Dabrafenib Plus Trametinib Phase 2 Data Inspire Hope for Targeted Therapy in Biliary Tract Cancer

Vivek Subbiah, MD

The addition of BRAF inhibitor dabrafenib (Tafinlar) to MEK inhibitor trametinib (Mekinist) induced an overall response rate (ORR) of 51% (95% CI 36–67) as treatment of patients with BRAF V600E-mutant cholangiocarcinoma, according to findings from the phase 2 ROAR study published in The Lancet. This prospective study demonstrated that the targeted therapy combination could serve as a much-needed treatment for this patient population with treatment-resistant advanced disease.

The ongoing open-label multicenter trial (NCT02034110), led by Vivek Subbiah, MD, of the University of Texas MD Anderson Cancer Center, enrolled 43 patients to the bile duct cohort who had all received at least 1 prior line of therapy and harbored a BRAF V600E mutation. The median overall survival (OS) of patients treated with chemotherapy for advanced disease is less than 1 year, which demonstrates a significant unmet need for new and effective therapies.

The median duration of response (DOR) was 8.7 months with the combination regimen, and 7 patients had an ongoing response lasting more than 12 months. The median progression-free survival (PFS) was 9.1 months, and the median OS was 13.5 months. Overall, 56.4% of patients were still alive at 12 months, and 35.8% of patients remained alive at 24 months.

At least 1 adverse event (AE) was observed in all patients, and the most common AEs included fever, nausea, vomiting, diarrhea, and fatigue. Grade 3/4 AEs were experienced by 24 (56%) patients, the most common being an increase in gamma-glutamyltransferase, which is an enzyme found in liver and bile ducts. However, the study authors noted these side effects were consistent with those seen in previous clinical trials for this combination in other cancer types.

The combination of dabrafenib and trametinib has been successful in other cancer types, particularly as treatment of patients with melanoma, non – small cell lung cancer (NSCLC), and anaplastic thyroid cancer. The combination was first approved by the FDA for the treatment of patients with advanced or metastatic BRAF V600-mutant NSCLC in June 2017 and then was approved in April 2018 for the adjuvant treatment of patients with BRAF V600E or V600K-positive stage III melanoma after complete resection. Following approval in May 2018, patients with unresectable or metastatic BRAF V600E-positive anaplastic thyroid cancer can be treated with dabrafenib and trametinib.

In an interview with Targeted Oncology, Subbiah, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discussed the positive findings from the phase 2 ROAR clinical trial, which evaluated the targeted therapy combination of dabrafenib and trametinib as treatment of patients with cholangiocarcinoma harboring a BRAF V600E mutation.

TARGETED ONCOLOGY: Could you provide an overview of the current treatment landscape for patients with cholangiocarcinoma?

Subbiah: Biliary tract cancer is an aggressive disease with poor clinical outcomes. Most patients with this malignant disease at diagnosis are at an advanced stage and the 5-year survival is 18%. The standard of care for patients with biliary tract cancer includes resection for most patients with surgical disease, and chemotherapy, which is basically gemcitabine and cisplatin. In advanced disease, this chemotherapy is associated with a PFS of 8 months, and a median OS of 12 months. Again, as we know, biliary tract cancers include intrahepatic cholangiocarcinoma, which is referred to as a bile duct cancer, the extra hepatic cholangiocarcinoma and gallbladder cancers.

The recurrence rate prognosis and genomic landscape differ depending upon the tumor location. As we sequence these patients and as clinical NGS is becoming more available, this rare disease has become a poster child for precision oncology. Genetic mutations including the IDH1 aberration, FGFR2 fusions, HER2 genes, and BRAF V600E alterations have been identified in patients with biliary tract cancer. This creates a possibility of targeted treatments for this population. So again, in the last year alone, the treatment landscape has changed for this disease, especially with these tumors harboring these genetic alterations.

TARGETED ONCOLOGY: How common is the BRAF mutation in patients with cholangiocarcinoma?

Subbiah: Mutations in the BRAF gene have been reported in approximately 5% to 7% of biliary tumors, and it could be enriched in the biliary tract cancer. What we know so far is patients with BRAF V600E-mutated intrahepatic cholangiocarcinoma have a higher tumor stage at time of resection, a greater likelihood of lymph node involvement, and unfortunately, worse long-term survival than patients without the BRAF mutation.

TARGETED ONCOLOGY: What was the rationale for evaluating this combination in patients with BRAF-mutant biliary tract cancer?

Subbiah: We have demonstrated in previous trials with single-agent BRAF inhibitors that they have shown promising activity in cholangiocarcinoma. In fact, the vemurafenib basket study was 1 of the first studies that showed that BRAF inhibition can be used in cholangiocarcinoma. Although we showed early activity, we also, with monotherapy BRAF inhibitors, we get toxicity including secondary skin cancer, and again, the DOR prompted us to evaluate better treatments. In addition, pembrolizumab (Keytruda) has also been used in biliary tract cancers unfortunately, that the microsatellite instability (MSI)-high patients represent only a small set of biliary tract cancers.

We needed a better treatment option for this population, and the combination of a BRAF plus MEK inhibitor is now standard of care for metastatic adjuvant melanoma, for NSCLC and anaplastic thyroid cancer. The combination of BRAF plus MEK inhibitor that shown us that the risk of AEs, including the cutaneous squamous cell cancers, are reduced. Interestingly, from the melanoma, lung cancer, and anaplastic thyroid cancer, we know that it shows an overall increased survival and also PFS when compared to just BRAF inhibitor monotherapy. Our early publications with a few anecdotal case reports have used combination treatment with dabrafenib and trametinib in biliary tract cancer that have shown manageable tolerability and favorable results when compared with single-agent BRAF treatment.

These all form evidence that a combination treatment is warranted in this specific subset of patients. Based on this, we design this oncology agnostic research plan, which is a role basket study. This was designed to assess the activity and safety of dabrafenib and trametinib in patients will be BRAF V600E-mutated cancers, including rare cancers like the anaplastic thyroid cancer, biliary tract cancer, gastrointestinal stromal tumor, adenocarcinoma of the small intestine, hairy cell leukemia, low-grade glioma, high-grade glioma, and multiple myeloma, among others. In this cohort, we report the results for patients with BRAF V600E-mutated biliary tract cancer. To our knowledge, this is the first prospective analysis of a cohort of patients with BRAF V600E alterations in biliary tract cancer treated with a combination of a BRAF and a MEK inhibitor.

TARGETED ONCOLOGY: What were the findings from this study?

Subbiah: As you know, this study is a part of an ongoing phase 2 open-label single-arm multicenter rare oncology agnostic basket study, the ROAR basket study. Patients were eligible for the biliary tract cohort if they were older than 18 and had BRAF V600E-mutated unresectable, metastatic and locally advanced or recurrent biliary tract cancer who had received previous systemic treatments. All these patients were treated with oral dabrafenib 150 mg twice daily and trametinib 2 mg once a day until disease progression. The primary end point was the ORR, which was determined by RESIST version 1.1, which is the response evaluation criteria in solid tumors in the intent-to-treat population, and the intent-to-treat evaluable population, which comprised of all patients, regardless of receiving treatment who were evaluable or not.

These results are based on an interim analysis. Between March 2014 and July 2018, 43 patients with BRAFV600E-mutated biliary tract cancer were enrolled to the study and were deemed evaluable.

The median follow-up was 10 months, and investigator-assessed overall response was achieved in 51% of the 43 patients, which is 22 of the 43 patients. An independent reviewer assessment assessed an ORR of 47%, which is 20 or 43 patients. The most common AEs grade 3 or worse was an increase in gamma glutamyltransferase in 5 patients, and 17 patients had serious AEs while 9 had been treatment-related AEs. The most frequent event was pyrexia. Again, no treatment-related deaths were reported. This is a combination that has been widely used in melanoma, recently in NSCLC, and anaplastic thyroid cancer. The AEs were not new when we compare that with the melanoma, lung, and thyroid database. Given that these patients have been relapsed/refractory from multiple lines of therapy, this presents them with a manageable safety profile.

TARGETED ONCOLOGY: How did these findings compare with other trials evaluating target therapies in this space?

Subbiah: When this trial was designed, our standard of care testing for next-generation was not standard of care, and right now, as I said earlier, cholangiocarcinoma has become a poster child for precision oncology. Recently, an FGFR inhibitor was approved for FGFR fusion-positive cholangiocarcinoma, and we've seen the activity of IDH1 inhibitors as well. There have been publications of HER2 targeted therapies in this space. These cholangiocarcinomas also benefit from tissue agnostic histology-independent approvals, like the MMR, MSI-high, NTRK, and the recent TMB. However, these are subsets of patients, and this study reports the BRAF V600-mutated cohort.

Regarding the magnitude of benefit, I think this compares favorably well to all the targeted therapies in this space. Overall when you see this response rate, I think this compares favorably well with other targeted therapies, like FGFR2 or IDH1, in cholangiocarcinoma. Interestingly, the first study that evaluated an FGR inhibitor was in patients with FGFR-altered cholangiocarcinoma. The response rate was 15%, and the median PFS was 6 months. In another study with IDH1-mutated cholangiocarcinoma, the ORR was 2%, and the median PFS was three months in patients with advanced biliary tract cancer, again with a similar MEK inhibitor selumetinib, the response rate was [also low], and the median PFS was 4 months. In a study combining a VEGF inhibitor in combination with trametinib in the advanced biliary cancer, the response rate was 5%. If you compare that with immunotherapy, like pembrolizumab, the ORR was 6% with a median PFS of 2 months. With nivolumab, the ORR was 20% with a PFS of 3 months. When you compare all these studies, the magnitude of benefit in terms of ORR of over 50% is favorable in this cohort.

We need to be thoughtful that these patients were relapsed or refractory have progressed from our standard lines of therapy. It would be interesting to see how the combination would work in earlier lines of therapy. If we start diagnosing these patients as a molecule of subtype, and if we can give this combination upfront when we compare that with chemotherapy, I think it would be interesting to see how these responses compare with upfront standard therapies.

TARGETED ONCOLOGY: How often should genomic testing be conducted in this patient population?

Subbiah: We need universal genomic testing. Again, we need not just for BRAF V600 alteration, as I mentioned, bile cancers is a disease that unless we test these patients, we would not know early if this patient's tumor harbors an actionable alteration. We have to test these patients upfront and especially these rate cholangiocarcinoma patients because we have the treatment options for them to benefit, not just for BRAFV600E alterations; we need to test these patients with a broad-based comprehensive panel that includes fusions, so that if a patient harbors BRAF V600E alteration can get a BRAF plus MEK combination therapy. The patient who harbors an FGFR2 fusion can receive an FGFR inhibitor, IDH inhibitor, a HER2 inhibitor, or are maybe candidates for immunotherapy, especially if they are TMB high or MSI high. If they have an NTRK fusion, they could also get the NTRK inhibitors. Most recently, they have a RET fusion, they can even be enrolled on 1 of the RET inhibitor targeted therapies, ao again, universal genomic testing is needed to win the war against cancer.

TARGETED ONCOLOGY: What are the implications of these findings?

Subbiah: We know now that this combination is very active in cholangiocarcinoma. What we've shown that from this study is that it supports the combination of dabrafenib and trametinib as an option for patients with refractory BRAF V600E-mutated biliary tract cancer, a treatment-resistant population, for whom, to our knowledge, there is no effective treatment available.

The clinical benefit, based on this study, supports the use of this combination therapy as a treatment option for patients with BRAF V600E-mutated cholangiocarcinoma, and again, routine testing for BRAF V600E mutations should be considered in all patients with biliary tract cancer.

TARGETED ONCOLOGY: Are there any next steps planned for this research?

Subbiah: Biomarker findings need to be validated in a larger study, and if it essentially should continue to seek that, we need to test these patients earlier in the disease course. Once we offer these treatments, we need to find what is the mechanism of resistance in these patients. Continued research in this field earlier in the disease course would be the next steps.

TARGETED ONCOLOGY: What do you hope oncologists take away from all of this?

Subbiah: For an oncologist, especially treating bile disease, my personal opinion is that universal genomic testing should be the message to win the war against cancer. Again, cancer is a genetic disease, and before testing a patient, we will not know if their tumor harbors a specific alteration. The more we test, the more we find. In these COVID-19 times, we know that unless we test, we cannot find the disease, so genomic testing should be a part of diagnosis, especially in these rare diseases. If you are serious in efforts to winning the war against cancer, I strongly believe, in my personal opinion, that we need to do universal comprehensive genomic testing in all these patients.

_References

_{Targeted therapy combination effective for patients with advanced cholangiocarcinoma and BRAF mutations. News Release. August 17, 2020. Accessed August 19, 2020. https://bit.ly/327LrjZ}

_{Subbiah V, Lassen U, Elez E, et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial. Lancet. doi:10.1016/S1470-2045(20)30321-1}