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A treatment approach that has made its mark in advanced NSCLC is the combination of immunotherapy with other immunotherapies (immuno-oncology, IO) or with chemotherapy. On that treatment playing field, is durvalumab (Imfinzi) a game-changing team player?

The agent certainly scored in the trial, boosting overall survival (OS) in patients with unresectable, stage III NSCLC that had not progressed after concurrent chemoradiotherapy. The PACIFIC findings , which approved the trial's regimen in 2018.

Subsequently, the phase II COAST trial looked at durvalumab alone, or combined with oleclumab or monalizumab, as consolidation therapy. In COAST, there was a confirmed objective response rate (ORR) that was numerically higher with durvalumab plus oleclumab (30.0%) and durvalumab plus monalizumab (35.5%) versus durvalumab (17.9%) alone, with progression-free survival (PFS) prolonged with both combinations (hazard ratios 0.44 and 0.42, respectively), reported Roy S. Herbst, MD, PhD, of Yale New Haven Health/Smilow Cancer Hospital in New Haven, Connecticut, and colleagues in the (JCO).

The findings "really speak to the fact that [IO] combinations may be the way to go in the future to target either innate or acquired resistance to immune inhibitors," Herbst told

COAST results were first presented at the 2021 European Society for Medical Oncology congress, and at the time, stated that a plan was underway to "start a registrational trial with the hope of bringing these new treatment options to patients that further increase the potential for cure in this setting."

In an , Nathan A. Pennell, MD, PhD, of the Cleveland Clinic, reiterated a point that has been kicking around for time: Trial endpoints can make a in the ultimate value of a treatment regimen.

In COAST in particular, one issue with the use of ORR was that it may have been less effective at predicting IO efficacy "where response can be delayed or misleading, and some have suggested that duration of response may be a better end point," Pennell stated.

Overall, Pennell acknowledged that "the best approach will take time to determine, [and] the end points chosen for trials in unresectable stage 3 NSCLC have a major impact on development. For earlier stage trials, PFS is likely the best end point given the need for earlier assessments of efficacy although even here follow-up can take years ... For late-stage trials, OS is clearly the gold standard end point for efficacy, although it does take much longer and require larger trials to assess, and in the stage 3 NSCLC population where the median survival is many years ... there is a risk of the field moving on before OS reporting out."

So COAST results were a win, but that was just one game. How did durvalumab do in another trial, CCTG BR.34? Investigator Natasha B. Leighl, MD, of Princess Margaret Cancer Centre in Toronto, highlighted the results of that study at the 2022 ASCO annual meeting.

What was the impetus for the trial, "?"

Leighl: PD-1-axis inhibitors are now standard in the first-line therapy of patients with advanced lung cancer, either as monotherapy in those with high tumor-PD-L1 expression or in combination with chemotherapy. CTLA-4 and PD-1 immune checkpoints impair T cell activation and function by a distinct mechanism. Preclinical and clinical studies on dual checkpoint inhibition demonstrate synergistic activity. And this therapeutic approach is now standard in melanoma and kidney cancer.

In lung cancer, nivolumab plus ipilimumab recently improved survival compared to platinum chemotherapy irrespective of tumor PD-L1 expression and tumor mutation burden levels. Durvalumab plus tremelimumab also in a recent study did not improve survival compared to platinum chemotherapy. However, plasma T and B [cells] ≥20 mutations per megabase has been identified as a potential predictor of benefit from the combination.

What was the trial protocol?

Leighl: This international multicenter prospective study enrolled patients with stage IVa or b squamous or non-squamous NSCLC who were chemotherapy-naive for metastatic disease and had EGFR-wild-type or ALK-fusion-negative tumors. Patients were required to have a performance status of 0 or 1, no prior autoimmune disease, no active brain metastases. And stratification factors at the time of randomization included squamous versus non-squamous subtype, stage IVa versus b, and smoking status.

Patients were allocated in a one-to-one fashion to receive either durvalumab plus tremelimumab for four cycles followed by durvalumab maintenance until disease progression or the same plus chemotherapy. Patients with squamous carcinoma received gemcitabine-based treatment. And those with non-squamous received pemetrexed-based therapy, including pemetrexed maintenance in addition to immunotherapy ... [the sample size was] 300 patients with 155 survival events required to perform the final analysis. At median follow-up of 16.6 months, 157 patients have passed leading to the final analysis.

Seventy percent had stage IVb disease, 18% had squamous carcinoma, 19% had PD-L1 tumor cell expression in 50% of cells or greater, and 23% were defined as having high blood TMB [tumor mutational burden] using the 20 mutations per megabase cutoff. Overall, this represents a very high-risk study population, but again, with characteristics balanced between both harms.

The primary objective of BR-34 was to compare OS [overall survival] between the patients receiving durvalumab and tremelimumab and those receiving the same plus chemotherapy.

What were some of the main findings?

Leighl: The addition of chemotherapy to durvalumab and tremelimumab did not improve survival, with a hazard ratio of 0.88 and a P value of 0.46. The median survival time with durvalumab and tremelimumab was 14.1 months, and 16.6 months with the addition of chemotherapy. There was no difference in OS with the addition of chemotherapy across clinical subgroups. There were some interesting trends, including by sex, the presence of brain metastases, and pathologic subtype, but none of these were significant.

Seventy percent of patients at the time of final analysis had stopped protocol therapy and were eligible for further treatment. In the durvalumab-plus-tremelimumab arm, more patients went on to receive subsequent treatment, 66%, in particular, systemic therapy, 47%, of whom most received platinum doublet therapy, 42% thus far.

PFS was significantly improved with the addition of chemotherapy to durvalumab and tremelimumab with a hazard ratio 0.67 and a P value of 0.0035. Median PFS was 3.2 months with the immunotherapy combination and 7.7 months with chemotherapy added. The finding of improved PFS with chemotherapy was consistent across clinical subgroups.

PFS in those with high blood-based TMB was not different with the addition of chemotherapy, but was significantly improved in those with low blood-based TMB, with a hazard ratio of 0.59 and a P value of 0.0031. However, the test for interaction was negative, with a P value of 0.20.

What is the take-home message from the trial?

Leighl: The addition of chemotherapy to durvalumab plus tremelimumab did not improve [OS] in the BR-34 trial. It did improve PFS [progression-free survival] and response in patients with high-risk disease. We did not identify a subgroup where combination checkpoint inhibition was superior to that same combination plus chemotherapy.

Patients with high blood-based TMB had longer survival and PFS than those with low blood-based TMB, but this was prognostic, not predictive in our trial, as all patients received durvalumab plus tremelimumab ... analyses of quality of life, plasma genomics, and cost are ongoing.

Read the COAST study here.