Irinotecan Monotherapy Appears as Efficacious as Capecitabine Combo in Advanced Gallbladder Cancer

A phase 2 multicenter study evaluated the efficacy of capecitabine (Xeloda) plus irinotecan (CAPIRI) compared with irinotecan alone as treatment of patients with advanced gallbladder cancer. The prospective superiority study randomized patients to receive either treatment, with the primary end point being overall survival (OS) in

Recent data, which were presented during the 2020 World Gastrointestinal Cancer Congress, have been reported with a median of 6 months of follow-up. However, the doublet was not able to achieve the superior OS end point at this time point. The median OS was similar in both arms at 5.16 months with CAPIRI (95%CI, 4.26-6.06) versus 6.28 months with the single agent (95% CI, 4.25-8.3).

There were very little differences in terms of quality of life between the 2 arms, although the doublet led to requiring dose modifications in 27% of patients compared with 9% in the comparator arm with irinotecan alone. Overall, it appears that irinotecan is as efficacious as the doublet in the second-line treatment of advanced gallbladder cancer.

In an interview with Targeted Oncology, Anant Ramaswamy, MD, a medical oncologist with Tata Memorial Hospital in Mumbai, India, discussed the findings from the phase 2 study of capecitabine plus irinotecan compared with irinotecan alone as treatment of patients with advanced gallbladder cancer.

TARGETED ONCOLOGY: What is the rationale for using this regimen?

Ramaswamy: There is limited evidence for second-line treatment in advanced biliary tract cancer and gallbladder cancers also. Available evidence shows that there is some benefit of chemotherapy, but we don't know what is the correct regimen to use, so we used capecitabine plus irinotecan because primarily a majority of these patients have already got platinum in the first-line setting. We wanted to use a non-cross resistance regimen. We published data from our institution, so that is why we used this particular combination in the trial.

TARGETED ONCOLOGY: Has this regimen shown efficacy in the space before?

Ramaswamy: We have used capecitabine and irinotecan versus irinotecan; there is phase 2 single-arm data, and there is data for FOLFIRI. Since capecitabine is an oral congener, we thought it would be convenient to use that combination. We published retrospective data showing that it is feasible with good outcomes.

TARGETED ONCOLOGY: Could you go over the methods of design and the patient population included in this study?

Ramaswamy: This was a randomized phase 2 prospective study. We based our statistical assumptions on a 6-month OS of 55% with irinotecan, which is based on the single-arm phase 2 data, and 70% with capecitabine, which is based on our own retrospective data.

They were all patients with advanced gallbladder cancer who had previously received gemcitabine/cisplatin, gemcitabine...platinum, or gemcitabine alone as first-line therapy and had progressed over that. They had to have an ECOG performance status of 0 to 1 with adequate endocrine function. These were the basic inclusion criteria for our study.

TARGETED ONCOLOGY: What are the findings from this study?

Ramaswamy: We completed accrual in January and had an immediate follow-up of approximately 5 and a half months. The primary end point of this study, which is OS, the CAPIRI combination did not achieve the primary endpoint of superior OS compared to irinotecan. In fact, the 2 arms had almost identical median OS rates at 5.2 months and 6.2 months [respectively]. This suggests that monotherapy is probably as efficacious as a doublet in the space of second-line treatment for advanced gallbladder cancers.

Besides OS, considering this is a fragile cohort of patients, we got a look at quality of life and side effects as well. In terms of quality of life, again, there was no difference between the 2 arms, and of course, the doublet arm required many more dose modifications. Almost 25% of patients required dose modifications, while only 9% required this with monotherapy. For all this put together in terms of primary end point, as well as other end points, it is likely monotherapy is as good as tablet based on this face to study.

TARGETED ONCOLOGY: Could you elaborate on some of the strengths and weaknesses of this study?

Ramaswamy: One of the good things is that a lot a large part of data in gallbladder cancers does not come from high prevalence regions. India is a region of high prevalence, especially the Indo-gangetic belt, and that is a major strength. It is representative of what happens with advanced gallbladder cancers.

Second, it was a collaborative study with another large national cancer institute, so this was a study with the collaboration of 2 of the largest centers in the country. It is representative of how gallbladder cancers are seen in this country. In a lot of tumors, like colorectal cancers or breast cancers, it is often seen in the advanced setting, that monotherapy is probably as good as combination [therapy]. This is a step in the same direction. Monotherapy is probably as good as combination chemotherapy.

It's a phase 2 design, and we had only gallbladder cancers, so the results cannot be directly extrapolated to all biliary tract cancers, and it would have been great if we had looked at biomarkers, but that was not part of the study.

TARGETED ONCOLOGY: What unanswered questions remain in this space?

Ramaswamy: There are a number of unanswered questions with respect to advanced biliary tract cancers because it is not 1 of the common cancers or even not 1 of the more common gastrointestinal cancers, except in certain geographical areas. Other than the fact that we've had 1 randomized study in the first-line setting, and that is 1-decade old. There has not been any groundbreaking work in this space, although, over the last 2 years, we are finding more and more data and studies for the same. For example, in cholangiocarcinoma, we are now beginning to identify targets for which drugs are being found and they seem to be doing better in terms of comparisons to chemotherapy. There are targets like FGFR rearrangements in cholangiocarcinoma, IDH mutations. There's also some data for HER2 in biliary tract cancers, but because of the lack of gallbladder cancer is very common, it somehow lags behind the other components of biliary tract cancers in terms of research.

TARGETED ONCOLOGY: What is your take home message?

Ramaswamy: The main takeaway is that gallbladder cancers have, with currently available treatment options, slightly limited survival as compared to other gastrointestinal cancers. Within those confines they are already a fragile group of patients because of the degree of liver metastases pre-treatment, prior history of obstructive jaundice, so, any treatment option in these cancers may not have great efficacy, but also should be safe and easily usable. This study is 1 such in that we've identified monotherapy as giving moderately efficacious survival, but being very safe in terms of being able to use the treatment.