Regorafenib/Pembrolizumab Misses PFS End Point in MSS CRC, But Biomarker Analyses Are Ongoing

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Afsaneh Barzi, MD, PhD, discusses the safety and efficacy of regorafenib in combination with pembrolizumab in patients with MSS colorectal cancer and describes potential next steps for further exploration of novel combinations in this population.

Afsaneh Barzi, MD, PhD

Afsaneh Barzi, MD, PhD

Although the combination of regorafenib (Stivarga) and pembrolizumab (Keytruda) failed to significantly improve progression-free survival (PFS) in patients with microsatellite stable (MSS) colorectal cancer (CRC) in a phase 1/2 study (NCT03657641), ongoing biomarker analyses seek to identify those who may derive a longer duration of benefit from this approach, according to Afsaneh Barzi, MD, PhD.

Data from the trial, which were presented during the 2022 Gastrointestinal Cancers Symposium, showed that the doublet resulted in a median PFS of 2.0 months (95% CI, 1.8-3.5) among a total of 70 patients, which fell short of statistical significance. However, in a subset of patients who received prior radiotherapy (n = 23), the combination resulted in a median PFS of 4.4 months (95% CI, 2.0-8.4) vs 1.8 months (95% CI, 1.6-2.0) in those with no prior radiotherapy (P = .0025).

“We are not the only group that is reporting prior radiotherapy as a potential factor that results in benefit from immunotherapy. In a study that was published in The Lancet in 2017, patients with non–small cell lung cancer who received prior radiotherapy achieved a higher magnitude of benefit from pembrolizumab,” Barzi explained. “In the population of patients [with CRC], this prior radiotherapy exposure has never been reported, and this is intriguing. Biomarker discovery for exploring the biomarker of patients with better PFS is ongoing, and hopefully, we will get the opportunity to report [more on this] in the near future.”

In an interview with OncLive®, Barzi, a medical oncologist and director at Employer Strategy (AccessHope), as well as an associate professor in the Department of Medical Oncology and Therapeutics Research at City of Hope, discussed the safety and efficacy of regorafenib in combination with pembrolizumab in patients with MSS CRC and described potential next steps for further exploration of novel combinations in this population.

OncLive®: What is the current standard of care (SOC) for patients with MSS CRC? Why are novel combinations in the immunotherapy realm needed?

Barzi: Patients with metastatic CRC have several treatment options available in the advanced setting. Frontline chemotherapy in combination with biological therapy, [for example], FOLFOX [leucovorin, 5-fluorouracil (5-FU), and oxaliplatin] and FOLFIRI [leucovorin, 5-FU, and irinotecan], in combination with bevacizumab [Avastin], can be used in appropriate patients with EGFR antibodies. [These approaches are] predominantly used in first- and second-line therapy in CRC, and they are very effective.

However, once we are past those lines of therapy in patients in the metastatic setting, the options are single-agent regorafenib; trifluridine/tipiracil [TAS-102; Lonsurf], which is a single-agent chemotherapy; and with new data, TAS-102 plus bevacizumab.In a minority of the patients with NTRK fusions, that is a potential option; however, that is a very small group of patients.

Therefore, treatment options in patients with metastatic CRC is limited. Given that CRC is not only a common disease, but the third-most common cause of cancer mortality in the United States, looking for alternative therapies to change the outcome of the disease is an area of unmet need.

What served as the basis and rationale for this phase 1/2 study?

In patients with MSS CRC, immunotherapy has not been shown to be beneficial or effective. Therefore, there is a search for appropriate combinations that can make the patients or their tumors sensitive to immunotherapy.

One of the combinations that has been high on the list is that of VEGF inhibitors and immunotherapy. Regorafenib is a multikinase inhibitor with a significant effect on VEGFR2. Given that [regorafenib] has single-agent activity in CRC, it seems like a promising [approach] to [combine this agent with] pembrolizumab as a potential [way] to overcome the resistance to pembrolizumab alone in patients with MSS CRC.

Could you elaborate on the design of this study, and the patient population enrolled?

For the phase 1 [portion of the research], the goal was to identify the recommended phase 2 dose [RP2D] of regorafenib to be used in combination with a fixed dose of pembrolizumab. The dose of pembrolizumab was 200 mg every 3 weeks. During phase 1, regorafenib was given in 3 cohorts [at] 80 mg on days 1 through 14 for a 21-day cycle, 120 mg on days 1 through 14 for 14 days out of 21 days, and 160 mg [for the same cycle]. After identifying the RP2D, the study was going to continue to phase 2 with the same eligibility criteria.

The primary end point of phase 2 was PFS, in comparison with historical data from regorafenib seen in the phase 3 CORRECT trial [NCT01103323]. This study was initiated in June 2019 at USC Norris Comprehensive Cancer Center, and then completed accrual in July 2021; accrual was pretty rapid.

We had a total of 74 patients, but 1 patient did not meet the eligibility criteria; as such, 73 patients met the criteria. Of those patients, 10 were treated on the phase 1 portion of the research, and 63 were treated on the phase 2 portion. Out of the 10 patients who were treated on phase 1, only 3 were treated with a dose other than the RP2D. As such, a total of 70 patients were treated with the RP2D, which was 80 mg of regorafenib on days 1 through 14, for a 21-day cycle, in combination with pembrolizumab at 200 mg every 3 weeks.

The study population was very diverse. Almost half were minority, with 53% [of patients] being White, and the rest [representing other] racial and ethnic groups. Moreover, this was a fairly young patient population with a median age of 54 years and a range, of 23 years to 81 years, and 51% were female.

In terms of the important biomarkers in this space, 71% of the patients had RAS mutation. It is important to look at that in terms of the background of RAS mutations, [which are] expected in roughly 50% of patients with CRC. [Additionally], these patients had significant metastatic burden, with 40% of them having metastatic disease in more than 3 organs. As expected, these treatments were offered in subsequent lines of therapy. Sixty-one percent of the patients had the treatment in the second or third line, and a smaller group of patients had it in [even later] lines of therapy.

What were the efficacy data reported?

Unfortunately, the study did not show the PFS [benefit that we expected with the combination], which would have been 2.85 months in this patient population. The PFS in the phase 2 portion of this study was 2 months. However, we did see other interesting signals.

Although we did not have any objective responses, 49% of the patients had stable disease, and that is significant; that means that nearly half of these patients achieved some benefit from this treatment. The median duration of stable disease was 2.9 months, which is really good in comparison to [single-agent] regorafenib and is significantly better for this patient population.

The median OS in this patient population was 9.6 months, which is numerically much better than SOC regorafenib, in this case. Although the primary end point of this study was not met, there were some other intriguing data that will hopefully pave the way to further explore this sort of treatment for this patient population in the future.

What was observed in terms of the safety profile of the combination?

The safety profile of the combination was consistent with what has been previously reported. We did not see any unexpected signals. The most common grade 3 and 4 toxicity was rash, which was expected. [Additionally], hypertension was commonly observed, as well as elevation of liver enzymes, both of which were expected from either 1 of the agents [alone] and in combination.

Although this study was negative, are any next steps planned for this research?

In the subgroup analysis, looking at the Cox proportional hazards model, we identified a few subgroups that derived benefit from this treatment; this includes those with no liver metastases at study entry, [as] they had longer PFS, those who had prior radiotherapy, and those who had surgery to their metastatic disease.

When we put this into a multivariate analysis to see how these variables could predict better outcomes, the only variable that remained statistically significant was prior radiotherapy. In other words, patients who received prior radiotherapy, either for treatment after primary disease or for treatment of metastatic disease prior to enrollment on this study, had a significant benefit from this treatment. In that population, which included a total of 23 patients, the median PFS was 4.4 months, ranging from 2.0 months to 8.4 months—this was significantly better.

Is there anything else about the study that you wanted to emphasize?

It is important to put these data in context. This is not the first study that is looking at the combination of regorafenib and immunotherapy. At least 2 cohorts from the United States and 2 international cohorts [have reported data].

Generally speaking, this treatment does not seem to be effective for the most part. The use of this [approach]should be retained for patients who are enrolled on a clinical trial, and its use in standard practice should be avoided. That perhaps limits the exposure of the patient to toxicities that they may experience and allows a more formal collection of the data in patients who can benefit, [which would] allow advancing the science and making more options available for patients who are in needof these options.


  1. Barzi A, Azad NS, Yang Y, et al. Phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite stable colorectal cancer (MSSCRC). J Clin Oncol. 2022;40(suppl 4):15-15. doi:10.1200/JCO.2022.40.4_suppl.015
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