Durvalumab Alone or Combined With Novel Agents for Unresectable Stage III Non Small Cell Lung Cancer Update From the COAST Randomized Clinical Trial summary

In this PACULit episode, we review the COAST randomized phase 2 trial evaluating durvalumab after platinum-based chemoradiotherapy for unresectable stage III NSCLC, with or without two novel agents: oleclumab (anti-CD73) and monalizumab (anti-NKG2A). The discussion covers trial design, the biological rationale (adenosine pathway and NKG2A inhibition), patient selection, and the primary and secondary endpoints (objective response rate, progression-free survival, overall survival, safety). Key results showed objective response rates of 23.9% with durvalumab alone, 35.0% with durvalumab plus oleclumab, and 40.3% with durvalumab plus monalizumab, with significant improvements in progression-free survival for both combination arms and no definitive overall survival benefit yet. Safety was comparable across arms, and the episode discusses implications for ongoing phase 3 PACIFIC-9 and future clinical practice.

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Britany: Welcome back to PACULit, your daily literature update for clinical pharmacists and physicians. Today, we’re diving into the COAST trial update, which explores durvalumab alone or combined with novel agents for unresectable stage III non-small cell lung cancer. Seth, it’s great to have you here to unpack this important study.

Seth: Thanks, Britany. I’m excited to discuss this. Unresectable stage III NSCLC remains a tough clinical challenge. Despite the PACIFIC trial establishing durvalumab consolidation after concurrent chemoradiotherapy as the standard, relapse rates hover around 50 to 60 percent. So, the COAST trial’s approach to enhance outcomes by adding novel immunomodulators is timely.

Britany: Absolutely. Patients with unresectable stage III NSCLC typically undergo platinum-based concurrent chemoradiotherapy, but many still progress. The PACIFIC trial showed durvalumab improved progression-free and overall survival, but the unmet need remains. COAST tries to address this by targeting additional immune checkpoints beyond PD-L1.

Seth: Right. COAST evaluates combining durvalumab with oleclumab, an anti-CD73 antibody, and monalizumab, an anti-NKG2A antibody. Both target immune inhibitory pathways that dampen antitumor immunity. Preclinical data suggested these agents could synergize with PD-L1 blockade to enhance immune responses.

Britany: That’s key. CD73 is involved in adenosine production, which suppresses immune activity in the tumor microenvironment. Blocking CD73 with oleclumab could reduce this immunosuppression. Similarly, NKG2A is an inhibitory receptor on natural killer and CD8+ T cells, and monalizumab blocks this checkpoint to restore cytotoxic function.

Seth: Exactly. The COAST trial enrolled patients with unresectable stage III NSCLC who had completed platinum-based concurrent chemoradiotherapy without progression and had an ECOG performance status of 0 or 1. These were relatively fit patients eligible for consolidation immunotherapy.

Britany: The trial builds directly on the PACIFIC foundation. It’s a phase 2, open-label, randomized clinical trial conducted globally, randomizing 186 patients in a 1:1:1 ratio to durvalumab alone, durvalumab plus oleclumab, or durvalumab plus monalizumab. The intervention lasted up to 12 months.

Seth: The primary endpoint was investigator-assessed confirmed objective response rate, with secondary endpoints including progression-free survival, overall survival, and safety. Descriptive statistics summarized baseline characteristics, and Kaplan-Meier estimates assessed survival outcomes.

Britany: The trial excluded patients with prior immunotherapy, active autoimmune disease, or uncontrolled comorbidities, standard to minimize confounding safety risks.

Seth: Yes, the open-label design could introduce some assessment bias, but the randomized nature and global enrollment add robustness. Baseline characteristics were well balanced, with median age around 65, mostly stage IIIA or IIIB disease, and predominantly adenocarcinoma histology.

Britany: ECOG 0–1 status ensured patients were ambulatory and relatively fit, important when considering tolerability of combination immunotherapies. Organ function criteria were strictly applied to ensure safety.

Seth: Moving to results, the confirmed objective response rate was 23.9% with durvalumab alone, compared to 35.0% with durvalumab plus oleclumab, and 40.3% with durvalumab plus monalizumab. Although not statistically significant due to phase 2 design, the trend favors the combinations.

Britany: Both combination arms showed significant improvements in progression-free survival. The hazard ratio for PFS was 0.59 for durvalumab plus oleclumab and 0.63 for durvalumab plus monalizumab compared to durvalumab alone—a meaningful reduction in risk of progression.

Seth: No nominal improvement in overall survival was observed yet, which is expected given the phase 2 nature and follow-up duration. Longer-term data from the ongoing phase 3 PACIFIC-9 trial will be critical to confirm survival benefits.

Britany: Safety profiles were comparable across all arms, with no new or unexpected adverse events. Immune-related adverse events were consistent with known durvalumab profiles, and adding oleclumab or monalizumab didn’t increase toxicity significantly.

Seth: That’s reassuring. Clinically, this suggests combining durvalumab with these novel agents could enhance efficacy without compromising safety, a key consideration in consolidation therapy.

Britany: Let’s discuss mechanisms further. Oleclumab’s inhibition of CD73 reduces extracellular adenosine, which suppresses T-cell and NK-cell activity, potentiating the immune response initiated by PD-L1 blockade with durvalumab.

Seth: Monalizumab blocks NKG2A, an inhibitory receptor that dampens cytotoxic lymphocyte function. By releasing this brake, monalizumab may restore NK and CD8+ T cell activity, complementing durvalumab’s effect on PD-L1.

Britany: These mechanisms highlight the rationale for combining checkpoint inhibitors targeting different pathways to overcome tumor immune evasion. It’s promising in unresectable stage III NSCLC, where durable control is challenging.

Seth: Clinicians should be aware of potential immune-related adverse events when combining these agents, such as pneumonitis, colitis, or endocrinopathies. Monitoring protocols should be rigorous, especially given prior chemoradiotherapy exposure.

Britany: Good point. Drug interactions are minimal since these are monoclonal antibodies, but vigilance is needed for overlapping toxicities with supportive care medications like corticosteroids or antibiotics, which can modulate immune responses.

Seth: Another clinical pearl is patient selection. The trial included only ECOG 0–1 patients without progression after cCRT. In real-world practice, patients with poorer performance status or comorbidities might not tolerate these combinations as well.

Britany: Exactly. Tailoring consolidation immunotherapy requires careful assessment of functional status and comorbidities. Ongoing trials like PACIFIC-9 will provide more definitive guidance on which patients benefit most.

Seth: PACIFIC-9 is a phase 3 trial evaluating durvalumab combined with oleclumab or monalizumab in a larger unresectable stage III NSCLC population. Its results will be pivotal to potentially change the standard of care.

Britany: Until then, COAST provides encouraging signals that adding these novel agents can improve objective response rates and progression-free survival without compromising safety. It’s an exciting development in immunotherapy.

Seth: From a pharmacist’s perspective, supporting patient adherence to durvalumab consolidation and educating about immune-related adverse events remain critical. The addition of oleclumab or monalizumab will require similar vigilance.

Britany: To summarize, unresectable stage III NSCLC patients completing platinum-based cCRT currently benefit from durvalumab consolidation, but relapse remains a challenge. COAST suggests combining durvalumab with anti-CD73 or anti-NKG2A antibodies may enhance disease control.

Seth: While overall survival data are pending, improved objective response rates and progression-free survival are promising. Safety profiles remain manageable, supporting further investigation in phase 3 trials.

Britany: Thanks for this insightful discussion, Seth. For our listeners, staying updated on evolving immunotherapy strategies is essential to optimize patient outcomes in unresectable stage III NSCLC.

Seth: Thanks, Britany. It’s always a pleasure to delve into cutting-edge clinical research with you. Looking forward to the next update.

Britany: That wraps up today’s PACULit literature update. Be sure to review the full COAST trial publication for more details. Until next time, stay curious and keep advancing patient care.