Sun Spotlights Advances Made in Advanced/Metastatic Gastric and GEJ Adenocarcinoma

Despite the second- and third-line therapies that are rapidly emerging in gastric cancer, there is still a great need for effective first-line treatment options, according to Weijing Sun, MD, FACP, who added that although immune checkpoint inhibitors have been examined in the frontline setting, results have not been as favorable as projected.

Although results from the ATTRACTION-2 trial (NCT02267343) indicated that nivolumab (Opdivo) showed promise when used in heavily pretreated patients with advanced gastric or gastroesophageal junction cancer,1 immunotherapy has yet to demonstrate impressive clinical activity when examined in the frontline setting, according to Sun.

For example, in the phase 3 KEYNOTE-062 trial (NCT02494583), investigators evaluated the safety and efficacy of pembrolizumab (Keytruda) plus chemotherapy versus single-agent pembrolizumab versus chemotherapy alone in the first-line treatment of patients with advanced gastric cancer.

Results showed that although pembrolizumab was noninferior to chemotherapy in terms of overall survival (OS) benefit in patients with a combined positive score (CPS) of 1 or greater (HR, 0.91; 99.2% CI, 0.69-1.18), the monotherapy was not superior.2 Moreover, pembrolizumab plus chemotherapy was not found to be superior to chemotherapy either in terms of survival benefit in patients with a CPS of 1 or greater (HR, 0.85; 95% CI, 0.70-1.03; P =.05) or those with a CPS of 10 or greater (HR, 0.85; 95% CI, 0.62-1.17; P =.16).

“In gastric cancer, like many other diseases, several advances have been made in the past few years, such as [the emergence of] immune checkpoint inhibitors and targeted therapies. Interestingly, this space has more second- and third-line options [compared with] first-line options,” Sun explained. “Some of the first-line [approaches] still include fluorouracil (5-FU) and platinum-based chemotherapy. We do have some markers to guide our treatment decisions; however, [many are] not specific to gastric cancer.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Sun, the Sprint Professor of Medicine Oncology and director of the Division of Medical Oncology at the University of Kansas Medical Center, as well as an associate director of the University of Kansas Cancer Center, discussed challenges faced with frontline therapies in gastric cancer, as well as key clinical trials in the space.

OncLive®: Could you spotlight some of the advances made for patients with gastric cancer who progress on frontline treatment?

Sun: Findings from the phase 3 RAINBOW trial ​demonstrated significantly improved OS with ramucirumab plus paclitaxel compared with placebo/paclitaxel in [previously treated] patients with advanced gastric or gastroesophageal junction adenocarcinoma. This is now a very commonly used combination that is generally well tolerated.

​Patients from North and South America, Europe, Asia, and Australia were included in the trial population. Patients appeared to benefit [with this treatment], irrespective of location, suggesting this regimen has utility across a diverse patient population.

In the third-line setting, we have TAS-102 (trifluridine/tipiracil; Lonsurf), which [was examined in] the TAGS study. This is an oral medication that is a traditional metabolic inhibitor. [TAGS] included patients from Asia, Europe, and the United States.

[Both approaches are available in] the second- and third-line treatment settings. Of course, [the field] is [in a] better than [it was] before because we now have treatment options [to choose from] in the [later-line] settings.

Immune checkpoint inhibitors have received regulatory approval for when patients progress on standard therapy. Studies have shown that the [higher the] PD-L1 expression, [the higher] the likelihood of response to an immune checkpoint inhibitor, which could be either nivolumab (Opdivo) or pembrolizumab. Based on [what has been seen], aside from maybe patients with microsatellite instability [(MSI)–high disease], checkpoint inhibitors are not really indicated [for use in the second-line setting] at this moment.

You mentioned the RAINBOW trial. What should be known about the toxicities associated with this approach?

The [combination evaluated in the] RAINBOW study is generally very patient and user friendly. The only caveat is that paclitaxel is given 3 weeks on, and 1 week off, while ramucirumab is given once every other week. As such, toxicity could be an issue. Different modified [schedules are sometimes used in practice]. However, [these approaches are] not FDA approved, so we need to be careful. Understandably, giving the second week of paclitaxel could be difficult. 

What was the significance of the TAS-102 approval in this disease? What role does it play in the treatment paradigm given the emergence of newer approaches?

The first effective chemotherapy in the gastric cancer space was 5-FU. We now have 5-FU, capecitabine, S-1 (Teysuno), which is being used in Asia, and TAS-102, which was the agent that was evaluated in the TAGS trial.

The TAGS trial was interesting because many patients were treated with prior lines of therapy and progressed, but they responded to TAS-102. Many of those patients had progressed on standard oxaliplatin, cisplatin, or paclitaxel. Many patients had received [prior] ramucirumab, as well. Some of these patients even received previous treatment with immune checkpoint inhibitors. 

The metabolic mechanism behind the drug reminds us to not forget that it still has [a role in the paradigm]. Currently, we're more focused on immune checkpoint inhibitors, so we tend to forget about some of the other traditional cytotoxic treatments that have been very effective.

The disadvantage is that this medication is relatively nonselective, although it is also generally very useful for the population. Overall, this is a well-tolerated, effective drug. Since this is an oral agent, we wondered whether its absorption would be different for patients who had undergone prior gastrectomy versus those who did not. However, the outcomes of both groups proved to be similar, which means that this drug can be absorbed very well.

What is the role of immunotherapy in gastric cancer? What was learned from the ATTRACTION-2 trial?

This trial is interesting; it [examined a checkpoint inhibitor as] a third-line treatment and it enrolled a Korean, Japanese, and Asian population. At that time, the study did not evaluate PD-L1 expression as a biomarker. Regular supportive care [served] as the control. 

The study proved that single-agent nivolumab works as a third-line treatment option. This was similar to what we learned from the KEYNOTE-059 trial with pembrolizumab. The effectiveness of these agents as monotherapies in these cancers has been demonstrated. However, we still don’t know why first-line treatment [with these agents] is not going as we expected.

Could you expand on the data reported from the KEYNOTE-062 trial examining pembrolizumab as frontline treatment?

Traditionally, we start looking for drug efficacy in the third-line setting, and then we examine the approach in the second-line setting. After this, we will try see whether we can move the drug to the first line.

The KEYNOTE-062 trial asked the question of: Can we use checkpoint inhibitors in the first-line setting, either as a single-agent or combined with chemotherapy?

The study has an interesting [hierarchic statistical] design and it had 3 [treatment] arms. Single-agent pembrolizumab was compared with chemotherapy [in patients with a PD-L1 CPS of 1 or more], which is considered a noninferiority [evaluation]. For other end points, chemotherapy combined with pembrolizumab was compared with chemotherapy alone, and this was considered a superiority [evaluation].

The results were also pretty interesting; neither showed any superiority.

The conclusion is a little arbitrary, in my opinion. The conclusion of our study, which was published in Jama Oncology in September 2020, was that single-agent pembrolizumab was noninferior to chemotherapy [in terms of OS].

Ultimately, this was a very confusing trial and, currently, we cannot say whether pembrolizumab combined with chemotherapy or as a single agent is the standard of care. The FDA may have a challenging time analyzing those data to make a final decision.

The combination of lenvatinib (Lenvima) and pembrolizumab showed more favorable results in the first-line setting. Could you speak to this a bit?

We implemented the EPOC 1706 trial to further examine why immune checkpoint inhibitors have not worked as we expected [in the first-line setting]. We know angiogenesis inhibitors are used in the second-line setting. Previously, ramucirumab was combined with FOLFOX as a first-line [regimen], which turned out to be an active trial.

This was a relatively small, phase 2 study. Lenvatinib, an angiogenesis TKI, was combined with pembrolizumab. [This trial was] without selection, which means that treatment was not based on MSI or PD-L1 expression. Importantly, results showed that when given as a frontline treatment, the response rate was around 70%, which is way better than any others we have seen in the first-line [setting]. Data from the 2020 ASCO Virtual Scientific Program showed that the median PFS for this study was about 7 months and the median OS had not yet been reached. With this combination, we may be able to solve the problem we have been having in terms of frontline treatment. It’s important to remember that this is only a single-arm, phase 2 trial, but the results are very encouraging.

What key challenge would you like to see addressed with future research efforts?

Treating patients with gastric cancer can be very challenging. Nutrition is based on the stomach. As such, when patients have a disease on their stomach, it’s very difficult. Oftentimes, when patients have more advanced disease, they are already malnourished. This is a major challenge, compared with other diseases. We have a lot of hope, but we need to figure out how we can improve first-line treatment beyond 5-FU and platinum-based combinations.

References

1. Kang Y-K, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2):a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461-2471. doi:10.1016/S0140-6736(17)31827-5
2. Shitara K, van Cutsem E, Bang Y-J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370