Headway Made in GI Cancer Treatment, But Progress Needed

Brandon Smaglo, MD, FACP

With a new FDA approval in the third-line setting for patients with gastric cancer and research hinting at the opportunity for a personalized medicine approach, the space is bursting with new data to consider.

Regarding the advanced setting, results from the phase III TAGS trial, in which investigators evaluated trifluridine/tipiracil (TAS-102; Lonsurf) in heavily pretreated patients with metastatic gastric cancer, showed that the oral therapy is effective and has a manageable safety profile regardless of prior gastrectomy.

Median overall survival (OS), which was the primary endpoint, was 5.7 months for those who received TAS-102 compared with 3.6 months in those who were given placebo (HR, 0.69; P = .0003).¹ The 1-year OS rate for those in the TAS-102 arm was 21% compared with 13% for those in the placebo arm.

“While the survival advantage was real, it was also pretty slight,” said Brandon Smaglo, MD, FACP, an assistant professor and medical director of Hematology/Oncology at the Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine. “But the fact that it was so well tolerated makes it very attractive.”

These findings led to the February 2019 FDA approval of TAS-102 for adult patients with metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who were previously treated with ≥2 prior lines of chemotherapy that included a fluoropyrimidine, a platinum, and HER2/neu-targeted therapy, if appropriate.²

Findings from the phase III KEYNOTE-061 trial, which compared pembrolizumab (Keytruda) with paclitaxel in patients with advanced gastric/GEJ cancer who progressed on first-line chemotherapy with a platinum and fluoropyrimidine, did not show a significant survival benefit with the PD-1 inhibitor.³ However, data did suggest that there may be gradations of PD-L1 positivity allowing for the selection of patients who could potentially benefit from pembrolizumab, said Smaglo.

“To be able to make treatment decisions based upon that is really revolutionary, we'll see a lot more information from that study or from that approach in the near future,” he added.

However, more work is needed in the adjuvant space, where investigators have not moved the bar for over a decade.

“Our standard of care for the management of adjuvant treatment in gastric cancer goes back to 2 studies—one from 2001, one from 2006,” said Smaglo. “That we haven't moved the bar since then is disappointing, but I'm hopeful that a lot of what we're seeing in the advanced space will also move into the adjuvant space so that we can finally achieve better outcomes in a more consistent manner for those patients as well.”

OncLive: Could you discuss the TAGS trial and the key findings?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, which took place just prior to the recent TAS-102 approval, Smaglo highlighted investigational treatment approaches for patients with gastric cancer and called for further research in the adjuvant setting to move the needle forward.Smaglo: TAGS was an interesting trial, largely because it was a study in the very late-line treatment of [patients with] gastric cancer—a third-line of treatment or higher. In many cancers, we do have multiple lines of therapy, but in gastric cancer, we've really been focused a lot on first-line therapy, with only a little bit [of a focus] on second-line treatment. So, to have a study that was focused on that late-line [of therapy] was very unique and it turned out to be very important for the management of our patients.

There are a couple of things that I take away from that study. Number one, the therapy that is used is a very easy therapy for many patients to tolerate, particularly compared with doublet or triplet combinations of chemotherapy drugs. [Second], it's a therapy that patients take as a pill.

For [a patient] who may have been on therapy for 1 year or more—[who had] to constantly come in for infusions and deal with the dregs of that back-and-forth [travel]—to be able to take a medicine at home and still get good oncologic care is really impressive. Also, for [a patient] to have perhaps a few months of a survival advantage with a therapy is oftentimes questionable, but to get that advantage and still have a very good quality of life and [be able to maintain that] good quality of life is very important, and that seemed to be demonstrated by the TAGS study.

What was the rationale for the KEYNOTE-061 trial and what were the results?

[This drug] is going to fill an important niche for patients who still have a good performance status and still have a desire to stay on therapy—but have been through a lot of treatment already—have already experienced many adverse events and have run through many different treatments. [TAS-102 is for] those who still have a desire to fight, don't want to just go home and be on palliative care, and maybe are in good enough health where that's maybe not the right thing for them. It is going to fill an important need in that space for these patients, so it's wonderful.KEYNOTE-061 was a study that was looking to see if we could move the immunotherapy pembrolizumab into the second-line treatment space. We already have an understanding that we can use it in third-line setting for select patients—particularly those whose tumors are what [have] PD-L1 expression. KEYNOTE-061 used a comparator arm, looking at a standard chemotherapy—in this case, paclitaxel—in an effort to show that the immunotherapy might be better for those patients in that space.

Unfortunately, it wasn't a positive trial, although there are some takeaways suggesting that some patients benefited from pembrolizumab. Survival wasn't better, but the duration of response and the tolerability seen with pembrolizumab seemed to be better than chemotherapy. The [interesting] thing that we've learned from that study is that within that subset of patients who have a PD-L1—positive tumor, there actually may be gradations of positivity that may allow us to select, even within that subset, which subsets are going to benefit from that therapy and which are not. Specifically, those tumors with a higher degree of PD-L1 positivity seem to benefit from the drug, whereas those with a lower positivity did not.

Where does ramucirumab (Cyramza) fit into the treatment paradigm?

We're talking about personalizing therapy, and so far, what that has mostly meant is that we check for some biomarker. It’s either present or it's not, and that's the end of it. Now, to be able to break that down and be able to say "Okay, the biomarker is present, but to what degree?" To be able to make treatment decisions based upon that is revolutionary, and we'll see a lot more information from that study or from that approach in the near future.Ramucirumab is a monoclonal antibody; it is in the space of antiangiogenics, which is nothing new. We've been using antiangiogenic antibodies in the form of bevacizumab (Avastin) to treat a variety of cancers for a very long time. Although, in gastric cancer, bevacizumab [was found to] not to be effective, or at least the studies were not statistically significant for a benefit. Therefore, it's unique that ramucirumab was able to move into that space and be the first antiangiogenic that we can use for gastric cancer.

What is the role of immunotherapy in the treatment of patients with gastrointestinal (GI) cancers?

Some studies, going back almost 5 years ago, have established its role in the second-line space, and the natural next step would be to see if we could move it into the first-line setting. We were hopeful from the RAINFALL study that we would see a benefit to adding ramucirumab to standard chemotherapy upfront. Unfortunately, that didn't pan out; the OS data did not meet a statistically significant endpoint, so we have not moved that into our first-line treatment for these patients. It doesn't take away from any of the benefit, the effect, or the opportunity to treat patients with it in the second-line setting, but in the first-line space, we're still not using antiangiogenic antibodies to treat [patients with] gastric cancer.There are a couple of things that stand out regarding the role of immunotherapy in gastric cancer that really excite me. First, for a long time, [patients with] GI cancers—and gastric cancers in particular—have not seen the benefit of immune-based therapies. We were all very excited a few years ago when [these agents] started to have such great benefit in melanoma, kidney cancer, etc.

Then, we started to learn that certain cancers just didn't have that benefit and that was disappointing. What we've learned since then is that not all of these GI cancers, and certainly not all gastric cancers, are going to benefit from immunotherapies. However, for a select few patients, the responses are so incredible that it's worth understanding a patient's individual tumor to make those recommendations for therapy. What we've learned in the process is how individualized these tumors really are, how to assess them, and to be able to turn that assessment into what is appropriately termed a personalized treatment selection.

Beyond immunotherapy, are there any other promising agents in the pipeline?

The next step is going to be understanding how, for those tumors that are ineligible for immunotherapy based on their baseline characteristics, we're going to be able to stimulate or modify those tumors with other therapies—such as chemotherapies and antibodies—so that those immunotherapies can become effective to treat them. We've seen some of that evidence with early-phase data using nivolumab (Opdivo) with ramucirumab and other data with trastuzumab (Herceptin) and pembrolizumab—where it actually doesn't matter what the PD-L expression is, because the PD-L1 expression seems to go up with the other stimulating drug. That's so exciting—to be able to change the tumor biology to make it sensitive to a drug is something that we've not yet been able to do. Therefore, I'm looking forward to seeing how we will be able to modulate that tumor biology in a meaningful way and then offer immunotherapy to these patients.ASCO just announced its Cancer Advance of the Year as [progress in] treatment for [rare cancers]. I would certainly put gastric cancer into this category. Therefore, one of the things that I'm most excited about is getting to a point where we're able to take an individual's tumor biopsy, learn about that individual gastric cancer, and make some very focused recommendations to that patient that will hopefully spare them a lot of the toxicity that comes with more aggressive generic chemotherapy. [We may be able to] put them onto a treatment course that may include biologics, small molecules, and immunotherapy that will be tailored to what they really need.

What challenges still need to be addressed in the space?

What we're learning is that that tumor biology is constantly in evolution with treatment and so being able to come back and re-personalize the tumor's biology and treatment options, based upon how it has responded to initial therapy, is going to be a huge step forward. Just in a very broad sense, what I'm most excited about in this cancer space is not just immunotherapy or a specific targeted therapy, but how we're going to be able to select for and against these different treatment [approaches] for individuals going forward.One of the biggest challenges, particularly in the gastric cancer space, is how difficult it is for patients to deal with the tumors themselves. Unfortunately, these are tumors that very quickly have pretty significant clinical effects on our patients. They make it difficult to eat, to maintain a good energy level, a good quality of life, and they quickly cause a lot of pain. All of those features make it difficult to be aggressive with therapy because, unfortunately, most of our therapies just augment or add to that clinical burden that our patients experience. Finding ways to treat patients in a manner where it's quick, but also not compounding the symptoms that they're already experiencing, will be a challenge for the foreseeable future.

Throughout [the State of the Science Summit], we spoke a lot about the advances made in the metastatic space, and unfortunately, that's appropriate in gastric cancer because so often we are dealing with advanced cancers. There are patients though, fortunately, who are cured or have the option of being cured of their cancer, and one of the challenges in these situations has a lot to do with identifying the appropriate adjuvant therapy for these patients.

We've talked a lot about immune therapy, targeted therapies—all of this is in advanced cancer. In the localized cancer setting, we're still using just chemotherapy, or perhaps radiation, in the adjuvant treatment [of these patients]. There are some studies that are going to come down the pike in the near future that are going to look at a lot of these targeted agents, and especially the immune therapies, in the adjuvant setting, and I would be very hopeful to see the bar moved there.

References

1. Arkenau H-T, Tabernero J, Shitara K, et al. TAGS: a phase III, randomized, double-blind study of trifluridine/tipiracil (TAS-102) versus placebo in patients with refractory metastatic gastric cancer. Ann Oncol. 2018;29(suppl 8; abstr LBA25). doi: 10.1093/annonc/mdy424.027.
2. FDA Approves Taiho Oncology’s Lonsurf® (trifluridine/tipiracil) for Adult Patients With Previously Treated Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma. Taiho Oncology. Published February 25, 2019. https://bit.ly/2NtSZpw. Accessed February 25, 2019.
3. Shitara K, Özgüriglu M, Bang Y-J, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomized, open-label, controlled, phase 3 trial. Lancet. 2018;392(10142):123-133. doi: 10.1016/S0140-6736(18)31257-1.