Select Topic:
Browse by Series:

Later-Line Therapy Innovations in MCRC

Insights From: Tanios Bekaii-Saab, MD, Mayo Clinic; Fortunato Ciardiello, MD, PhD, Seconda Universita di Napoli; Axel Grothey, MD, West Cancer Center & Research Institute
Published: Thursday, Aug 15, 2019



Transcript:

Axel Grothey, MD:
Every patient with metastatic colorectal cancer who can’t be cured by surgery of liver metastasis resection, etc, still represents an unmet need. Even though we have a lot of agents available, patients will eventually succumb to their disease. So we need to do better. We need to find a way to improve outcomes for patients. That’s clearly our goal. And we need to utilize all the knowledge that we’ve been generating over the last years—in terms of tumor biology, interactions with immunotherapy—and really funnel that into the design of clinical trials.

We need to look at relevant preclinical models that give us signals where we can actually move study  drug combinations forward into clinical practice, into clinical trials. Clearly 1 of the emphases right now is trying to make immunotherapy work in patients where immunotherapy didn’t work before, in the I/O [immuno-oncology] combinations either for immunotherapy agents that get combined or modulators of immune responses. That’s 1 area.

And secondly, also looking at molecular profiling of patients, teasing out subgroups of colorectal cancer patients who could respond to targeted agents. There’s a BRCA mutation group in colorectal cancer that could potentially be responsive to PARP inhibitors; clearly HER2-overexpressing tumors have very interesting data with HER2-targeted agents. The patient’s BRAF mutations, you know, which are represented in national target. They have interesting studies now with agents that can target certain KRAS mutations; the G12C patients, which make a certain subgroup of patients with metastatic colorectal cancer. So we have specific inhibitors here that can target this patient population.

We are looking at molecular profiling and making immunotherapy work in patients where it didn’t work before. I think these are the most exciting areas of drug development right now.

Fortunato Ciardiello, MD, PhD: Regorafenib as itself is an important modulator of the angiogenesis and interaction between stromal and cancer cells. And its multikinase activity by blocking different kinase receptors and different types of cells can play a major role. Within this possibility, regorafenib can block specific receptors in regulatory immune cells and in the stroma, then in some way can help activate the immune system. Given this very strong potential biological rationale, a series of phase I studies have been started. Among these, there is a very interesting study that has been presented for the first time at ASCO [American Society of Clinical Oncology Annual Meeting] and while meeting here in Chicago in 2019, called the REGONIVO study. This study, that was presented by a group of Japanese colleagues, was a phase I classical dosage escalation study of regorafenib with a dosage stepping from 80 to 120 to 160 mg per day every 3 weeks, 1 week of rest, with the addition of standard-dose nivolumab every 2 weeks.

And Japanese colleagues did this phase I study in MSS [microsatellite stable] colorectal cancer patients and in gastric cancer patients. Both patient populations were heavily pretreated chemorefractory patients. And then they did an extension after defining the best tolerated dose for the combination of regorafenib plus nivolumab in both tumor types for a total of 50 patients. The important message from this study is that although these are preliminary findings that should be extended phase II study, eventually in a randomized phase III study. The most important message is that this combination was really promising in signs of activity in this heavily pretreated population, in which immunotherapy, especially for metastatic MSS colorectal cancer, as we said earlier, has no effect at all.

In fact, in about 25 patients with metastatic colorectal cancer treated in this phase I expanded study with the combination of nivolumab and regorafenib, the best combination in terms of activity and tolerability is regorafenib 80 mg per day. This combination gives an interesting response rate of about 33% to 36%. So 1 of 3 patients in this trial had a major clinical response, and this is quite remarkable because we expect basically 0 responses by nivolumab and about 1% or 2% responses by regorafenib in this set of patients. As I said before, regorafenib is mostly cytostatic rather than cytotoxic, and nivolumab does not work at all in patients with MSS metastatic colorectal cancer. Therefore, about 33%—or let’s say 1 of 3 response rate—was quite remarkable.

More interesting, the duration of response was quite remarkable. If I recall well, the median progression-free survival was in the range of 6 months. You should expect a range between 1½ and 3 months with regorafenib or TAS-102 in this patient population and basically no activity of nivolumab by itself in this patient population. And also the expected survival is relatively longer, although data are not mature yet. Therefore, I think this REGO-NIVO [regorafenib- nivolumab] combination, which regorafenib is using to immunomodulatory response to a PD-1 [programmed cell death protein 1] inhibitor of a relatively low dose, 80 mg with a very well-tolerated adverse-effect profile, could be a new important option for those patients, MSS metastatic colorectal cancer in which there is no hope with immunotherapy so far. Because PD-1 and PD-L1 [programmed death-ligand 1] inhibitor by itself has failed. Even modulation with MEK inhibition has failed. So these are good news. Obviously, after this good news, we need a stronger evidence that can be based only on clinically and mechanistically sound further clinical trials.

What this combination has as a mechanism of potentiation of PD-1 activity is that regorafenib could inhibit and block some lymphocytes that usually are blocking the immune response. In this way, regorafenib is restoring a potential immune-competent infiltrate in the tumor, and by blocking PD-1 at the same time, all the cells could be mounting immune response to the cancer cells and could be fully activated. And so at least a subgroup of metastatic colorectal cancer patients whose tumors are considered cold for immunotherapy can be rendered, by this combination, potentially hot.


Transcript Edited for Clarity
Slider Left
Slider Right


Transcript:

Axel Grothey, MD:
Every patient with metastatic colorectal cancer who can’t be cured by surgery of liver metastasis resection, etc, still represents an unmet need. Even though we have a lot of agents available, patients will eventually succumb to their disease. So we need to do better. We need to find a way to improve outcomes for patients. That’s clearly our goal. And we need to utilize all the knowledge that we’ve been generating over the last years—in terms of tumor biology, interactions with immunotherapy—and really funnel that into the design of clinical trials.

We need to look at relevant preclinical models that give us signals where we can actually move study  drug combinations forward into clinical practice, into clinical trials. Clearly 1 of the emphases right now is trying to make immunotherapy work in patients where immunotherapy didn’t work before, in the I/O [immuno-oncology] combinations either for immunotherapy agents that get combined or modulators of immune responses. That’s 1 area.

And secondly, also looking at molecular profiling of patients, teasing out subgroups of colorectal cancer patients who could respond to targeted agents. There’s a BRCA mutation group in colorectal cancer that could potentially be responsive to PARP inhibitors; clearly HER2-overexpressing tumors have very interesting data with HER2-targeted agents. The patient’s BRAF mutations, you know, which are represented in national target. They have interesting studies now with agents that can target certain KRAS mutations; the G12C patients, which make a certain subgroup of patients with metastatic colorectal cancer. So we have specific inhibitors here that can target this patient population.

We are looking at molecular profiling and making immunotherapy work in patients where it didn’t work before. I think these are the most exciting areas of drug development right now.

Fortunato Ciardiello, MD, PhD: Regorafenib as itself is an important modulator of the angiogenesis and interaction between stromal and cancer cells. And its multikinase activity by blocking different kinase receptors and different types of cells can play a major role. Within this possibility, regorafenib can block specific receptors in regulatory immune cells and in the stroma, then in some way can help activate the immune system. Given this very strong potential biological rationale, a series of phase I studies have been started. Among these, there is a very interesting study that has been presented for the first time at ASCO [American Society of Clinical Oncology Annual Meeting] and while meeting here in Chicago in 2019, called the REGONIVO study. This study, that was presented by a group of Japanese colleagues, was a phase I classical dosage escalation study of regorafenib with a dosage stepping from 80 to 120 to 160 mg per day every 3 weeks, 1 week of rest, with the addition of standard-dose nivolumab every 2 weeks.

And Japanese colleagues did this phase I study in MSS [microsatellite stable] colorectal cancer patients and in gastric cancer patients. Both patient populations were heavily pretreated chemorefractory patients. And then they did an extension after defining the best tolerated dose for the combination of regorafenib plus nivolumab in both tumor types for a total of 50 patients. The important message from this study is that although these are preliminary findings that should be extended phase II study, eventually in a randomized phase III study. The most important message is that this combination was really promising in signs of activity in this heavily pretreated population, in which immunotherapy, especially for metastatic MSS colorectal cancer, as we said earlier, has no effect at all.

In fact, in about 25 patients with metastatic colorectal cancer treated in this phase I expanded study with the combination of nivolumab and regorafenib, the best combination in terms of activity and tolerability is regorafenib 80 mg per day. This combination gives an interesting response rate of about 33% to 36%. So 1 of 3 patients in this trial had a major clinical response, and this is quite remarkable because we expect basically 0 responses by nivolumab and about 1% or 2% responses by regorafenib in this set of patients. As I said before, regorafenib is mostly cytostatic rather than cytotoxic, and nivolumab does not work at all in patients with MSS metastatic colorectal cancer. Therefore, about 33%—or let’s say 1 of 3 response rate—was quite remarkable.

More interesting, the duration of response was quite remarkable. If I recall well, the median progression-free survival was in the range of 6 months. You should expect a range between 1½ and 3 months with regorafenib or TAS-102 in this patient population and basically no activity of nivolumab by itself in this patient population. And also the expected survival is relatively longer, although data are not mature yet. Therefore, I think this REGO-NIVO [regorafenib- nivolumab] combination, which regorafenib is using to immunomodulatory response to a PD-1 [programmed cell death protein 1] inhibitor of a relatively low dose, 80 mg with a very well-tolerated adverse-effect profile, could be a new important option for those patients, MSS metastatic colorectal cancer in which there is no hope with immunotherapy so far. Because PD-1 and PD-L1 [programmed death-ligand 1] inhibitor by itself has failed. Even modulation with MEK inhibition has failed. So these are good news. Obviously, after this good news, we need a stronger evidence that can be based only on clinically and mechanistically sound further clinical trials.

What this combination has as a mechanism of potentiation of PD-1 activity is that regorafenib could inhibit and block some lymphocytes that usually are blocking the immune response. In this way, regorafenib is restoring a potential immune-competent infiltrate in the tumor, and by blocking PD-1 at the same time, all the cells could be mounting immune response to the cancer cells and could be fully activated. And so at least a subgroup of metastatic colorectal cancer patients whose tumors are considered cold for immunotherapy can be rendered, by this combination, potentially hot.


Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Clinical Practice Connections™: From Diagnosis to Emerging Immunotherapeutic Options: Understanding the Burden and Risks in Peanut AllergySep 28, 20191.0
Enduring CME activity from the School of Breast Oncology®: 2018 Mid-Year Video UpdateSep 28, 20192.0
Publication Bottom Border
Border Publication
x