Expert Expands on Recent Advances With Actionable Alterations Spanning GI Cancers

Nathan Bahary, MD, PhD

The emergence of actionable alterations has allowed the field of gastrointestinal (GI) cancer to shift away from traditional chemotherapy approaches to the adoption of more personalized treatment approaches, according to Nathan Bahary, MD, PhD, who added that these targeted therapies are now being explored in combination with different immunotherapies to elicit stronger, more durable responses.

“Targeted therapies have helped different subsets of patients, whether that is a larger subset of patients with intrahepatic cholangiocarcinoma or a smaller subset of those with pancreatic cancer. However, in mismatch repair—deficient [dMMR] colorectal cancer [CRC], several patients still do not respond,” Bahary explained. “In an attempt to help them achieve better and longer-lasting responses, ongoing research efforts are now focused on integrating the use of immunotherapies with targeted therapies. This [approach] has previously shown great promise in hepatocellular carcinoma [HCC] and other GI tumors.”

In an interview with OncLive^® during the 2020 Institutional Perspectives in Cancer webinar on Precision Medicine, Bahary, an associate professor at the University of Pittsburgh School of Medicine, as well as a medical oncologist and hematologist at the University of Pittsburgh Medical Center​ Hillman Cancer Center, discussed the importance of seeking targetable alterations in GI cancers, as well as recent advancements in the space. 

OncLive^®: Could you highlight the prevalence of FGFR2 translocations in patients with biliary cancer? How are these patients treated?

Bahary: Biliary tract cancers are one of the most recalcitrant tumors to treat. We have seen incremental progress with chemotherapy; however, targeted treatments, including FGFR2 inhibitors, truly changed the landscape. FGFR2 translocations are observed in about one-fourth to one-third of patients with intrahepatic cholangiocarcinoma. 

Pemigatinib [Pemazyre] is a selective, potent, oral inhibitor of FGFR1/2/3. An open-label, phase 2 study of pemigatinib in patients who harbored FGFR2 fusions was recently published in Lancet Oncology. Interestingly, [results showed] 3 complete responses [CRs] and about 50 patients achieved stable disease. Moreover, about one-third of patients demonstrated partial responses and only 16 out of 107 patients progressed. Many of these responses were durable, which led to the recent approval of pemigatinib for the treatment of patients with FGFR2 translocated, previously treated, unresectable, locally advanced, or metastatic cholangiocarcinoma.

Could you expand on the role of ivosidenib (Tibsovo) in patients with biliary cancer who harbor IDH1 mutations? 

IDH1 mutations occur in about 10% to 13% of patients with intrahepatic cholangiocarcinoma. Ivosidenib was previously approved for the treatment of patients with acute myeloid leukemia who harbored IDH1 mutations. 

In another study, a significant progression-free survival (PFS) advantage [was reported], as well as a durable response. This trial, opposed to earlier trials, allowed for crossover. We didn't see an overall survival [OS] benefit, but I'm certain there will be one, given the response and durability. 

What is the prevalence of the BRAF V600E mutation in patients with intrahepatic cholangiocarcinoma? How did this targetable mutation make its way into the space? 

The BRAF V600E mutation made its mark in melanoma, where the combination of a BRAF and a MEK inhibitor is the standard of care for BRAF V600E-mutated disease. Notably, the same mutation is seen in about 1% to 2% of patients with intrahepatic cholangiocarcinoma. 

However, a combination of dabrafenib [Tafinlar] and trametinib [Mekinist], which is BRAF/MEK inhibitor combination, was evaluated in the ROAR study. The overall response rate was about 50% and nearly all patients achieved some clinical benefit, such as stable disease, partial response, and CR. For a small subset of patients, durable responses were certainly observed. 

Are there any other key targetable alterations that you wanted to highlight?

ROS1 and ALK translocations are also found in biliary cancers. HER2 overexpression is one that's very intriguing because it has mostly been seen in extrahepatic cholangiocarcinoma. As many as 10% of patients with extrahepatic cholangiocarcinoma have HER2 overexpression.

I've also seen several patients with extrahepatic cholangiocarcinoma who derived a remarkable benefit from trastuzumab [Herceptin]. Of course, looking forward, we must determine whether we should use combinations similar to those in breast cancer. 

With regard to pancreatic cancer, what are some of the targetable alterations that have emerged and how do you approach testing for them?

In terms of somatic mutations, KRAS is seen in about 90% of patients with pancreatic cancer; this is usually what marks the disease, but it’s also seen in several other tumor types as well. 

We’re now noticing that a number of hereditary pancreatic cancers will turn up primarily within the BRCA1/2 and PALB2 realm; however, we also see recurring ATM [alterations] and mutations in the CHECK1 gene, as well.

Recently, a wonderful multicenter study that enrolled about 300 patients found a number of germline mutations that can be used to help prognosticate, assist patients with familial issues, and even [inform treatment].

In this large study, we looked at patients with pancreatic ductal adenocarcinoma [PDAC] who harbored somatic mutations. We uncovered that about 12% of the patients with PDAC did not harbor KRAS mutations. At least 30% to 40% of those patients had recurring RAS and MEK [mutations], along with [alterations in] other pathways. 

At this point in time, we feel it's important to not only utilize next-generation sequencing, but also germline testing in pancreatic cancer.

Could you shed light on the growing role of PARP inhibitors in pancreatic cancer?

It’s been known for a long time that BRCA-mutated tumors, including pancreas tumors, are particularly susceptible to drugs such as cisplatin and mitomycin, which will crosslink DNA and impair their repair, along with BRCA mutations.

PARP inhibitors have been well defined in treating patients with similarly mutated breast and ovarian cancers. Recently, the POLO trial investigated the use of maintenance olaparib [Lynparza] in germline BRCA2-mutated pancreatic cancer. 

It's been known for some time that BRCA-mutated tumors are more susceptible to agents that can inhibit DNA repair, and BRCA-mutated tumors are particularly sensitive to DNA crosslinking agents such as cisplatin and mitomycin. PARP inhibitors have been well described in treating patients with similarly mutated breast and ovarian cancers.

In the POLO trial, patients who had a response to cisplatin or oxaliplatin did not progress on therapy. There also appeared to be a PFS benefit for these patients. 

Interestingly, there's some sort of cross resistance that goes on. From earlier studies, if [a patient is] resistant to [platinum-based chemotherapy], chances are that they will be resistant to olaparib, too. Even so, this has made a big impact on our patients who've had a wonderful response to cisplatin, irinotecan, or any other chemotherapy they received. In my own practice, we’ve had patients on olaparib who maintained wonderful responses for over 1 year, without disease progression. 

What options are available to treat patients with BRAF-mutated CRC?

Until recently, the prognosis of BRAF-mutated CRC was incredibly poor. The median OS was around 26 months to 30 months and, for non–BRAF-mutated disease, it was only about 11 to 14 months. As such, BRAF/MEK combinations were explored; although, [these regimens] didn't result in the same durable responses that we saw in melanoma. 

However, the updated results from the BEACON trial, which were presented during the 2020 ASCO Virtual Scientific Program, demonstrated a dramatic improvement in tumor response and OS for patients who were treated with the BRAF inhibitor encorafenib [Braftovi], the MEK inhibitor binimetinib [Mektovi], and the EGFR inhibitor cetuximab [Erbitux] versus standard chemotherapy. 

No benefit was seen with the BRAF and MEK inhibitors but the BRAF and EGFR inhibitor alone did seem to provide patients with a survival benefit. 

In your own practice, how do you treat patients with dMMR CRC? 

dMMR is a very interesting entity within CRC and is only observed in about 15% of patients; about 12% of those are going to be somatic and only 3% are germline, which refers to Lynch syndrome. You must determine whether patients have Lynch syndrome, because it puts them at risk for uterine, ovarian, stomach, and bowel cancers; it also has important implications for family members. 

Somatic activity loss, which is much more common, is usually caused by hypermethylation of the MLH1 promoter. However, in either case, those tumors that have dMMR actually do better than those that do not harbor dMMR.

Next, there is adjuvant therapy. If we remove an early-stage tumor, studies have shown that the use of fluoropyrimidine is actually harmful to patients. 

Moving to the metastatic setting, it’s also known that patients have a better OS. But previously, multiple studies have shown that the use of a checkpoint inhibitor in the second-line setting actually has a very high response rate, as well as a high durability rate.

The most recent data, which were also presented during the 2020 ASCO Virtual Scientific Program, came from a randomized study and showed that pembrolizumab [Keytruda] alone was superior to standard-of-care chemotherapy in the first-line setting. A large PFS and durability difference [was observed] compared with standard chemotherapy. The patients did very well, so this should be a new standard of care. 

What does the future look like? Are any novel therapies currently under exploration?

Several trials were presented during the 2020 ESMO Virtual Congress; these efforts evaluated the utility of immunotherapy in gastric and GEJ cancers. Although this is going to be an interesting [area of research], all these therapies are still under exploration. 

Immunotherapy and targeted therapy combinations in HCC, as well as immunotherapies in the esophageal cancer space are also currently under exploration. More information is to come.