Is there a role for triple chemotherapy in advanced biliary tract cancer?

Biliary tract cancers (BTCs) are a heterogeneous group of malignancies that includes intrahepatic cholangiocarcinoma (iCCA), perihilar cholangiocarcinoma (pCCA), distal cholangiocarcinoma (dCCA) and gallbladder cancer (GBC) (1). Despite significant progresses in diagnosis and disease classification in the last few decades leading to a higher detection rate and incidence, the pathogenetic pathways and molecular mechanisms underlying BTC development are still the subject of discussion. This, together with the intrinsic aggressive behaviour of these malignancies, has limited the improvement in everyday clinical management (2).

For over a decade, cisplatin plus gemcitabine (CisGem) has been the mainstay of palliative chemotherapy for locally advanced and metastatic BTC on the basis of the results of the ABC-02 trial (3). In this randomized, phase III trial, the combination of CisGem showed a significant improvement in terms of overall survival (OS) over gemcitabine monochemotherapy [hazard ratio (HR), 0.64; 95% confidence interval (CI): 0.52–0.80; P<0.001].

Recently, the scenario of first-line therapy for patients with advanced BTC has been revolutionised after the promising results of the TOPAZ-1 trial, which first assessed the combination of chemo-immunotherapy in these malignancies. The association of the abovementioned chemotherapy backbone with durvalumab [an anti-programmed death-ligand 1 (PD-L1) humanized antibody] demonstrated an HR for OS of 0.80 (95% CI: 0.66–0.97; P=0.021) in favor of the durvalumab arm that was confirmed in the updated analysis showing an advantage in 24-month OS rate over chemotherapy alone, respectively 23.6% (95% CI: 18.7–28.9%) and 11.5% (95% CI: 7.6–16.2%) (4,5). Therefore, the triple therapy became the new standard of care in first-line therapy. The game-changing role of chemo-immunotherapy was subsequently confirmed by the similar trial KEYNOTE-966, that explored the combination of CisGem with the anti-PD-L1 pembrolizumab (6,7).

Besides the association of chemotherapy with anti-programmed cell death protein 1 (PD-1)/anti-PD-L1, other ways to strengthen the treatment panorama for advanced BTC patients have been covered in the last years and different trials of triple chemotherapy regimens were carried out (Table 1).

The PRODIGE 38-AMEBICA trial, enrolling 191 French patients, failed to demonstrate the superiority of the mFOLFIRINOX (5-fluorouracil/leucovorin, irinotecan and oxaliplatin) regimen, broadly used in advanced pancreatic cancer, over CisGem, with a 12-month OS rate of 47.9% (95% CI: 37.3–57.6%) in the mFOLFIRINOX arm and 55.7% (95% CI: 45.2–65.1%) in the CisGem arm (8).

After a couple of years, the results of another phase II study investigating the combination of the GAP regimen (CisGem plus nab-paclitaxel) were published, showing promising progression-free survival (PFS) and OS, with a manageable safety profile (9). Disappointingly, the subsequent SWOG-1815, a phase III trial comparing GAP to GemCis (10), failed to demonstrate a survival benefit with the triplet, with median OS of 14.0 and 12.7 months, respectively (HR 0.93, 95% CI: 0.74–1.19, P=0.58).

Only the Japanese trial KHBO1401-MITSUBA found positive results when comparing the previous standard first-line chemotherapy with CisGem plus the oral agent S-1. This trial enrolled 246 metastatic BTC and demonstrated a median OS of 13.5 months in the CisGem + S1 arm versus 12.6 months in the CisGem arm, respectively (HR 0.79, 90% CI: 0.638–0.996; P=0.046) (11).

The recent paper by Pressiani et al., published in the European Journal of Cancer, is part of this scenario (12). In this phase I/II trial, the authors evaluated the safety and activity of GEMOX (gemcitabine plus oxaliplatin) plus nab-paclitaxel based on the assumption that GEMOX could represent a valid alternative to CisGem (13,14) and to the promising results of the abovementioned phase II study, evaluating the addition of nab-paclitaxel to the standard doublet chemotherapy (9).

Between July 2017 and December 2020, they enrolled a total of 67 patients (10 in phase I part and 57 in phase II part) to receive study treatment; phase II was carried out in seven different Italian centres, while only the IRCCS Humanitas Research Hospital in Milan was involved in phase I part. Median PFS was 6.3 months (95% CI: 3.6–10.1) and median OS 12.4 months (95% CI: 8–23); the study did not meet its primary endpoint, because less than 39 out of 56 patients were free from progression or death at 6 months. In the overall population, 2 patients (3%) achieved a CR, 12 a PR (20%) and 31 a SD (46.3%), with a DCR of 67.2%. Treatment was well tolerated, and adverse events of any grade were reported in 59 out of 67 (88%) patients. The most common grade 3–4 drug-related adverse events encompassed haematological toxicities like neutropenia (13.4%), thrombocytopenia (3.0%) and anaemia (3.0%), but also peripheral neuropathy (7.5%) and asthenia (6.0%). One patient died of drug-related sepsis.

Considering the three trials conducted among western patients, with the appropriate limits of cross-trial comparison (due in this case to the different trials’ design and purposes), this work matched the results of the other two largest trials in terms of outcomes and objective responses. Notably, the latter was the only one to explore the role of triplet chemotherapy even in ampullary cancer, which were indeed excluded in SWOG-1815 and PRODIGE 38-AMEBICA.

An interesting post-hoc-analysis of the Pressiani et al. (12) trial showed different outcomes according to the primary tumor location: median OS and median PFS were longer for extrahepatic cholangiocarcinoma (eCCA) receiving GEMOX + nab-paclitaxel, 20.6 [95% CI: 12.4–not estimable (NE)] and 10.0 (95% CI: 3.9–12.4) months, respectively. On the same row, in the previously cited SWOG-1815 trial, GAP improved median OS over CisGem in two different cohorts of patients: the ones with locally advanced disease (19.2 versus 13.7 months with an HR 0.67, 95% CI: 0.42–1.06, P=0.09) and those with GBC (17.0 and 9.3 months, respectively; HR 0.74, 95% CI: 0.41–1.35, P=0.33) (10). In the PRODIGE 38-AMEBICA, patients with iCCA had better median PFS with CisGem over the triplet mFOLFOXIRI (HR 0.58; 95% CI: 0.39–0.85; P=0.01) (8). All these analyses should be interpreted with caution because of the limited number of patients included in these trials. However, in the evolving panorama of BTCs, the results of these subgroup analyses underline the need for a deeper insight into such a heterogeneous group of neoplasms.

An important point of weakness of all trials encompassing triplet chemotherapy, regardless of their negative results, is the comparison with an old standard of care, based on only chemotherapy, making their findings less applicable to today’s clinical practice.

Moreover, in the recent panorama ruled by the progressive attention to the molecular-driven subtypes of CCA, a deeper understanding of the differences among iCCA, eCCA and GBC could open the door to a more personalised treatment for non-molecularly driven tumors. As known, the three different types of CCA are not characterised by the same molecular and biological background (15), that reflects the different treatment responses observed among CCA subgroups and the need for subgroup analyses according to primary tumor site in BTCs.

Finally, despite the practice-changing results of TOPAZ-1 and KEYNOTE-966 trials that established new standards of care for cisplatin-fit advanced BTC, there is still a quote of patients’ refractory to chemo-immunotherapy. In such cases, further considerations are still necessary to enhance the efficacy of more promising chemotherapy combinations and to identify predictive factor of response.

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.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-215/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-215/coif). The authors have no conflicts of interest to declare.

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