This month, we’re taking a look at combination targeted therapy early phase trials for metastatic colorectal cancer (mCRC). 

Targeted therapies are available for select mutations (or variants of those mutations) in tumors in colorectal cancer. Unlike other cancers, it has been shown over and over again that monotherapy – use of a single targeted therapy drug – is not an effective strategy in colorectal cancer. 

We first discuss an innovative strategy of dose escalation in the first two trials. This is a new way of doing dose-escalation trials and is important from the patient perspective. 

Here’s why: 

Routinely, new drugs are first tested for safety, where the aim is to find dose-limiting toxicities (DLTs) and the maximum tolerated dose of the novel drug. These studies also look to find the recommended phase II dose (RP2D) to test in phase II trials. Once the safety and efficacy of these drugs used individually are known, then they are combined with other drugs and then tested again to find safety and efficacy information. 

In this format, patients get to try the drug in monotherapy trials, but usually are excluded from combination trials because prior monotherapy use is almost always an exclusion. 

In these two trials that Manju will discuss, this novel trial strategy allows the same patient to try monotherapy, and then upon progression on it, to get it as combination therapy. 

From the drug company perspective, they save time and are able to efficiently test the drug in combination in diseases where monotherapy might have very limited utility. 

Manju

BRAF 
PF-07284892 in Participants with Advanced Solid Tumors 

This is a 197-patient non-randomized trial to find the maximum tolerated dose (MTD) and the recommended Phase II Dose as single agent, and in combination with lorlatinib, encorafenib + cetuximab, or binimetinib and evaluate the safety and preliminary clinical activity of single agent, and each combination therapy, in advanced solid tumors including colorectal cancer. 

A couple of arms are relevant to colorectal cancer patients. One is the monotherapy arm with PF07284892, which is a SHP2 inhibitor (SHP2i). This arm is for patients with BRAF V600E-mutated colorectal cancer. For the same group of patients, there is also Cohort 3, where it is combined with encorafenib (BRAF inhibitor) and cetuximab (EGFR inhibitor) for BRAF V600E mutated colorectal cancer. The combination of encorafenib + cetuximab is FDA approved for BRAF-mutated colorectal cancer. In Cohort 3, patients with prior exposure to this drug combination are enrolled and will have the novel SHP2i. Cohort 4 is the same combination, but for patients without prior exposure to encorafenib + cetuximab. 

Cohort 5 includes the novel SHP2i binimetinib, an MEK inhibitor for patients with BRAF class III mutant solid tumors, including colorectal cancer. Part 2 has the same combination and patients, but with combination dose escalation. 

There is also a Part 2 with SHP2i + encorafenib + cetuximab, but where there is dose-escalation of SHP2i in this combination. 

DLTs and adverse events will be recorded as primary endpoints, as well as the overall response rate. As with a regular phase I trial, they will look at how the drug and combinations are doing in the body. They will also look at the duration of response and overall response with the dose escalations. 

This figure is from this paper titled SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy https://doi.org/10.1158/2159-8290.CD-23-0361 published in Cancer Discovery on August 4, 2023. As seen from the green box, the patient was able to stay on the SHP2 inhibitor (PF07284892) as monotherapy and in combination for over six months. 

• PD: progressive disease; SD: stable disease; uPR: unconfirmed partial response. 
• Drilon, Alexander, et al. "SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy." Cancer Discovery (2023): OF1-OF13. 

A Study to Learn About the Study Medicine Called PF-07799933 in People With Advanced Solid Tumors

This phase I trial enrolls a total of 174 participants with various solid tumors. I will talk about the colorectal cancer part of this trial. The purpose of this trial is to learn about the safety and anti-tumor efficacy of a pan-RAF inhibitor (called PF-07799933) given as a single agent and in combination with cetuximab (EGFR inhibitor) in people with BRAFmutated colorectal cancer. Pan-RAF means it is  expected to work against BRAF V600 and non-V600 mutant cancers.  

Trial participants with BRAF-mutated colorectal cancer will receive PF-07799933, a tablet to take by mouth, one or two times a day. They may also receive cetuximab. Cetuximab will be given weekly (or every two weeks) in the clinic as a shot administered in the vein or port (intravenous, IV).  

A variety of safety and tolerability related outcomes, as well as efficacy related endpoints like overall response rate, duration of response, disease control rate, etc. will be assessed in this trial. This trial is open in 34 study locations in the US, Canada, and Israel. 

Maia 

KRAS   

The KRAS mutation is present in more than a third of all colorectal cancers; in other words, about two in five colorectal cancers are KRAS+ (mutated). KRAS mutation was historically considered “undruggable” until a few years ago. Since it is associated with resistance to EGFR targeted therapy, agents like cetuximab (Erbitux^®) and panitumumab (Vectibix ^®) are not part of the standard of care for patients with KRAS-mutated colorectal cancer: They are recommended only for patients with wild-type KRAS (wtKRAS).  

In recent years, substantial advances have been made with new generation inhibitors able to specifically target one of many variants of the KRAS mutation: the G12C KRAS mutation. The more notable of this type of inhibitor are adagrasib (formerly MRTX849; commercial name KRAZATI^®, by Mirati) and sotorasib (formerly AMG 510; commercial name LUMAKRAS^®, by Amgen). However, several other molecules are in development, with the goal of expanding the targets to other KRAS variants, such as G12D, G12V, G13C. We will mention some of the trials ongoing, that may be of interest for patients with colon or rectal cancer with this mutation. 

In early phase trials, KRASG12C inhibitors as monotherapy (given alone) showed inferior efficacy in patients with colorectal cancer compared with non-small cell lung cancer. Therefore, combination strategies to overcome the resistance are now being investigated in clinical trials. 

In a cohort of 40 patients with colorectal cancer with the KRAS G12C mutation in the phase Ib study CodeBreak 101, the combination of sotorasib (oral) and panitumumab (intravenous) showed a tumor objective response rate (ORR) of 30% and a disease control rate (DCR) of 90%. Although treatment‐related adverse events (TRAE) were observed in 92.5% of patients, no TRAE was grade > 3 (severe) or resulted in treatment discontinuation. The CodeBreak 101  phase I/II trial (NCT04185883) continues recruiting and includes other combinations for colorectal cancer patients. 

In the KRYSTAL-1 study, 32 patients with colorectal cancer with the KRAS G12C mutation were treated with adagrasib (oral) and cetuximab (intravenous). The ORR was 46% among 28 evaluable patients and DCR was 100%. The median progression free survival (PFS) was 6.9 months (patients had an average of three earlier lines of systemic therapy). The KRYSTAL-1 phase I/II trial (NCT03785249) continues recruiting; given its promising results, a phase III trial with the combination, now only for colorectal cancer patients, is recruiting: KRYSTAL-10 (NCT04793958). Also, a phase I trial (NCT05722327) combining adagrasib, irinotecan and cetuximab is listed as “not yet recruiting” at the M.D. Anderson (by August 2023). 

Early positive data came for LY3537982 (Loxo/Lilly’s KRAS G12C inhibitor, oral) in the phase I trial (NCT04956640) for several cancers with this mutation, colorectal included. Even as a monotherapy, LY3537982 led to a 10% ORR and a 90% DCR in the 20 colorectal cancer patients. In one trial arm for lung cancer, it showed a favorable safety profile in patients treated with a combination with immunotherapy (something that is challenging, regarding side effects). Also, it was active in patients with lung cancer who had previously taken another KRAS G12C inhibitor. 

The trial is recruiting and in the dose expansion part uses the inhibitor administered orally either alone or with another investigational agent (cetuximab, in the case of colorectal cancer patients). 

MRTX1133 is a highly selective inhibitor of KRAS G12D mutation, being studied in a phase I/II clinical trial (NCT05737706) for safety, tolerability, and anti-tumor activity in patients with advanced solid tumor malignancy with this mutation. Expansion cohorts in pancreatic, colorectal, and lung cancer are part of the design of this trial. 

When we talk about “targeted therapies,” we usually refer to small molecule inhibitors (mostly, pills) that aim to act over a specific mutation. However, they are also “targeted” immunotherapies, in the form of vaccines and even as adoptive cell therapy (ACT).  

ELI-002 2P is a RAS-targeting tumor vaccine, with preliminary antitumor activity in KRAS-mutated pancreatic ductal adenocarcinoma, colorectal cancer, and other solid tumors demonstrated in a phase I dose escalation study (AMPLIFY-201, NCT04853017; active and not recruiting new patients).  

There is a recruiting phase I/II trial, AMPLIFY-7P (NCT05726864) for patients with solid tumors with certain types of KRAS or NRAS mutant variants: G12D, G12R, G12V, G12A, G12C, G12S, G13D. 
This trial is for patients with a CT scan that shows no evidence of recurrent disease but who are positive circulating tumor DNA and/or elevated serum tumor biomarkers (such as CA19-9 and CEA), despite prior standard therapy including surgery and chemotherapy/radiation therapy where applicable. This may be an option for patients willing to undergo a clinical trial to prevent a recurrence. 

Stay Tuned for More!

Once a month, Maia and Manju spend time unpacking important research trials, tips, and advice for our community. Be sure to subscribe to sign up with Fight CRC and join COLONTOWN’s online community to continue receiving the most relevant updates in the CRC world!

You can also follow Maia (@sassycell) and Manju (@manjuggm) to stay updated on research and trials and visit ClinicalTrials.gov for more information on trials.

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. 

Be Sure to Check Out These Fight CRC Resources

Clinical Trial Finder

• Colorectal Cancer Clinical Trial Finder
• Colorectal Cancer Clinical Trials Brochure  

More Clinical Trial Conversations

• Cancer Cachexia (Unintended Weight Loss and Appetite Loss
• ASCO 2023 Highlights
• Learning About “Blue-button” Matching on Clinical Trials Day
• Fireside Chat About Clinical Trials
• Clinical Trials for Early-Stage Colorectal Cancer or Minimal Residual Disease

2 thoughts on “Clinical Trials for CRC with Targeted Therapies for BRAF and KRAS Mutations”