2022 GI ASCO Clinical Trial Studies

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Clinical Trial Conversations
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Clinical trials are critical to finding a cure for colorectal cancer. As an advocacy organization dedicated to supporting and empowering a community of patients, caregivers and families, Fight CRC has partnered with COLONTOWN to deliver a monthly blog series highlighting everything patients need to know about clinical trials and the best treatment options available. 

In this series, we hope to cover promising trials that are enrolling, lessons learned from past research, logistics and resources to joining a clinical trial, and provide relevant and timely updates for our colon and rectal cancer community. 

2022 GI ASCO

The 2022 Gastrointestinal American Society of Clinical Oncology (GI ASCO) conference concluded last month and researchers from around the world gathered to discuss the latest research updates in GI cancers. We asked our clinical trial champions, Maia and Manju, to unpack some of the most relevant research studies from 2022 GI ASCO to help our community understand progress and where the research is headed.

If you haven’t met Maia or Manju yet -- you can learn more about them here!

Here are the studies that Maia and Manju are most excited about from 2022 GI ASCO.

Maia: 

First up from 2022 GI ASCO is the phase Ib/II trial of onvansertib (PCM-075, PLK1 inhibitor) in combination with FOLFIRI + bevacizumab in second-line treatment of KRAS-mutated metastatic colorectal cancer (mCRC). In second-line treatment of mCRC patients with diverse KRAS mutations, the combination of onvansertib and FOLFIRI-bev was well-tolerated. There were low-grade treatment-emergent adverse events, which were tolerable, and it showed a promising overall response rate (ORR) of over 30% and progression-free survival over nine months. The study showed that an early decline in the presence of mutant KRAS in plasma (that is, just after the first cycles of treatment) was correlated with response. This means that it may be a viable biomarker for exploration in the future. (Abstract #100 Trial NCT03829410)

The phase II study of pembrolizumab, binimetinib, and bevacizumab in patients with MSS refractory mCRC is important as well.The combination of the immunotherapy pembrolizumab (Keytruda), binimetinib (Mektovi) and bevacizumab (Avastin), three drugs that are FDA approved, induced a median PFS of 5.8 months for patients with refractory MSS mCRC.

In the trial, ongoing at the University of Colorado, five patients achieved a partial response, 24 patients reached stable disease, and 29 patients derived a clinical benefit at the first re-staging at two months. In the poster presented during the meeting, the authors concluded: “Toxicity from these three approved drugs is well-established and observed toxicity in this trial was as expected,” […]  “The combination…has promising activity in treatment-refractory mCRC with some patients achieving deep and durable responses and a majority of patients deriving clinical benefit at time of first disease re-staging.” (Abstract #118 Trial NCT03475004)

There were a couple of clinical trials that combined immunotherapy with the approved, standard therapies for mCRC that did not have good results. Although the results were disappointing, they show us what does not work, or works partially, which is a step in the right direction: With more accurate information, patients and doctors are able to make better decisions about what treatments are worth pursuing. As advocates, we’re grateful for all results being shared!

One of those trials was the phase I/II study of regorafenib (rego) and pembrolizumab (pembro) in refractory microsatellite-stable (MSS) CRC. It did not meet its primary end-point for phase II: significant improvement in progression-free survival (PFS). Median PFS was 2.0 months, which did not meet the prespecified PFS of 2.85 months. Median overall survival (OS) was 9.6 months. The most common adverse events were just the usual/typical ones from the drugs, and the doses of those drugs, used in the trial. Given its negative result, the researchers analyzed data beyond what was planned in the trial design (post hoc analysis): The analysis revealed that patients with no liver metastases and those treated with prior radiotherapy achieved longer PFS. More studies will be searching for biomarkers/specific characteristics to determine subgroup(s) of patients who may benefit from these treatments. (Abstract #15 Trial NCT03657641

The other trial that did not meet expectations was nivolumab plus mFOLFOX6 and bevacizumab for first-line treatment of mCRC. Researchers shared the results from the phase II of this phase II/III clinical trial, CheckMate 9X8, that investigates investigates the addition of the immunotherapy nivolumab (Opdivo) to first-line standard-of-care (mFOLFOX6 and bevacizumab) of mCRC. The combination did not demonstrate a statistically significant improvement in PFS, compared to SOC alone. Even if the primary endpoint of PFS was not met, nivolumab + SOC showed higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC, along with acceptable safety, in first-line treatment. This indicates that further research is required to identify patients’ characteristics of a subgroup of mCRC that might benefit with the combination in the first-line treatment. (Abstract #8 Trial NCT03414983)

Manju:

An amazing and potentially practice-changing study of Induction PD-1 Blockade in Subjects With Locally Advanced Mismatch Repair Deficient Solid Tumors had a complete clinical response rate of 100% for rectal cancer. (Trial NCT04165772)

This was one of the most exciting results from 2022 GI ASCO. Early stage or locally advanced (stage II or stage III) MSI-H rectal cancer accounts for about 5%-10% of all rectal cancers. A large proportion of MSI-H rectal cancer is made up of Lynch syndrome patients, who may be quite young. Currently, all patients with locally advanced rectal cancer get treated with a combination of chemo-RT, chemotherapy, and surgery. For patients with MSS rectal cancer, this aggressive treatment is quite effective in curing their cancer, but many patients are left with long-term life-altering side effects from radiation, chemotherapy and surgery. Patients with MSI-H rectal cancer may not respond as well to 5FU containing chemotherapy. Studies have shown that immunotherapy works well in advanced (metastatic) MSI-H colorectal cancer. 

The idea of the small phase II study conducted at Memorial Sloan Kettering Cancer Center was to see how effective immunotherapy is in early stage disease and to use it in place of chemotherapy for patients with locally advanced MSI-H rectal cancer. Patients with a complete response to immunotherapy alone would have the option of omitting radiation and surgery and thus be spared side effects from both. In the study, patients with locally advanced deficient mismatch repair (dMMR) or MSI-H rectal cancer (stage II and stage III rectal cancer) were treated with a single agent PD-1 inhibitor, dostarlimab, for six months. Response was assessed at the end of treatment with PD-1 inhibitor. If the patients had a clinical complete response, they could undergo observation and forgo radiation and surgery. If they did not have a complete response, they would receive standard chemo-RT and then be evaluated again to potentially avoid surgery. 

The response rate to the PD-1 inhibitor was presented. So far, 16 patients were enrolled, of which 11 completed the six months of PD-1 inhibitor. All 11 patients showed a complete clinical response and, therefore, did not need chemo-RT or surgery and are being followed up with observation. These results suggest a new approach for treatment of MSI-H locally advanced rectal cancer, where treatment with PD-1 inhibitor alone may potentially help avoid chemo-RT and surgery, and the associated long-term side effects. Further patient accrual is ongoing, and this trial is certainly on my list to watch closely. (Abstract #16

There were also promising and much awaited results for the phase I/II trial of Encorafenib, Cetuximab, and Nivolumab in Treating Patients With Microsatellite Stable, BRAFV600E Mutated Unresectable or Metastatic Colorectal Cancer. (Trial NCT04017650)

Though the Beacon doublet (encorafenib+cetuximab, E+C) is a much welcome new treatment for MSS BRAF V600E mutated metastatic CRC, the response time is not as long as patients would like it to be. This E+C+N trial tests if targeting BRAF, EGFR, and PD-1 simultaneously, could result in more efficacy/ better treatment. In this single arm study done at MD Anderson Cancer Center as a phase I/II trial, MSS mCRC patients with tumors having a BRAFV600E mutation who have progressed on one or two previous lines of therapy, but have not yet had BRAF, EGFR or MEK inhibitor or immunotherapy, were enrolled. The trial looked at the best overall response and safety/tolerability of the combination. 

So far, 26 patients have been enrolled, of which 22 were evaluable for response. No dose-limiting toxicities were seen, but grade 3-4 treatment-related adverse events occurred in four out of 22 patients, and a headache was the most commonly reported treatment-related side effect in all patients who had any side effects. An overall response rate of 50% (11 out of 22), disease control rate of 96%, median PFS of 7.4 months, median OS of 15.1 months, and median duration of response of 7.7 months makes this a very promising treatment combination for this subset of patients with poor survival. Of the 11 patients who continue to remain on the study,  two patients are now at 100 weeks of treatment. The follow-up randomized Phase II SWOG 2107 trial is coming soon where 75 patients will be randomized 2:1 to E+C+N vs. E+C. (Abstract #12

More Clinical Trial Conversations

If you missed our webinar with Dr. Van Morris of MD Anderson Cancer Center, be sure to check it out here! Dr. Morris dives into these trials and discusses how this type of research will help us find a Path to a Cure