Cholangiocarcinoma Paradigm Expands for Select Patients With the Disease

Susan Pandya, MD

Ivosidenib tablets (Tibsovo), were recently approved by the FDA for the treatment of IDH1-mutated cholangiocarcinoma, as detected by an FDA-approved test. While the approval is a step in the right direction, select subgroups of patients with cholangiocarcinoma require alternative options.

According to Susan Pandya, MD, the vice president of clinical development at Servier, prior to the approval of ivosidenib, the mainstay of treatment for this disease has been chemotherapy. Despite IDH1 mutations occurring in 20% of patients with cholangiocarcinoma, no therapy was approved to target that mutation specifically until the approval of ivosidenib.

Results from the phase 3 ClarIDHy trial (NCT02989857), which served as basis for the approval, showed that ivosidenib tablets improved the median progression-free survival compared with placebo (HR, 0.37; 95% CI, 0.25, 0.54], P <.001). The treatment also reduced the risk of death by 21% compared with placebo. The median overall survival in the ivosidenib treatment arm was 10.3 months compared with 7.5 months (HR, 0.79; 95% CI, 0.56-1.12; 1-sided P =.093).

Ivosidenib is fairly well tolerated, according to Pandya. The most common adverse events include low-grade fatigue, nausea, vomiting, and diarrhea.

In an interview with Targeted Oncology^TM, Pandya discussed the impact ivosidenib has had on the cholangiocarcinoma space, along with remaining unmet clinical needs.

TARGETED ONCOLOGY: Can you explain the mechanism of action for ivosidenib? How does it treat cholangiocarcinoma?

PANDYA: Ivosidenib is an oral targeted therapy and it specifically targets the mutant IDH1 enzyme. And in a variety of different cancers, IDH1 mutations exists, and specifically in cholangiocarcinoma, we see IDHmutations in about 20% of patients. And the way the drug works is that it targets the mutants, in a selected potent manner and thereby reduces an oncometabolite associated with mutant IDH1 disease known as 2-hydroxyglutarate. So, when we suppress 2-hydroxyglutarate, we believe we are changing the epigenetic wiring of the tumor to help slow the progression of the disease and hopefully slow down the cancers ability to continue to spread. When we developed ivosidenib, that's really where we started to learn more about the biology of targeting IDH mutations.

For a long time now, cholangiocarcinoma has remained a disease with a huge unmet need with very few efforts to really advance progress for patients. The mainstay of treatment for patients in the advanced or metastatic setting has primarily been chemotherapy regimens that were developed over 10 years ago. Very few targeted therapies exist for patients with cholangiocarcinoma. And because IDH1 mutations are considered to be one of the most common genetic abnormalities associated with the disease, the unmet need is being fulfilled substantially by the approval of ivosidenib in patients with IDH1 mutated cholangiocarcinoma. So, we do find that this is a type of disease is very difficult to treat with conventional therapies. This novel approach provides a new way of targeting the tumor in a very different mechanistic way compared to how we think about cytotoxic chemotherapy. And you see that not only through the efficacy data that we presented, but also the safety profile, and that the drug is very well tolerated and again, has a unique profile compared to what you typically would see with chemotherapy. So, we are excited to offer an oral non-cytotoxic targeted therapy option for patients where typically their disease would have only been amenable to chemotherapy-based treatments. We view this as fulfilling an unmet need, but also substantial progress for patients.

What are some of the toxicities associated with ivosidenib?

So, most of the adverse events are low grade in nature, meaning they're manageable, and they consist mostly of fatigue, nausea, vomiting, diarrhea.

Which patients are ideal candidates for ivosidenib?

The patient population that was enrolled in the ClarIDHy trial (NCT02989857) is really where our label sits right now. So, patients who've received previous treatment for their disease, gemcitabine/cisplatin is still considered a standard frontline chemotherapy option for newly diagnosed patients with advanced or metastatic disease. So, the ideal patient really would be somebody that's already received a chemotherapy regimen and has an identified IDH1 mutation based on FDA approved next generation sequencing panel. And that really is the ideal candidate. I think that when making these decisions for patients, patients and their clinicians need to have frank discussions about goals of care, and pick regimens that are in keeping with that, and that are tolerable and can help a patient maintain their quality of life.

Even with ivosidenib's approval, what unmet needs still exist for this patient population?

Little progress has been made. And while this represents a very big move in the right direction, and opening the doors, especially for targeted therapy approvals, more work needs to be done. So, as we are understanding the different actionable mutations in the disease, and the way by which we can consider novel combinations. I think there's an opportunity here to really understand from the biology that we've learned to date and consider combination therapy options in the earlier line setting where hopefully you can have the greatest impact for patients not only on progression free survival, but also overall survival.

This was a global effort. So, while this drug is currently approved in the United States, this was based on a global randomized phase 3 study. We had 6 different countries participating. So, you know, it just speaks to, again, the unmet need and engagement on the part of the investigator community. And of course, on the part of patients and their families. I would also add that secondary end point was inclusive of health-related quality of life.