclusion criteria (n=1,106) was 69, and >95% were male. Most (86.4%) were current smokers or had a history of former tobacco use. Pathological analysis revealed that 48.1% had adenocarcinoma histology, 48.4% had squamous cell histology, and 0.5% large cell histology, 0.3% had neuroendocrine histology, and 0.1% had sarcomatoid histology. The majority, 60%, had stage 3A disease, whereas 34.5% had stage 3B, and 3.3% had stage 3C disease. Median progression-free survival was 19.9 months (95% CI 16.9 – 23.6), and median overall survival was 34.9 months (95% CI 29.7 – not reached). However, when compared with historical controls [3], it became evident that the addition to durvalumab to chemoradiation doubled the overall survival.

Analyses indicated that adenocarcinoma histology (HR 1.14; P=0.03) predicted progression. Furthermore, older age (HR 1.03, P< 0.0001) and stage 3B/3C disease (HR 1.05;  P=0.008) predicted inferior overall survival.

Only 18.4% of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 19.4% discontinued durvalumab due to progression, 23.4% discontinued because of immune-related adverse event, and 1.9% died during treatment.

Physician’s Weekly spoke to Dr. Nithya Ramnath, section chief of oncology at the University of Michigan, to obtain more information.

Do the number of adjuvant durvalumab cycles matter?

“This was a study conducted by retrospective analysis of over a thousand stage 3 NSCLC patients. We collected this data from what is called a corporate data warehouse, which basically houses the patient data for actually all the veterans, with any kind of medical condition. It is a very rich database that we can access. The cohort we studied had more stage 3a patients compared with 3b and 3c. Looking at the treatments that they received, the standard of care is chemoradiation, but followed by durvalumab maintenance, based on the PACIFIC trial in 2017. We found, compared to historical controls, that the survival of the veteran population with stage 3 NSCLC had improved significantly after the introduction of durvalumab, doubled even, given the caveats of comparing two disparate groups in historical controls.

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To answer your question, It did not seem to matter whether patients received fewer or more number of durvalumab maintenance cycles. The average number of cycles in our cohort was 5.7. That the efficacy was maintained with fewer cycles definitely came as a surprise to us. The PACIFIC trial had a median of 14 cycles, with similar outcomes. These data warrant additional research.”

Were there different toxicities in veterans vs the PACIFIC cohort?

‘’We went back to see why durvalumab was discontinued in some of those patients. Of course, the majority, stopped treatment because of progression of their cancer. But -perhaps unique to our veteran population, immune-mediated toxicity caused 23.4% patients to discontinue durvalumab prematurely, specifically pneumonitis. The incidence of pneumonitis was 2 to 4-fold  what was reported in the PACIFIC population.

We do not quite know the reasons for this. We cannot make lot of assumptions and conclusions from a retrospective database. This is speculation, but veterans do tend to have significant COPD, although other comorbidities are also important to consider. It was clear from this study that the incidence of pneumonitis in this population might be a bit higher. This is important to understand because, since the duration of durvalumab maintenance did not seem to have an impact on overall survival or median survival. Therefore, it follows reason to think that it might be possible to tailor doses of durvalumab, in order to avoid adverse events.

We would have to necessarily look at this hypothesis prospectively. For example, we would need a large study, of roughly 1,500 patients, randomizing them to either 6 or 12 months of durvalumab. Then we could stratify patients who are at higher risk for pneumonitis based on potential exploratory biomarkers. This would have to be a complex statistical multivariate model, which then informs the end points of progression free and overall survival at 6 months versus 12 months of durvalumab maintenance. This study is being designed currently, as we speak. It will be looking for a place for funding next, and will allow for a crossover.”

Is there any complimentary biomarker or radiomics approaches being taken?

“We are in the process of putting together some pilot data; in fact, we just sent a colleague at the Cleveland Clinic preliminary scans on 6 patients to see if he could use his radiomics algorithm to sort of predict who might get toxicity from durvalumab.

The fact is we are moving the needle in lung cancer. So in my lifetime we have seen it move significantly and even in the veteran population, we have seen a near doubling of survival. So obviously multiple factors contribute to that performance status, stage migration and the treatment, obviously, but I would like to see more of our patients benefit from these newer therapies, at the same time a reducing physical and financial toxicity would be an important role.”

  1. Sankar K, et al. Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.DOI: 10.1200/JCO.2021.39.15_suppl.8546 Journal of Clinical Oncology39, no. 15_suppl (May 20, 2021) 8546-8546.
  2. Antonia SJ, et al. PACIFIC Investigators. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC. N Engl J Med. 2018 Dec 13;379(24):2342-2350.
  1. Desilets A, et al. Durvalumab therapy following chemoradiation compared with a historical cohort treated with chemoradiation alone in patients with stage III non-small cell lung cancer: A real-world multicentre study. Eur J Cancer. 2021 Jan;142:83-91.