Second-line nivolumab with paclitaxel in biomarker-enriched gastric cancer: not all biomarkers are created equal but is the question even relevant anymore?

Incorporating immune-checkpoint inhibition (ICI) via anti-programmed cell death 1 (PD-1) antibodies in the initial treatment of advanced gastric cancer (GC) has led to improved survival, particularly in patients whose tumors express programmed death-ligand 1 (PD-L1) (1,2). However, there has been no demonstrable benefit for ICIs in the second-line setting in immunotherapy-naïve patients—an increasingly rare situation.

In the US, the relevance of this question has diminished, given blanket approvals of first-line ICI plus chemotherapy in any patient with advanced esophageal, gastroesophageal junction (GEJ) or gastric adenocarcinoma, HER2-negative (3) and -positive (4). Ironically, one contemporary population that this question applies to are patients with Claudin18.2 positive tumors who, in the near future, are expected to receive zolbetuximab with chemotherapy (5,6).

As we know from the global KEYNOTE-061 (7), and similarly seen in the East Asian KEYNOTE-063 (8) study, single agent anti-PD-1 therapy in the 2^nd-line setting is not preferred to chemotherapy—overall survival (OS) was not superior [9.1 vs. 8.3 months, hazard ratio (HR) 0.82, 95% confidence interval (CI): 0.66–1.03] and progression-free survival (PFS) was shorter [1.5 vs. 4.1 months, HR 1.27, 95% CI: 1.03–1.57] in patients treated with pembrolizumab compared to paclitaxel. However, the survival curves crossed after 8 months with delayed but sustained benefit seen in a subset of patients treated with pembrolizumab (7). This phenomenon has been observed in multiple other studies of anti-PD-1/anti-PD-L1 inhibitors in various tumors (9-11) and highlights the need for both biomarker-driven strategies and combination treatment approaches to overcome the delayed antitumor response of single agent ICI.

In Gastric Cancer, Lee and colleagues reported their findings from the phase 2 K-umbrella-03 study which evaluated the combination of nivolumab and paclitaxel in immune biomarker-enriched GC patients (12). The Authors selected patients with PD-L1-positive, Epstein-Barr virus (EBV)-positive or deficient mismatch repair (dMMR) HER2-negative GC who had previously received first-line chemotherapy with a fluoropyrimidine/platinum doublet. For added context, this was a substudy of the larger K-umbrella study of 4 biomarker cohorts: (I) epidermal growth factor receptor (EGFR) overexpressed [immunohistochemistry (IHC) 2+/3+] cohort for treatment with a pan-ERBB inhibitor; (II) PTEN loss/null cohort for treatment with a PIK3Cb inhibitor; (III) nivolumab cohort; and (IV) patients without predefined biomarkers for standard of care treatment (13). The investigators are certainly to be congratulated on the design of what at the time was a state-of-the-art umbrella study designed to simultaneously test multiple compelling hypotheses.

Unfortunately, K-umbrella-03 was ultimately a negative study that did not achieve its primary objective of improved PFS with the nivolumab/paclitaxel combination in this immune biomarker-enriched population. The null hypothesis of the study was a median PFS of 2.9 months, while the alternative hypothesis was a median PFS of 4.4 months, based on the RAINBOW study of paclitaxel with or without ramucirumab (14). The median PFS was 3.9 months (range, 2.7–5.5 months) with a median OS of 11.2 months (range, 6.0–18.7 months) and an objective response rate (ORR) of 23.3%. Although this was a negative study, there were once again glimmers of activity: in those who responded to nivolumab-paclitaxel, the median duration of response was 16.7 months. Exploratory analyses suggested that baseline interleukin-1 receptor antagonist levels could help predict for response to the treatment strategy.

Several factors impact the interpretability and relevance of the results from this study. Lee and colleagues enrolled a heterogenous group of patients with GC who were positive for at least 1 of 3 immune biomarkers with dramatically differential degrees of benefit from immunotherapy. Patients with PD-L1 Combined Positive Score (CPS) ≥1 tumors made up 95.8% of the study group. The tumor subtypes that we would expect to benefit dramatically from ICI—dMMR and EBV-positive tumors—only made up 4.2% and 10.4% respectively of patients enrolled, or 8 out of the 48 patients. These small numbers make it difficult even to draw definitive conclusions about the benefit of this combination in these patients. In fact, the authors found no significant association between mismatch repair (MMR) status and survival within their study population. Of course, there is little doubt about the role of immunotherapy in dMMR tumors; deficient MMR status is a widely accepted predictive biomarker and pan-tumor indication for treatment with ICI (15). Specifically in dMMR GC, ICI has been shown to be active regardless of the line of therapy it is administered (16).

Meanwhile, EBV-positive GC, which is characterised by intra-/peri-tumoral immune cell infiltration with genomic amplification of the locus containing genes encoding PD-L1 and PD-L2 (17), was previously described to have a remarkable ORR of 100% to ICI in a small cohort of six patients (18). However, findings from recent studies have been more mixed: no responses to camrelizumab were seen in six EBV-positive GC patients who had failed two prior lines of chemotherapy (19); 1 of 4 patients treated with toripalimab had a response (20) and; 1 of 3 EBV-positive patients treated with either pembrolizumab or nivolumab responded (21). In K-umbrella-03, an ORR of 33% (1 of 3 patients with measurable disease) was observed in EBV-positive patients treated with nivolumab/paclitaxel. Taken together, these data suggest that EBV positivity is an imperfect biomarker with apparent significant heterogeneity. Larger prospective studies or even retrospective series are needed to clarify its role as an independent predictive biomarker for immunotherapy benefit.

Since results from the RAINBOW trial were published in 2014, ramucirumab/paclitaxel has become the global standard of care in the 2^nd-line setting in a biomarker-unselected population, demonstrating improved median OS (9.6 vs. 7.4 months, HR 0.807, 95% CI: 0.678–0.962), improved PFS (4.4 vs. 2.9 months, HR 0.635, 95% CI: 0.536–0.752) and higher ORR (27% vs. 16%) compared to paclitaxel (14). As such, more relevant studies have built on this standard.

The benefit of adding nivolumab to ramucirumab/paclitaxel was evaluated by Nakajima and colleagues, who conducted the single-arm phase 2 UMIN-CTR trial that enrolled ICI-naïve patients without biomarker enrichment (22). This regimen was associated with an ORR of 37.2%, median PFS of 5.1 months, and median OS of 13.1 months. Patients with PD-L1 CPS ≥1 tumors seemed to do better than those with PD-L1 CPS <1 tumors (median OS 13.8 vs. 8.0 months). Therefore, the findings of this study and K-umbrella-03 support the notion that adding ICI to paclitaxel (with or without ramucirumab) to an ICI-naive population in the 2^nd-line setting may be beneficial but it is challenging to tease out the patients who truly benefit.

A more contemporary and relevant iteration of the Nakajima study is the planned SWOG S2303 study (NCT06203600), which is anticipated to open shortly in the US. This is a randomized phase II/III study that will address the benefit of adding nivolumab to ramucirumab/paclitaxel as 2^nd-line therapy in patients with PD-L1 CPS ≥1 GEJ/GC, whose disease has previously progressed on 1^st-line ICI plus chemotherapy. Essentially, the question is whether there is a benefit to continuing an ICI beyond progression into the next line of therapy.

Finally, the field has also moved on from the evaluation of an anti-PD-1/PD-L1 antibody alone with chemotherapy. Several promising novel combinations being tested in completed or ongoing global 1^st-line phase 3 trials include the use of lenvatinib/pembrolizumab with chemotherapy in the LEAP-015 trial (NCT04662710) and the addition of anti-TIGIT antibodies alongside anti-PD-1 and chemotherapy in the STAR-221 trial (NCT05568095). The outcomes of these studies are eagerly anticipated.

Acknowledgments

Funding: 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.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-15/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-15/coif). J.R.C. has received travel support from AstraZeneca. G.K. has received research funding to his institution from AstraZeneca, BMS, CARsgen, Daiichi Sankyo, I-MAB, Jazz, Merck, Oncolys, Pieris, Triumvira and Zymeworks; consulting fees from Astellas, AstraZeneca, Bayer, BMS, Daiichi Sankyo, I-MAB, Jazz, Merck, Pieris and Zymeworks; travel support from Dava Oncology and I-MAB. The authors have no other 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.

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