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Mark Yarchoan, MD, lays out the evolution of drug development in biliary tract cancer, discusses the findings from the TOPAZ-1 trial, and shares the positive future direction of immunotherapy in this disease.
The addition of durvalumab (Imfinzi) to gemcitabine and cisplatin elicited a modest yet durable survival benefit in biliary tract cancer, according to Mark Yarchoan, MD, who added that the development of additional treatments in this disease are dependent on innovations with immunotherapy.
On September 2, 2022, the FDA approved durvalumab in combination with gemcitabine and cisplatin in adult patients with locally advanced or metastatic biliary tract cancers.1 The approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235), where the triplet improved median overall survival (OS) at 12.8 months (95% CI, 11.1-14.0) compared with 11.5 months (95% CI, 10.1-12.5) with chemotherapy alone (HR, 0.80; 95% CI, 0.66-0.97; P =.021).
“[Gemcitabine, cisplatin, and durvalumab] will become a new standard of care [SOC] option for many patients with advanced-stage disease,” Yarchoan said in an interview with OncLive®.
In the interview, Yarchoan, an associate professor of oncology and co-leader of the Liver Cancer Multidisciplinary Clinic at Johns Hopkins Medicine, laid out the evolution of drug development in biliary tract cancer, discussed the findings from the TOPAZ-1 trial, and shared the positive future direction of immunotherapy in this disease.
Yarchoan: Biliary tract cancer is unfortunately a treatment-resistant tumor type. It’s an aggressive cancer. The median survival for patients with advanced-stage disease is about a year. Unfortunately, most patients with earlier-stage disease often relapse shortly after surgery. This is a cancer that needs a lot of help and new therapies.
One of the challenges is one we share with many other cancers, which is that this is a rare cancer, and patients are geographically split apart all over the country, which, in the past, has made it difficult to accrue a large number of patients to large, randomized phase 3 trials. Until recently, most of the drugs we had for biliary tract cancer had been borrowed from other more common tumor types.
That being said, [patients with biliary tract cancer have] recently been the beneficiaries of the development of tumor-agnostic drug approvals. In the past couple of years, there have been tumor-agnostic approvals of pembrolizumab [Keytruda], NTRK inhibitors, and BRAF inhibitors, most recently with trametinib [Mekinist] plus dabrafenib [Tafinlar]. These drugs are clearly active in cholangiocarcinoma. There are always patients with cholangiocarcinoma in these tumor-agnostic trials, and they tend to respond. That has been incredibly helpful for our field.
[The TOPAZ-1 trial showed that] the combination of gemcitabine, cisplatin, and durvalumab was superior to gemcitabine and cisplatin alone in patients with advanced biliary tract cancer. This was a global study.
The added benefit of durvalumab was relatively modest, even though TOPAZ-1 was a positive study. The median OS was prolonged by only about one month, but progression-free survival [PFS] and response rates were also prolonged with the addition of durvalumab.
The combination was well tolerated, and immune-related adverse effects were infrequent with durvalumab, so [safety will likely not hinder the] adoption [of this combination].
[However], there are patients who I wouldn’t offer the combination to. We have data from a phase 2 trial [NCT02392637] showing that gemcitabine, cisplatin, and nab-paclitaxel [Abraxane] is a highly active triplet, and that combination is currently [being investigated] in a phase 3 study [NCT03768414] vs gemcitabine plus cisplatin. Even without phase 3 data, [this combination is] something we’ve adopted [at Johns Hopkins] for patients with locally advanced disease or borderline resectable disease, where the primary goal is tumor reduction. It’s something that I would use, even though we only have phase 2 data, for patients who need a response, patients with extensive symptomatic disease [who need quick tumor debulking].
There’s also an ongoing phase 3 study of gemcitabine plus cisplatin and pembrolizumab, [the KEYNOTE-966 trial (NCT04003636)], that should read out soon. That study is similar to the TOPAZ-1 study, but there is a key difference in the design. In the [TOPAZ-1] study, patients received 6 months of gemcitabine plus cisplatin and then continued with durvalumab monotherapy. In the ongoing [KEYNOTE-966] study, patients are receiving gemcitabine, cisplatin, and pembrolizumab, and then continuing gemcitabine as a maintenance therapy with or without pembrolizumab.
If both studies are positive, that will suggest that immune checkpoint inhibitors are truly a new SOC in the frontline. If the KEYNOTE-966 study is negative, [then it may be possible that] the TOPAZ-1 study was positive because it did not include a maintenance therapy, as it was randomized against placebo in the maintenance setting. The KEYNOTE-966 study is going to be important for determining how helpful checkpoint inhibitors are in the frontline.
The excitement of immunotherapy has always been that the responses are deep and durable, much more so than other treatment modalities. In the TOPAZ-1 study with durvalumab, we saw that separation between the [OS] curves increases over time, and there appears to be a tail at the end of the follow-up period where the patients [who received durvalumab] appear to be doing significantly better. That’s why many of us would adopt this as a SOC in the frontline setting, even if the median OS is not much different between the durvalumab-containing arm and the placebo arm.
In terms of biomarkers, the contribution of durvalumab appeared to be relatively similar across anatomic subsets of biliary tract cancer. [It appeared to have a benefit] in both PD-L1–positive and PD-L1–negative patients, so we wouldn’t use PD-L1 to select patients.
TOPAZ-1 was an all-comers study that included patients across different molecular subtypes, and it included patients with or without mismatch repair deficiency. We’re all eagerly awaiting a subgroup analysis that will look at the benefit of durvalumab across the different molecular subsets of cholangiocarcinoma.
This is a heterogeneous disease. We have patients with FGFR fusions who are completely clinically and pathologically different from patients with TP53 mutations and KRAS mutations who tend to have more extrahepatic disease. It will be interesting to see if durvalumab appears to provide a benefit across the major molecular subsets of this cancer.
I suspect that [the TOPAZ-1 regimen] will be widely adopted in clinical practice, because TOPAZ-1 was a randomized phase 3 study that clearly showed OS, PFS, and overall response rate [ORR] benefit without much toxicity.
It’s a positive study, but even if durvalumab becomes widely adopted, it’s important to remember that our outcomes still lag behind many other tumor types. The ORR was only 26.7% with the triplet, and the benefit over gemcitabine plus cisplatin was quite modest. [We should not] become complacent. We need to do better for these patients, and I hope that even if this [triplet] is widely adopted, we continue to look at new frontline regimens that do even better.
Cholangiocarcinoma is generally an immune-resistant tumor type. The response rates with PD-1 or PD-L1 monotherapy in the largest studies that have been done have generally ranged from about 5% to 10%. Unfortunately, even though there is activity, it is modest with these agents.
We need a better understanding of mechanisms of resistance to immunotherapy in cholangiocarcinoma and new rational strategies to make these tumors more amenable to immunotherapy. That’s where my research is focused as a laboratory-based translational researcher. We’re excited about exploring novel strategies that could eventually move into the frontline setting to make these tumors respond better.
I’m honored to be part of a clinical study run through the Cancer Therapy Evaluation Program, which is part of the National Cancer Institute, for which we’re a lead site. My colleague, Nilofer Saba Azad, MD, [of Johns Hopkins Medicine], is the overall principal investigator, and my friend and colleague Gregory B. Lesinski, MPH, PhD, [of Winship Cancer Institute of Emory University], is an important laboratory partner for this study, which is looking at a novel immunotherapy combination of atezolizumab [Tecentriq] plus a CD27 agonist plus a MEK inhibitor.
We previously enrolled a randomized study of a PD-L1 inhibitor with or without the MEK inhibitor cobimetinib [Cotellic]. This was technically a positive study for the doublet, as there was a modest PFS benefit with the dual therapy vs single-agent therapy. However, the activity was not enough to get overly excited about, as the response rate was in the single digits for the doublet.
In our lab research, we focused on trying to understand why the doublet didn’t work, because it looked promising in mouse studies. We found that MEK inhibitors have a complicated immune effect. They make the tumors more amenable to immunotherapy, but they also have a negative effect of dampening T-cell activation, and that is both a good thing and a bad thing for immunotherapy. We found that adding an immune-activating agent like a CD27 inhibitor could overcome the detrimental effects of MEK inhibitors in T-cell activation. This is a totally novel strategy that we’re testing now in a phase 2 clinical trial, and we look forward to seeing if there’s activity for the triplet.
We want to better understand the immune microenvironment in cholangiocarcinoma. My colleague, Marina Baretti, MD, [of Johns Hopkins Medicine], is leading a perioperative study investigating gemcitabine, cisplatin, and pembrolizumab, seeking to understand the mechanisms of response and immune resistance to the current strategy of triplet therapy in this cancer.
Finally, many of us are working to understand how different DNA mutations in cholangiocarcinoma affect the tumor immune microenvironment. How do FGFR2 fusions or rearrangements affect the microenvironment? How do IDH1/2 mutations affect the tumor microenvironment? If we can understand the immune microenvironment in these biologically distinct groups of cholangiocarcinoma, then we can develop more personalized treatments and combination strategies. This is something that is ongoing.