Revisiting consolidation immunotherapy: the promise of COAST after PACIFIC

The publication of the PACIFIC trial in 2017 was a landmark moment in thoracic oncology, fundamentally redefining the standard of care for patients with unresectable, stage III non-small cell lung cancer (NSCLC) (1). For a patient population previously facing grim prognoses after concurrent chemoradiotherapy (cCRT), the addition of 12 months of consolidation durvalumab, an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody, has significantly improved outcomes. The trial demonstrated a median progression-free survival (PFS) benefit of 11.2 months over placebo and, more importantly, a durable overall survival (OS) benefit that has held firm over time. The 5-year update confirmed this paradigm shift, with an OS rate of 42.9% in the durvalumab arm versus 33.4% for placebo (2). This established a new benchmark, a “PACIFIC plateau”, that subsequent efforts have struggled to surpass (3).

Despite this remarkable success only 33.1% of patients in the durvalumab arm of the PACIFIC trial remained progression-free by 5 years (2). This highlights a critical, persistent unmet need to improve upon this standard. The mechanisms of resistance to PD-L1 blockade in this setting are complex, involving intrinsic tumor factors, T-cell exhaustion, and the evolution of an immunosuppressive tumor microenvironment (TME) following the inflammatory insult of cCRT (4,5). Logically, the next step in therapeutic development has been to add novel agents to the durvalumab backbone, with combinations designed to overcome these specific resistance pathways.

The most intuitive hypothesis of moving immunotherapy earlier to be given concurrently with cCRT has now proven to be a clinical dead end in major phase 3 trials. PACIFIC-2 has shown the inefficiency of concurrent durvalumab, and CheckMate 73L and ECOG-ACRIN EA5181 have shown that this approach fails to improve survival outcomes compared to the PACIFIC standard (6-8). The increased toxicity of combining chemotherapy, radiation, and immunotherapy simultaneously appears to negate any theoretical synergistic benefit, leading to more treatment discontinuations. These important, if negative, trials have provided a crucial lesson: the consolidation phase, as established by PACIFIC, remains the critical viable window for safe and effective immunotherapy intervention in this setting.

COAST: building on the plateau with sound biology

It is in this challenging context that the updated analysis of the COAST trial by Aggarwal et al. (9). COAST is a phase 2, open-label, randomized platform study designed to build upon the PACIFIC standard. It evaluated durvalumab alone or in combination with two novel immunotherapies: oleclumab (an anti-CD73 monoclonal antibody) or monalizumab (an anti-NKG2A monoclonal antibody).

The preclinical rationale for these specific combinations is strong and is rooted in the biological consequences of cCRT itself. Radiotherapy, while killing cancer cells, also induces a complex, dichotomous immune response. It can promote anti-tumor immunity by releasing tumor antigens, but it can also promote an immunosuppressive TME to facilitate tissue repair and immune homeostasis (10). This ambiguous side of radiation is mediated, in part, by the very pathways COAST seeks to exploit.

Oleclumab targets CD73, an ecto-enzyme highly expressed on both cancer and immune cells in the TME (11). Primary function of CD73 is to convert extracellular AMP to adenosine. Adenosine is a potent immunosuppressive signaling molecule that cripples anti-tumor immunity by binding to A2a receptors on T-cells and natural killer (NK) cells, effectively putting them to sleep. Importantly, radiation is a known upregulator of CD73 (12). The hypothesis is therefore: cCRT creates the problem (adenosine-mediated immunosuppression), and oleclumab offers the solution, blocking adenosine production to re-awaken the immune response and enhance PD-L1 blockade.

Monalizumab targets NKG2A, an inhibitory C-type lectin receptor found on the surface of NK cells and a subset of activated CD8⁺ T-cells (13). Its sole ligand is human leukocyte antigen-E (HLA-E), a non-classical major histocompatibility complex (MHC) class I molecule. Under normal conditions, HLA-E expression signals “self”, protecting healthy cells from NK-cell-mediated killing. However, many solid tumors, including NSCLC, overexpress HLA-E as an immune evasion strategy, effectively displaying a universal “don’t kill me” signal. Like CD73, HLA-E expression is also robustly induced by radiation (14). By blocking the NKG2A/HLA-E interaction, monalizumab is hypothesized to unleash both the innate (NK cell) and adaptive (CD8⁺ T-cell) immune systems, preventing tumor escape and synergizing with durvalumab.

The updated COAST results reported by Aggarwal et al., with a mature median follow-up of 30.1 months, present a compelling, if complex, picture. The study’s primary endpoint, investigator-assessed objective response rate (ORR), was not met. While ORRs were numerically higher in the combination arms (35.0% for durvalumab + oleclumab and 40.3% for durvalumab + monalizumab, vs. 23.9% for durvalumab alone), the differences were not statistically significant. This “failure” should be interpreted with caution. ORR, as defined by response evaluation criteria in solid tumors (RECIST) criteria, is a notoriously difficult and potentially misleading endpoint in the post-cCRT consolidation setting (15). Differentiating radiation-induced pneumonitis and fibrosis from true tumor progression is a persistent clinical challenge, and measurable disease is often hard to assess after definitive cCRT (16,17). A lack of significant ORR difference, therefore, should not be seen as a failure of the drugs, but perhaps as a failure of the endpoint in this specific clinical context.

Instead, the trial’s key secondary endpoint, PFS, delivered the study’s striking headline. Both combinations substantially prolonged median PFS compared to durvalumab monotherapy. The durvalumab plus oleclumab arm achieved a median PFS of 21.1 months, and the durvalumab plus monalizumab arm reached 19.8 months. Both stand in stark contrast to the 7.3-month median PFS observed in the durvalumab-alone control arm, translating to impressive hazard ratios of 0.59 [95% confidence interval (CI): 0.37–0.93] and 0.63 (95% CI: 0.40–0.99), respectively. The 12-month PFS rates are particularly illustrative, showing 63.5% (oleclumab arm) and 73.2% (monalizumab arm) of patients free from progression, compared to only 37.6% in the control arm.

Furthermore, OS, though data maturity was low at 39.7%, trended favorably for both combinations. The hazard ratio for OS was 0.69 (95% CI: 0.40–1.20) for the oleclumab arm and 0.77 (95% CI: 0.44–1.33) for the monalizumab arm. While not statistically significant, these are encouraging signals in a phase II study. Crucially, these clinical benefits came without a significant toxicity tax. The safety profiles of the combinations were consistent with the known profiles of each agent. Grade 3 or higher treatment-emergent adverse events were reported in 40.7% of the oleclumab arm, 34.4% of the monalizumab arm, and 45.5% of the durvalumab-alone arm. This lack of new or exacerbated safety signals, particularly concerning pneumonitis, is a critical finding that supports the viability of these combinations.

A control arm discrepancy

These PFS results are undeniably impressive and represent a powerful “signal” of activity. However, a critical and sober analysis must address the performance of the control arm. The median PFS of 7.3 months for durvalumab monotherapy in COAST is less than half of the 16.8 months reported in the landmark PACIFIC trial (1,9). It is also significantly lower than the median PFS seen in the PACIFIC-R real-world analysis (21.7-month), Checkmate 73L (15.6 months) and ECOG-ACRIN EA5181 (16.8 months), as well as other real-world cohorts like SPOTLIGHT (17.5 months), RELEVANCE (24.0 months), Western Sweden cohort (23 months) and CA209-7AL (15.7 months) (6,7,18-22).

This large discrepancy complicates interpretation. It forces us to ask the question: is the remarkable relative benefit (the hazard ratio) driven entirely by the power of the combinations, or is it amplified by an underperforming control arm? The authors rightly acknowledge this, noting several key imbalances between the COAST and PACIFIC cohorts. The COAST population had a higher proportion of patients with stage IIIB or IIIC disease and a lower proportion of patients who had received cisplatin-based chemotherapy (versus carboplatin). These factors are well-known to confer a poorer prognosis and likely contributed to the control arm’s performance. The endpoint of PFS is further complicated by the difficulty of radiologically assessing progression following radiotherapy (23,24).

Could the 7.3-month median PFS of the control arm, in fact, be a more accurate reflection of outcomes in a higher-risk stage III population? Importantly, it is highly unlikely that these imbalances can account for the entire threefold difference in median PFS. The fact that two novel agents, with distinct biological mechanisms, both demonstrated a profound and similar magnitude of benefit over the control arm suggests a promising treatment effect.

Molecular profiling: a missing piece in COAST

COAST provides no detailed reporting of tumor molecular profiles, despite the now-established impact of drivers and co-mutations (e.g., EGFR, ALK, KRAS subtypes, STK11, KEAP1, LRP1B) on both prognosis and responsiveness to PD-L1 blockade (21,25-28). An imbalance in mutations between arms could therefore act as an important, unmeasured confounder. For example, a higher proportion of “immune-cold” EGFR-mutated tumors in the durvalumab-alone arm, or more KRAS-mutated, immunotherapy-sensitive tumors in the combination arms may account for a large part of the effect seen in the COAST cohort. Future ad hoc translational analysis of COAST biospecimens, including driver- and co-mutations, would clarify how much of the benefit reflects true drug effect versus underlying molecular enrichment.

By contrast, the ongoing phase III PACIFIC-9 trial designed off the signal from COAST incorporates a more modern biomarker analysis: patients must be EGFR/ALK wild-type, PD-L1 is centrally assessed, and pre-CRT tissue is mandated, enabling a prospective translational program (29). However, comprehensive genomic stratification by KRAS, STK11, KEAP1 and other co-mutations is not built into the publicly available trial schema, meaning that these critical determinants of response will again be explored retrospectively rather than controlled for at the design level.

A platform for the future: COAST, PACIFIC, and the neoadjuvant frontier

So, where does this leave the clinician and the patient? For now, the standard of care remains unchanged. Consolidation durvalumab monotherapy remains the “PACIFIC plateau”. However, the “COAST” and “PACIFIC” branded studies represent a broad platform approach to exploring peri-operative and locally advanced disease. In the resectable, neoadjuvant setting, the AEGEAN trial established the benefit of neoadjuvant durvalumab plus platinum-based chemotherapy followed by adjuvant durvalumab (30). Building on that backbone, NeoCOAST studied triplet neoadjuvant regimens by adding agents such as oleclumab or monalizumab to durvalumab-chemotherapy (31), and NeoCOAST-2 utilizes a modular platform to evaluate durvalumab-chemotherapy plus oleclumab or other next-generation combinations, mirroring the COAST philosophy while pursuing rapid, biology-driven iterations before surgery (32).

This is the true importance of the COAST trial reported by Aggarwal et al. It serves as a crucial signal-finding study for the entire durvalumab platform. If the combinations of durvalumab + oleclumab or durvalumab + monalizumab are proven effective in PACIFIC-9, they may not only become the new standard in the stage III consolidation setting, they will likely become the prime candidates for the neoadjuvant (AEGEAN-like) and adjuvant backbones.

Aggarwal et al. are to be commended for this important update. Although COAST has not yet established a new standard of care, it provides a credible path forward at a time when concurrent strategies have largely disappointed. The trial provides a biologically coherent and clinically encouraging signal that post-CRT intensification may further improve outcomes, and the community now awaits PACIFIC-9 with great interest.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Shanghai Chest. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://shc.amegroups.com/article/view/10.21037/shc-2025-1-8/coif). S.I.S. receives grant from Assar Gabrielsson Foundation. E.A.E. receives grants from the Swedish state under the agreement on medical education and research (ALF), and grants from Assar Gabrielsson Foundation; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events form AstraZeneca and Johnson & Johnson. V.I.S. receives grants from the Swedish state under the agreement on medical education and research (ALF), the Swedish Research Council and the Swedish Cancer Society. A.H. receives grants from the Swedish state under the agreement on medical education and research (ALF), the Jubilee Clinic Cancer Fund and research grants from AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Boehringer Ingelheim. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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