PEARL trial: efficacy and challenges of durvalumab monotherapy in metastatic non-small cell lung cancer with PD-L1 expression of ≥25%

The treatment of metastatic non-small cell lung cancer (mNSCLC) has changed dramatically over the past decade. Historically, platinum-based chemotherapy was the mainstay of first-line treatment (1). However, with the advent of immune checkpoint inhibitors (ICIs), notably in populations with high programmed death-ligand 1 (PD-L1) expression, results have surpassed those of chemotherapy (2-4). In particular, patients with PD-L1 tumor proportion score (TPS) or tumor cell (TC) expression of 50% often experience significant survival benefits from monotherapy with ICIs such as pembrolizumab, atezolizumab, and durvalumab, making them established first-line options in clinical guidelines (3,5,6).

Durvalumab is an anti-PD-L1 antibody developed for use in advanced NSCLC and initially gained attention in the PACIFIC trial, in which it demonstrated favorable outcomes as maintenance therapy in stage III NSCLC (5). Subsequently, multiple studies have attempted to evaluate durvalumab in patients with metastatic NSCLC alongside a PD-L1 threshold of ≥25%, including the MYSTIC trial (7). This 25% cutoff was derived from preliminary findings in early durvalumab trials, setting it apart from the KEYNOTE series for pembrolizumab, which primarily uses thresholds of 1% or 50%.

Nevertheless, the evidence regarding the extent to which ICI monotherapy can be effective in patients with intermediate PD-L1 expression (here defined as 25–49%) is still limited. Indeed, in the KEYNOTE-042 trial, which targeted patients with PD-L1 TPS ≥1% (8), no clear overall survival (OS) superiority was observed for ICI monotherapy over chemotherapy in the TPS 1–49% subgroup; rather, ICI monotherapy did not necessarily offer substantial benefit unless the TPS is ≥50%. Consequently, building a body of evidence focusing on the “intermediate-expression” cohort (PD-L1 25–49%) is deemed essential. Although more aggressive treatment strategies—such as ICI plus chemotherapy or dual-ICI regimens—have recently become the standard (8,9), concerns regarding adverse events and patient backgrounds pose new challenges.

Thus, Lu et al. investigated the efficacy of durvalumab monotherapy (10) as the first-line treatment for NSCLC with PD-L1 ≥25% in the phase III PEARL trial and compared it with findings from the MYSTIC trial considering potential applications for patients who are not eligible for platinum-based chemotherapy.

Despite clear evidence e.g., KEYNOTE-024 (3) that ICI monotherapy substantially outperforms chemotherapy in patients with PD-L1 ≥50%, its advantage in the intermediate-expression group (25–49%) is less certain (6,7). Some trials have failed to detect a significant difference, and in many cases, chemotherapy or combination regimens are still favored. Against this background, determining how effectively durvalumab monotherapy performs in NSCLC with PD-L1 ≥25% is critical for informing treatment decisions.

The PEARL trial (PEARL; NCT03003962) is a phase III randomized comparative study designed to evaluate the efficacy and safety of durvalumab monotherapy compared with standard platinum-based chemotherapy in patients with mNSCLC who do not harbor epidermal growth factor receptor/anaplastic lymphoma kinase (EGFR/ALK) mutations and whose tumors exhibit PD-L1 TC expression of ≥25% (10). Eligible patients were histologically or cytologically diagnosed with NSCLC, had no EGFR/ALK mutations, had a PD-L1 (TC) expression rate of ≥25%, and had untreated stage IV disease. An Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 was also required. Patients were randomized in a 1:1 ratio to receive either durvalumab monotherapy (20 mg/kg every 4 weeks) or platinum-based chemotherapy (every 3 weeks for 4–6 cycles). For nonsquamous NSCLC, a pemetrexed-containing regimen was permitted; for squamous NSCLC, gemcitabine-containing regimens were acceptable.

The trial’s co-primary endpoints were as follows: (I) OS in the group with PD-L1 TC ≥25%, and (II) OS in the same PD-L1 ≥25% population who were deemed at low risk of early mortality (LREM) based on a statistical model incorporating baseline characteristics such as age, performance status, and lactate dehydrogenase (LDH) (10). The LREM model was designed to identify subgroups less likely to experience rapid tumor progression or death following ICI therapy. The secondary endpoints included OS in patients with PD-L1 TC ≥50%, progression-free survival (PFS), objective response rate (ORR), duration of response, and safety.

In an intention-to-treat analysis of the group with PD-L1 TC ≥25%, the median OS was 14.6 [95% confidence interval (CI): 12.2–16.9] months in the durvalumab arm compared with 12.8 (95% CI: 10.1–14.7) months in the chemotherapy arm [hazard ratio (HR) =0.84, 95% CI: 0.71–0.99; P=0.037] (10). Among the LREM population, durvalumab’s median OS was 14.6 (95% CI: 12.6–17.2) months, close to the 15.0 (95% CI: 13.1–16.8) months observed in the chemotherapy arm (HR =0.96, 95% CI: 0.79–1.15), showing no significant difference. However, because the prespecified HR for OS was set at 0.75 for the entire population and 0.69 for the LERM population as a primary endpoint, the results ultimately did not meet the threshold for significance.

Other important secondary endpoints (PFS and ORR) also did not demonstrate significant differences. The PFS for the durvalumab monotherapy group remained roughly on par with or only slightly higher than that of chemotherapy, and the ORR did not greatly exceed that of chemotherapy. These observations indicate that while ICI monotherapy may not necessarily provide superior early disease control, it could provide extended benefits for certain subgroups in the long term.

With regard to safety, the rate of grade 3/4 treatment-related adverse events was 15.5% in the durvalumab arm compared with 45.9% in the chemotherapy arm (10). Compared with platinum-based chemotherapy, durvalumab showed a favorable toxicity profile but did not achieve a significant OS improvement as per the primary endpoint. Furthermore, within the LREM cohort, no significant OS difference was observed, highlighting the need for a careful interpretation of the actual clinical advantage of durvalumab monotherapy in this group.

The PEARL trial had several noteworthy limitations. First, the population was predominantly Asian (~80%), which may limit generalizability to Western populations. Second, although the study targeted patients with PD-L1 ≥25%, approximately 73% of included patients had PD-L1 ≥50%, possibly skewing the outcome in favor of ICI efficacy. Third, while the LREM model was used to stratify patients by expected early mortality risk, its predictive performance has not been externally validated. Finally, the addition of a co-primary endpoint during the study may have introduced interpretational complexity, warranting cautious assessment of the trial’s conclusions.

Although PEARL hints that durvalumab monotherapy may improve the survival relative to chemotherapy, it did not definitively meet the criteria for significance. Notably, OS differences were further reduced in the LREM group, suggesting that patients at a higher risk of early tumor progression might benefit from chemotherapy-based combinations rather than ICI monotherapy. Conversely, durvalumab monotherapy may confer notable benefits in terms of reduced toxicity, which can be pivotal for older patients and those with comorbidities or limited tolerance for high-intensity regimens.

Among the major trials of durvalumab in advanced NSCLC, MYSTIC stands out as a predecessor to PEARL. The MYSTIC trial, which enrolled patients with PD-L1 TC ≥25% and randomized them to durvalumab ± tremelimumab versus chemotherapy (7), included patients with EGFR/ALK-negative mNSCLC in three arms: durvalumab monotherapy (n≒190), durvalumab plus tremelimumab (n≒180), and chemotherapy (n≒190). The key endpoints were OS and PFS in the PD-L1 ≥25% cohort treated with durvalumab ± tremelimumab versus standard chemotherapy.

As a key finding of the MYSTIC trial comparing durvalumab monotherapy with chemotherapy in patients with PD-L1 TC ≥25%, the median OS was 16.3 months versus 12.9 months (HR =0.76; 95% CI: 0.56–1.02) and the progression-free survival was 3.9 months versus 5.4 months (HR =1.09; 95% CI: 0.85–1.39). Because the prespecified HR for OS was set at 0.62, a significant difference was not achieved. Nevertheless, the results showed a similar trend to PEARL, that is, a numerical improvement in OS with durvalumab (7). Although no significant difference was noted, the OS improvement was numerically similar to that seen in PEARL. However, the PFS was shorter with ICI monotherapy, proposing that some patients experience early disease progression before the immune effect can manifest.

In both MYSTIC and PEARL, the HRs for OS in PD-L1 ≥25% tumors favored durvalumab over chemotherapy (0.76 in MYSTIC vs. 0.84 in PEARL), yet neither met the threshold for significance. These parallels highlight the “moderate efficacy” of durvalumab monotherapy in the intermediate–high PD-L1 group alongside its “statistical limitations”. The following are the results of clinical trials in which ICI monotherapy was used as the first-line treatment for NSCLC (Table 1). The summary in Table 1 was created based on key data extracted from these studies (3,6,8,10-17), including representative response rates and survival outcomes previously reported. In trials where PD-L1 ≥50% was set as the primary evaluation criterion, ICI monotherapy demonstrated significant superiority over chemotherapy in terms of OS, PFS, and ORR. Conversely, in clinical trials where the primary evaluation included populations with low PD-L1 expression, including PEARL, a significant superiority could not be demonstrated. Therefore, although ICI monotherapy can be considered a good treatment option for patients with PD-L1 ≥50%, establishing its significance in terms of treatment efficacy remains challenging for the 25–49% subset. For instance, although PEARL suggested a potential benefit, it did not reach significance. Further studies assessing genetic, environmental, and additional biomarker factors may help clarify the optimal role of durvalumab monotherapy.

In addition, durvalumab demonstrated a significant OS improvement when combined with chemotherapy plus tremelimumab in the POSEIDON trial (18), indicating that intermediate PD-L1 expressers may also benefit from combination approaches. Consequently, the use of durvalumab alone or in combination with other therapies should be weighed against the condition of each patient, including overall status and comorbidities.

With that in mind, under what circumstances should durvalumab monotherapy be considered? One clear scenario is in patients who cannot tolerate platinum-based chemotherapy. Although platinum doublet chemotherapy is a mainstay in advanced NSCLC (1,18), it often causes myelosuppression, nephrotoxicity, neuropathy, and other adverse events. For those with renal impairment or other severe comorbidities, standard chemotherapy may be unfeasible. In PEARL, durvalumab yielded a grade 3/4 toxicity rate of 15.5%, making it a safer alternative for older patients or frail individuals who may still derive a survival benefit.

Although KEYNOTE-189 and IMpower130 have shown that combining ICI with platinum chemotherapy dramatically improves OS (7,8) and such combinations are considered standard care in many guidelines, these regimens are neither feasible nor advisable for every case because of higher toxicity, cost, and performance status considerations. According to the current NCCN guidelines, although PD-L1 ≥50% clearly warrants ICI monotherapy as a first-line recommendation, the 25–49% subset often sees a recommendation for ICI plus chemotherapy (19). However, if the chemotherapy toxicity risk is deemed prohibitively high, durvalumab monotherapy could stand out as a viable solution.

Data from MYSTIC and PEARL indicate that some patients demonstrate rapid progression under ICI monotherapy. For these patients, a chemotherapy-based regimen (with or without an additional ICI) may be more appropriate. Identifying these individuals preemptively through supplementary biomarkers (e.g., tumor mutational burden or immune microenvironment analyses) is a pressing research goal. Gathering real-world data on durvalumab monotherapy will help define the subpopulations most likely to benefit from it, including older adults and those with concurrent illnesses.

In conclusion, PEARL showed that among patients with mNSCLC and PD-L1 ≥25%, durvalumab monotherapy numerically prolonged the survival compared with chemotherapy but did not achieve significance. This aligns with the findings from MYSTIC, whereby “ICI monotherapy has some benefit but may not be definitively superior to chemotherapy”. Nonetheless, a significantly lower incidence of adverse events under durvalumab is highly relevant, particularly for patients who cannot receive platinum regimens or ICI-chemotherapy combinations because of comorbidities or poor performance status. As ICIs remain central to NSCLC therapy, particularly for those with higher PD-L1 expression, therapeutic strategies for intermediate PD-L1 expression will likely further diversify with the addition of cytotoxic chemotherapy and anti-CTLA-4 combinations. Ongoing research into refined biomarkers and the analysis of real-world data may ultimately define how best to position durvalumab monotherapy within individualized treatment paradigms.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

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Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-46/coif). T.U. reports receiving payment or honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli Lilly, Guardant Health Japan, Kyowa Kirin, MSD, Novartis Pharma, Ono Pharmaceutical, Taiho, and Takeda. The other author has no conflicts of interest to declare.

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