Meeting News

Guest Commentary: ‘Intriguing’ ASCO data highlights new excitement in colorectal cancer

Photo of Van Morris
Van Morris

In this Guest Commentary, HemOnc Today Next Gen Innovator Van Morris, MD, medical oncologist in the department of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, discusses the results of three important clinical trials in colorectal cancer that were presented at the 2019 ASCO Annual Meeting. The trials investigated established and investigational regimens, including a FOLFOXIRI-bevacizumab treatment strategy in the front-line setting; a novel combination of an oral, multi-kinase inhibitor plus immunotherapy; and the first KRASG12C inhibitor to reach clinical development.

TRIBE-2

This year at ASCO, there were a couple of trials in colorectal cancer that were really interesting. One was the TRIBE-2 trial, which randomized patients with untreated, metastatic colorectal cancer to one of two treatment regimens. In one arm of the study, patients received FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan) and bevacizumab (Avastin, Genentech), with de-escalation, followed by reintroduction of the four-drug regimen only after progressive disease. In the other arm, patients received sequential FOLFOX and bevacizumab, followed by FOLFIRI (fluorouracil, leucovorin and irinotecan) and bevacizumab.

This was an important study because many oncologists have a lot of reluctance about using fluorouracil, oxaliplatin and irinotecan upfront for patients who have either right-sided tumors or RAS-mutated tumors. The concern is that once patients progress on those regimens, they will not have other effective treatment options. This trial addresses the question of whether it is appropriate to use FOLFOXIRI and bevacizumab upfront or the sequential regimen, which many oncologists still prefer.

The results showed that patients in the FOLFOXIRI and bevacizumab arm ultimately fared better with regard to the primary endpoint of PFS, which was measured from the time of randomization to the time of progression following the second rechallenge. As expected, patients responded better with FOLFOXIRI-bevacizumab than FOLFOX-bevacizumab in the first-line setting.

What was also interesting was that there was really no difference in second PFS between FOLFOXIRI-bevacizumab rechallenge vs. FOLFIRI-bevacizumab rechallenge. This is an important point to make as well.

These data certainly have given me much more confidence in using FOLFOXIRI-bevacizumab as front-line therapy. We know that anti-EGFR therapies as the biologic in combination with chemotherapy for right-sided, RAS wild-type tumors do not fare as well as a combination with a VEGF agent. As a result, I’ll likely use this regimen as presented by the TRIBE2 trial in untreated patients who either have right-sided tumors or RAS-mutated tumors.

REGONIVO

Another trial that I thought was interesting — with the caveat that the results are very early — was the REGONIVO trial. This trial assessed a combination of regorafenib (Stivarga, Bayer) plus nivolumab (Opdivo, Bristol-Myers Squibb) in 50 patients with either gastric cancer (n = 25) or colorectal cancer (n =25).

In colorectal cancer, we know that the general response rate to regorafenib is very low, around 1% to 2%. In patients who have microsatellite-stable colorectal cancer, the response rate of nivolumab is very poor as well. It was particularly interesting that for the 25 patients with colorectal cancer who received the combination of regorafenib and nivolumab, the response rate was 36%. Nine out of 25 patients had a response to this combination therapy, which is certainly more than we would have predicted based on the activity of each of these agents alone.

The authors presented correlative data showing that, in gastric cancer, the combination was associated in paired biopsies with a decrease in the number of regulatory T cells within the tumor. There seems to be some on-target effect of this combination, which supports the rational for the genesis of this study. With that said, I am very encouraged, though we need more data before making further recommendations about this combination. The recent IMblaze370 trial evaluating a MEK inhibitor in combination with a PD-L1 monoclonal antibody, which was a negative study reported earlier this year, is a great example of why we cannot rush to definitive conclusions based on early-phase data. Nevertheless, these early findings from REGONIVO are intriguing and I am very excited about future updates, as well as companion, correlative studies that will come out of this trial.

AMG 510, a KRAS G12C inhibitor

The last trial I want to highlight is abstract 3003, which evaluated the KRASG12C-specific inhibitor AMG 510 (Amgen).

Around 45% to 50% of patients with colorectal cancer have KRAS- or NRAS-mutated tumors. These are major oncologic drivers that, unfortunately, do not have targeted therapies yet that are effective in turning off the function of pathogenic activity as we have for other tumor types, such as BRAF-mutated tumors or HER-2/neu-amplified tumors.

This trial enrolled 14 patients with non-small cell lung cancer and 19 patients with colorectal cancer. The results indicate that there is some early signal associated with this agent. The data are early; 26 of the 35 patients are still receiving the study treatment. Still, I think the findings are very intriguing. This is one of the first signals that we may be able to treat patients with colorectal cancer and NSCLC with an inhibitor that specifically targets the KRAS-mutated oncoprotein. This is certainly a trial and a drug that we need to keep an eye on in the years to come. It will be important to try to understand how we can optimize not only combinations with this drug in the future, but also translating what has been done with KRASG12C to other mutated isoforms of KRAS and NRAS.

References:

Cremolini C, et al. Abstract 3508. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Fakih M, et al. Abstract 3003. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Fukuoka S, et al. Abstract 2522. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure: Morris reports no relevant financial disclosures.

Photo of Van Morris
Van Morris

In this Guest Commentary, HemOnc Today Next Gen Innovator Van Morris, MD, medical oncologist in the department of gastrointestinal medical oncology at the University of Texas MD Anderson Cancer Center, discusses the results of three important clinical trials in colorectal cancer that were presented at the 2019 ASCO Annual Meeting. The trials investigated established and investigational regimens, including a FOLFOXIRI-bevacizumab treatment strategy in the front-line setting; a novel combination of an oral, multi-kinase inhibitor plus immunotherapy; and the first KRASG12C inhibitor to reach clinical development.

TRIBE-2

This year at ASCO, there were a couple of trials in colorectal cancer that were really interesting. One was the TRIBE-2 trial, which randomized patients with untreated, metastatic colorectal cancer to one of two treatment regimens. In one arm of the study, patients received FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin and irinotecan) and bevacizumab (Avastin, Genentech), with de-escalation, followed by reintroduction of the four-drug regimen only after progressive disease. In the other arm, patients received sequential FOLFOX and bevacizumab, followed by FOLFIRI (fluorouracil, leucovorin and irinotecan) and bevacizumab.

This was an important study because many oncologists have a lot of reluctance about using fluorouracil, oxaliplatin and irinotecan upfront for patients who have either right-sided tumors or RAS-mutated tumors. The concern is that once patients progress on those regimens, they will not have other effective treatment options. This trial addresses the question of whether it is appropriate to use FOLFOXIRI and bevacizumab upfront or the sequential regimen, which many oncologists still prefer.

The results showed that patients in the FOLFOXIRI and bevacizumab arm ultimately fared better with regard to the primary endpoint of PFS, which was measured from the time of randomization to the time of progression following the second rechallenge. As expected, patients responded better with FOLFOXIRI-bevacizumab than FOLFOX-bevacizumab in the first-line setting.

What was also interesting was that there was really no difference in second PFS between FOLFOXIRI-bevacizumab rechallenge vs. FOLFIRI-bevacizumab rechallenge. This is an important point to make as well.

These data certainly have given me much more confidence in using FOLFOXIRI-bevacizumab as front-line therapy. We know that anti-EGFR therapies as the biologic in combination with chemotherapy for right-sided, RAS wild-type tumors do not fare as well as a combination with a VEGF agent. As a result, I’ll likely use this regimen as presented by the TRIBE2 trial in untreated patients who either have right-sided tumors or RAS-mutated tumors.

REGONIVO

Another trial that I thought was interesting — with the caveat that the results are very early — was the REGONIVO trial. This trial assessed a combination of regorafenib (Stivarga, Bayer) plus nivolumab (Opdivo, Bristol-Myers Squibb) in 50 patients with either gastric cancer (n = 25) or colorectal cancer (n =25).

In colorectal cancer, we know that the general response rate to regorafenib is very low, around 1% to 2%. In patients who have microsatellite-stable colorectal cancer, the response rate of nivolumab is very poor as well. It was particularly interesting that for the 25 patients with colorectal cancer who received the combination of regorafenib and nivolumab, the response rate was 36%. Nine out of 25 patients had a response to this combination therapy, which is certainly more than we would have predicted based on the activity of each of these agents alone.

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The authors presented correlative data showing that, in gastric cancer, the combination was associated in paired biopsies with a decrease in the number of regulatory T cells within the tumor. There seems to be some on-target effect of this combination, which supports the rational for the genesis of this study. With that said, I am very encouraged, though we need more data before making further recommendations about this combination. The recent IMblaze370 trial evaluating a MEK inhibitor in combination with a PD-L1 monoclonal antibody, which was a negative study reported earlier this year, is a great example of why we cannot rush to definitive conclusions based on early-phase data. Nevertheless, these early findings from REGONIVO are intriguing and I am very excited about future updates, as well as companion, correlative studies that will come out of this trial.

AMG 510, a KRAS G12C inhibitor

The last trial I want to highlight is abstract 3003, which evaluated the KRASG12C-specific inhibitor AMG 510 (Amgen).

Around 45% to 50% of patients with colorectal cancer have KRAS- or NRAS-mutated tumors. These are major oncologic drivers that, unfortunately, do not have targeted therapies yet that are effective in turning off the function of pathogenic activity as we have for other tumor types, such as BRAF-mutated tumors or HER-2/neu-amplified tumors.

This trial enrolled 14 patients with non-small cell lung cancer and 19 patients with colorectal cancer. The results indicate that there is some early signal associated with this agent. The data are early; 26 of the 35 patients are still receiving the study treatment. Still, I think the findings are very intriguing. This is one of the first signals that we may be able to treat patients with colorectal cancer and NSCLC with an inhibitor that specifically targets the KRAS-mutated oncoprotein. This is certainly a trial and a drug that we need to keep an eye on in the years to come. It will be important to try to understand how we can optimize not only combinations with this drug in the future, but also translating what has been done with KRASG12C to other mutated isoforms of KRAS and NRAS.

References:

Cremolini C, et al. Abstract 3508. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Fakih M, et al. Abstract 3003. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Fukuoka S, et al. Abstract 2522. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure: Morris reports no relevant financial disclosures.

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