Continuing on our ASCO journey, we now move into the gastrointestinal malignancies, which have several incredibly difficult-to-treat tumor types. In case you haven't seen the previous editions, I'll link them off below. But this series is designed to help you parse out some of the news that is not heavily publicized at ASCO, with the intent of helping you find gems that may have potential for later in 2018 or into the future.
Syndax may be able to enhance immunotherapy efficacy in microsatellite-stable colorectal cancer
Abstract 3557 - ENCORE 601: A phase 2 study of entinostat in combination with pembrolizumab in patients with microsatellite stable metastatic colorectal cancer
When pembrolizumab was approved for any relapsed advanced cancer that harbors microsatellite instability, most notably colorectal cancer, it had an unfortunate shadow: immune checkpoint inhibitors did not work at all in patients with microsatellite stable colorectal cancer, which is much more common than the unstable form. Thus, the race is on to see who can develop a drug that helps more patients respond. SNDX is currently developing entinostat, a histone deacetylase inhibitor, which has been shown to enhance anti-PD-1 antibody activity in preclinical studies.
This phase 2 trial looked at the combination of pembrolizumab and entinostat in advanced colorectal cancer that is microsatellite stable. Of the 16 patients enrolled so far, 6 remain on the study, one with a partial response. And indeed, this was the first response reported so far for pembrolizumab in microsatellite-stable colorectal cancer. Of course, the findings are still not mind-blowing; it's the first response, but it's still the only one that we've seen so far. So based on these findings, it would seem that even this combination does not appear to be a clear winner. But of course it's still early days, so there is the possibility that it will get turned around into something positive. Therefore, I feel pretty neutral on this one, with the caveat that if you buy based on this news, do not be surprised if the combo ends up failing.
Here's what pembrolizumab can REALLY do in colorectal cancer
Abstract 3514 - KEYNOTE-164: Pembrolizumab for patients with advanced microsatellite instability high (MSI-H) colorectal cancer
MRK is conducting the phase 2 KEYNOTE-164 study to assess the potential benefit of pembrolizumab specifically in patients with high microsatellite instability in colorectal cancer. The 63 patients enrolled in the study had a median of 2 prior therapies. After 12.6 months follow-up, 32% of patients had responded, with 2 complete responses and 18 partial responses. Importantly, the duration of response had not been reached. 76% of patients remained alive after 12 months.
These findings are what you really want to see with an immune checkpoint inhibitor. Although the response rate is not mind-blowing, the patients who did respond seem to have a very durable remission. Compare that to the 0% response rate you get when using PD-1 inhibitors in microsatellite-stable disease, and you have a no-brainer winner on your hands with pembrolizumab. Just like nivolumab, I expect the FDA will approve pembrolizumab specifically in the setting of colorectal cancer.
Veliparib continues to make little mark on the treatment landscape
Abstract 3543 - Phase 2 study of veliparib plus FOLFIRI ± bevacizumab versus placebo plus FOLFIRI ± bevacizumab in metastatic colorectal cancer
Of the five major PARP inhibitors in development, ABBV's veliparib is the only one to make little mark on the solid tumor treatment landscape. But the work continues, and this study reported at ASCO described the addition of veliparib to standard chemotherapy, with or without bevacizumab, in metastatic colorectal cancer. The rationale for this trial was the observation that veliparib could increase the activity of irinotecan (the "IRI" part of FOLFIRI) in preclinical models.
130 patients were randomized to receive either veliparib or placebo in combination with the standard therapy for previously untreated metastatic colorectal cancer. Unfortunately, veliparib improved neither the progression-free survival (HR 0.94) nor the overall survival (HR 1.27). Response rates appeared to actually be slightly lower in the veliparib arm, as well (56.9% vs. 61.5%).
Overall, these efficacy findings were disappointing, to say the least, and ABBV continues to struggle to make a mark for this agent. I don't think we'll be hearing that much more about veliparib development in colorectal cancer.
Gilead makes another early strike with its matrix protease inhibitor
Abstract 3578 - Results from a phase I study of andecaliximab in combination with FOLFIRI and bevacizumab in patients with second line metastatic colorectal cancer
The matrix metalloproteinase (MMP) 9 antibody andecaliximab is one of GILD's last frontiers of independent research that I am excited about beyond its acquisition of Kite Pharma. And it's reported a few studies at ASCO this year (one in breast cancer was covered earlier in the gold mining). This phase 1 trial focused on the safety of adding andecaliximab to chemotherapy, with or without bevacizumab. The study enrolled 44 patients who had measurable disease and prior treatment for their metastatic colorectal cancer.
One quarter of patients experienced serious adverse events, most commonly pulmonary embolism in 2 patients. The combination achieved a median progression-free survival of 9.2 months, with an overall response rate of 21%. At the time of the presentation, 27% of the patients remained on the study. These findings are a bit difficult to place into context without the full patient disposition. You see, patients who had prior bevacizumab generally have very low response rates on chemotherapy-bevacizumab, on the order of 10%. This study compares favorably to that, but if the patients do not have first-line bevacizumab, then the response rates are on par with what we see here.
So it's an important question to ask…how many patients had prior bevacizumab in this study? Of course, the primary objective was safety, so it's very good news that there was a signal of efficacy, as well.
Outlook: Neutral to positive
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