Therapeutic Options Available for Pancreatic Cancer, HCC Lead to New Challenges

Jimmy J. Hwang, MD

An emergence of new treatment options has revitalized the outlook for patients with metastatic pancreatic cancer and advanced hepatocellular carcinoma (HCC), but the next set of unanswered questions includes the role of immunotherapy and establishing second-line standards of care, respectively, said Jimmy J. Hwang, MD.

In metastatic pancreatic cancer, patients can be treated upfront with either FOLFIRINOX or gemcitabine combined with nab-paclitaxel (Abraxane). Results of the phase III MPACT study showed that gemcitabine/nab-paclitaxel improved progression-free and overall survival (OS) compared with gemcitabine alone (HR, 0.69; 95% CI, 0.58-0.82; P <.001) in patients with metastatic pancreatic cancer with a Karnofsky performance score ≥70.¹ Median OS was 8.5 months and 6.7 months, respectively, in the combination and single-agent gemcitabine arms.

“That's the challenge with this type of disease, but the benefit we have is that there are actually choices,” said Hwang, a gastrointestinal medical oncologist at Levine Cancer Institute. “All we used to have was gemcitabine, and with that, you don't have much of a choice with a one-size-fits-all approach.”

In the HCC paradigm, recent advances have given company to sorafenib (Nexavar), which was the lone FDA-approved agent for nearly a decade. For example, in the phase III REFLECT study, lenvatinib (Lenvima) was found to be noninferior to sorafenib in terms of OS in patients with previously untreated advanced HCC.² Median OS in the lenvatinib arm was 13.6 months compared with 12.3 months for sorafenib. Based on these findings, the FDA approved lenvatinib as a frontline treatment in HCC.

Researchers are hopeful that immunotherapy will make headway in HCC, Hwang says; however, recent data with pembrolizumab (Keytruda) suggest that it may be a challenge. In November 2018, the FDA approved the PD-1 inhibitor based on the phase II KEYNOTE-224 study, a decision that was contingent on positive phase III data from KEYNOTE-240. In February 2019, the FDA announced that while pembrolizumab showed a slight improvement in OS, it was not statistically significant.

OncLive: How would you define the metastatic pancreatic cancer space?

How do you choose between the 2 frontline options?

What therapies are being explored in clinical trials that could take these options to the next level?

In an interview at the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Malignancies, Hwang shed light on updates in both metastatic pancreatic cancer and advanced HCC that have created new complexities for researchers.Hwang: With regards to FOLFIRINOX and gemcitabine/nab-paclitaxel [in the frontline setting], how do we make the decision of who gets what? Are there ways we can do better? [Second-line therapy] was something that was inconceivable a decade ago, but it's pretty clear based on recent data that there is benefit [to using it]. Therefore, similarly to frontline therapy, what should we be doing?You can make choices based on efficacy—at least what we perceive to be differences in efficacy. You can make decisions based on logistics and on your patient's functional status and comorbidities. The same is true in the second-line setting. Because there are several different potential options to select for, you can have those discussions with patients about what they value. What kinds of risks are they willing to take, based on the benefits each treatment may potentially bring to the table?As with [other solid tumors], the 2 main areas of exploration end up being immunotherapy and targeted therapy. Targeted therapy, over the course of the last few years, hasn't panned out as well as we hoped. We are always looking for new targets.

Obviously, we hope for that immunotherapy breakthrough, but we haven't quite figured out what that target is. Immunotherapy has shown enough—there are some patients where it works, and the question ends up being, “How can we do better? Is it a combination with chemotherapy? Is it a particular patient population? Is it a combination approach with targeted therapies?” We will see how that plays out over the course of time.

What are some biomarkers that researchers hoped would have promise but did not pan out?

What insight can you share on the studies with PEGPH20?

Moving on to HCC, what are the key advances you would like to mention in this field?

For better or worse, as far as targeted therapies go right now, the initial wave has failed, unfortunately. The next steps we are looking at are very early in development, and the same can be said for immunotherapy. It is well established in other cancers, but in pancreatic cancer, we are just starting to get a feel for how to use it.We will see whether or not HER2 is something that's beneficial in pancreatic cancer. We will see if there are other stromal markers that end up being beneficial. When you look at something such as erlotinib (Tarceva), obviously, studies showed that there was some benefit to it. However, they looked at all the different, usual markers with regards to EGFR and RAS, and they couldn't find anything that would establish a biomarker explaining why there's a 7% difference in OS. Clearly, some people are benefitting; it's just a question of who those people are. The answer, right now, is "Nope, we can't [figure this out]."That is always a good question. It really becomes a question of, "Let's wait for the data to turn out positive before we begin to worry too much about it." Certainly, the data that have been published so far suggest that it may be a good selection marker for patients who may benefit from therapy. One of the interesting questions that always come up with any biomarker is, "Well, just because that selects for patients who will benefit, does that mean patients who don't have this marker won't benefit?" That part, to me, is less clear. I tend to be an advocate for trying to treat patients in a broader sense and then trying to understand the patients who are benefitting subsequently. However, that is also potentially a resource-heavy development strategy.HCC is an area where we have had a lot of development over the last 3 years—in particular, recognizing the amount of the time it takes to develop some of these products. We have gone from a place where sorafenib was the only drug we could use for nearly a decade, to a time where there are alternatives in the frontline setting. As with pancreatic cancer, as we spoke about earlier, we have gone from a world where second-line treatment beyond sorafenib was nonexistent, to one where we have several agents demonstrating improvement in survival compared with supportive care alone.

The question becomes, “What is the best way to treat?” Interestingly, all of the studies were performed at the same time and now the drugs are being FDA approved around the same time. There is a lot of scrambling in deciding what is the best way of integrating these different therapies. The approvals in the second-line setting are specifically for patients treated with prior sorafenib. Therefore, if a patient is getting an initial therapy instead of sorafenib, what do we do? It's a very interesting question.

Could you speak to the anticipation surrounding the CheckMate-459 trial?

The next challenge is how to best integrate these advancements into earlier-stage disease—patients who have had ablation, resection, and chemoembolization. Should we integrate these therapies earlier? The answer is, “We don't know for all of them.” Fortunately, or not so fortunately for patients, HCC is a relatively common disease. It is not recognized as such, but it is the third-leading cause of cancer mortality worldwide. There are a lot of patients out there who need treatment.The frontline nivolumab study, CheckMate-459, is a study that we participated in at Levine Cancer Institute along with many other institutions. Patients were randomly assigned to receive the standard sorafenib versus nivolumab. It's been an interesting study, in the sense that we actually completed accrual a long time ago and we have been waiting for results for a long time. Every 3 months, they push it back. The question is, “What does that end up meaning?” Hopefully, it is a positive thing, but we'll see.

Do you believe there is still a role for pembrolizumab in this patient population?

On the other hand, everyone presumed that pembrolizumab was going to be beneficial in the second-line setting. [Recent data] suggest that it actually wasn't better than supportive care alone. Even though something looks like it's beneficial, it just reinforces that we need to do the study to find out. Nivolumab will be revolutionary in many ways if it is beneficial.There are 2 ways one could answer that. One could say the answer with, "No, there shouldn't be." Certainly, not in this setting. Pembrolizumab was approved based on response rates in a single-arm study, whereas we have 3 randomized phase III studies compared with placebo in the second-line setting, where there is a clear survival benefit. Why would one be using pembrolizumab instead of one of those agents? I would argue that it would be very difficult to support that. From that standpoint, and certainly from a public health standpoint, I would say no. Does that mean patients can't derive any benefit from it? No, it doesn't mean that, and that's why you hesitate to make any treatment decisions until you see the actual data.

Are there any combination strategies being explored with the available agents in this space?

What do you think we will have learned in this field 1 year from now?

If you go based on the single-arm phase II study, about 20% of patients benefitted [from pembrolizumab]. The question will be, “Can we identify those patients?” I won't say there will never be a role for pembrolizumab, but [right now], I'd be hard-pressed to say, "Yes, we should be using it instead of those other agents."There are absolutely studies ongoing. As one might expect, they are combinations of one of the checkpoint inhibitors with a TKI. There are combination studies of all of those flavors that are ongoing. Atezolizumab (Tecentriq) is not approved in HCC at this time, but there is an ongoing study in the frontline setting combining that drug with bevacizumab (Avastin). Certainly, the early data in limited patient populations suggest there may be benefit, but as the KEYNOTE-240 study would show, just because it looks good, doesn't mean it would be.The main thing we will hopefully learn is whether or not nivolumab is beneficial compared with sorafenib in the frontline setting. Certainly, all the signals I've heard suggest we'll have that information. If lenvatinib is a confounding problem, as it will be for some studies, nivolumab will be a much greater confounding problem. Hopefully, we will see that checkpoint inhibitors are beneficial, which is a good problem to have—advancement is never a bad thing. Beyond that, we need to learn if integrating all of these therapies earlier is beneficial. How do we integrate these therapies with our colleagues who treat patients with modalities aside from chemotherapy? These are things we need to learn moving forward, and I'm not sure we'll know all of it within 1 year.

References

1. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. doi: 10.1056/NEJMoa1304369.
2. Kudo M, Ikeda K, Finn S, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable HCC: a randomized phase III noninferiority trial. Lancet. 2018;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.