Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discusses potential applications for circulating tumor (ct)DNA in colorectal cancer. 

ctDNA is an exciting approach for which several potential and promising applications may exist. For example, this approach could potentially be utilized in the resistance space, specifically with regard to resistance mechanisms, says Overman. Examining the blood can provide information regarding the totality of the lesions or cancer spots; this offers a good assessment of various resistance mechanisms, notes Overman. 

Another potential application is with regard to minimal residual disease; this could be used to help detect cancer at a very low level and potentially engage upon it to guide treatment, says Overman. Another area of exploration is determining whether ctDNA could be used as an early marker for disease responsiveness to determine whether a treatment is working or not, adds Overman. Notably, ctDNA allows for the identification of quick changes because it’s cleared rapidly; it’s quantitative and it reflects many important aspects of cancer.

Responses are commonly evaluated with the use of tumor markers or scans; ctDNA could potentially offer a better surrogate for tumor response than a CT scan or other common tumor markers, says Overman. Research efforts are dedicated to determining whether ctDNA could become a standard part of assessment in terms of disease responsiveness, concludes Overman. 

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Michael J. Overman, MD, discusses potential applications for circulating tumor DNA in colorectal cancer. 

Dr. Overman on Potential Application of ctDNA in CRC

Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discusses ongoing research with immunotherapy in microsatellite stable (MSS) colorectal cancer (CRC).

The vast majority of patients with CRC are proficient in mismatch repair, says Overman. These patients have a high unmet need. Although immunotherapy has not shown a lot of success in patients with MSS tumors, an abundance of research is being done to decipher the complex microenvironment and bring this therapy to patients.

One of the more encouraging preliminary combinations in this space is regorafenib (Stivarga) and nivolumab (Opdivo), says Overman. Updated data, which were presented at the 2020 Gastrointestinal Cancers Symposium, are encouraging. However, the study results need to be validated before the combination is made available to patients, concludes Overman.

Dr. Overman on Ongoing Research With Immunotherapy in Microsatellite Stable CRC

Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discusses factors to consider when choosing between regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) in the third-line treatment of patients with colorectal cancer.

There are no data to make clear distinctions between regorafenib and TAS-102; therefore, treatment decisions are often based on the safety profiles of the agents. In the decision-making process, we take the characteristics of the patient and their concerns into consideration, says Overman. Generally, regorafenib tends to result in many adverse events that are more challenging for patients, including fatigue; TAS-102 tends to be less toxic in that regard. However, there is no right or wrong decision when choosing among these agents, according to Overman.

Dose-escalating regorafenib may make the agent more tolerable for patients, based on the results of the ReDOS trial, which showed relatively equivalent outcomes with standard dosing and a dose-escalated approach, says Overman. The main end point of the trial was the number of patients who reached the third cycle of therapy, but several others showed similar outcomes between arms. Safety data also looked better with the dose-escalated approach, concludes Overman.

Michael J. Overman, MD, discusses factors to consider when choosing between regorafenib and TAS-102 in the third-line treatment of patients with colorectal cancer.

Dr. Overman on Choosing Between Regorafenib and TAS-102 in CRC

Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discusses second-line therapy options for patients with colorectal cancer.

At time of progression, standard second-line chemotherapy options are available depending on what was used in the frontline setting, says Overman. For example, if an oxaliplatin-based therapy was used in the frontline, often irinotecan can be used in the second-line. If a triplet composed of fluoropyrimidine, irinotecan, and oxaliplatin was used in the frontline, these agents can be reintroduced at the time of progression, after maintenance therapy, according to Overman.

For molecular subtypes, such as tumors harboring 

 alterations, or in those with mismatch repair deficiency, targeted therapies can be used in the second-line setting, says Overman. It is important to test for these mutations early on in the treatment journey as that information can be used to inform future treatment decisions.

In the third- and fourth-line refractory setting, oral agents, such as regorafenib (Stivarga) or TAS-102 (trifluridine/tipiracil; Lonsurf), can be used, adds Overman. Clinical trials are always an option as well, concludes Overman.

Michael J. Overman, MD, discusses second-line therapy options for patients with colorectal cancer.

Dr. Overman on Second-Line Therapy Options for Colorectal Cancer

Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine and committee vice chair at The University of Texas MD Anderson Cancer Center, discusses investigational targeted therapies in metastatic colorectal cancer (mCRC).

In the phase III BEACON CRC trial, investigators compared standard second-line FOLFIRI-based chemotherapy with either a triplet or doublet BRAF-targeted therapy in patients with metastatic 

 V600E—mutant disease. The doublet consisted of the BRAF inhibitor encorafenib (Braftovi) plus cetuximab (Erbitux), and the triplet was composed of encorafenib, cetuximab, and the MEK inhibitor binimetinib (Mektovi). The results indicated an improvement in overall survival (OS) with the doublet and the triplet over standard chemotherapy. Additional follow-up data that were presented at the 2020 Gastrointestinal Cancers Symposium showed similar OS in the doublet and triplet arms. Given that the doublet might have less toxicity, it has the potential to become a widespread treatment approach for patients with BRAF V600E mutations, says Overman.

No randomized data exist in the HER2 space. However, several combinations under investigation, including trastuzumab (Herceptin)/lapatinib (Tykerb) and trastuzumab/pertuzumab (Perjeta), have shown promising activity in single-arm studies. The randomized SWOG S1613 trial will randomize patients to receive either trastuzumab/pertuzumab or irinotecan/cetuximab and will hopefully shed light on the true benefit of HER2-targeted agents in this population, concludes Overman.

Dr. Overman on Investigational Targeted Therapies in mCRC

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses tailoring treatment approaches to molecular subsets in metastatic colorectal cancer (mCRC).

The field of mCRC is unique in that there a number of molecular subtypes that can potentially drive treatment decisions, Overman says. A patient with mCRC should undergo testing for microsatellite instability (MSI), 

. Moreover, there are promising data with single-agent and combination immunotherapy in patients whose tumors are MSI—high and mismatch repair deficient. Immunotherapy is currently being utilized in the second- and third-line settings, Overman notes, but ongoing studies are looking at this treatment in the frontline setting.

 V600E mutations, the National Comprehensive Cancer Network recommendeds vemurafenib (Zelboraf), cetuximab (Erbitux), and irinotecan as second-line therapy. Overman adds that the anticipated phase III data from the BEACON CRC trial could move the needle even further in this space.

Michael J. Overman, MD, professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses tailoring approaches to molecular subsets of patients with metastatic colorectal cancer.

Dr. Overman on Tailoring Approaches to Molecular Subsets in mCRC

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses unmet needs with immunotherapy in metastatic colorectal cancer (mCRC).

The biggest challenge with extending the reach of immunotherapy in this space is that despite the high level of activity, there is still a subset of patients who don’t respond to this approach. Because these patients have immunologic factors such as high mutation burden and many neoantigens, one would think that all microsatellite instability-high patients would benefit from immunotherapy. However, that is not the case.

There are clearly mechanisms of resistance at play that researchers have not yet discovered, says Overman. Moving forward, a big question will be whether these mechanisms can be identified and then exploited with targeted therapy or other strategies. There is a lot of hope that this can be accomplished with time, but right now it’s a lot of translational analysis. To date, the question remains unanswered.

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses unmet needs with immunotherapy in metastatic colorectal cancer.

Dr. Overman on Unmet Needs With Immunotherapy in mCRC

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses the ReDOS study in patients with metastatic colorectal cancer (mCRC).

ReDOS aimed to establish the optimal dosing strategy of regorafenib (Stivarga), a targeted agent in the treatment of patients with mCRC. While effective, this drug has some toxicity concerns including, but not limited to, hand/foot syndrome and fatigue. Traditionally, in a study like this, researchers have started with a very high dose and worked their way down to a lower dose. Overman says this approach tends to leave physicians with a starting dose that is lower than necessary. For this study, investigators used an escalation strategy, starting with a lower dose and quickly vamped up to a higher dose.

In the dose-escalation arm, patients began at 80 mg daily and increased every week up to 160 mg daily if no dose-limiting toxicities occurred. The control arm was treated with regorafenib at the standard dose of 160 mg daily. The primary endpoint was to assess the patients who made it to the third cycle of therapy, Overman says. Based on the findings, he concludes that this dose-escalation strategy is an effective approach for patients because the standard of care for regorafenib is tough to tolerate.

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses the ReDOS study in patients with metastatic colorectal cancer.

Dr. Overman Discusses ReDOS Study in mCRC

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses progress made with immunotherapy agents in gastrointestinal (GI) cancer.

CTLA-4 is an immune checkpoint inhibitor under investigation in GI cancer, says Overman. Several studies have examined combination therapies that target PD-L1 and CTLA-4, most notably, nivolumab (Opdivo) and ipilimumab (Yervoy). In July 2018, the FDA granted an accelerated approval to the immunotherapy combination for the treatment of adult and pediatric patients 12 years and older with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer following progression on a fluoropyrimidine, oxaliplatin, and irinotecan.

The combination demonstrated a 49% (95% CI, 39-58) overall response rate. Of the 58 patients who responded to the combination, 5 achieved a complete response and 53 achieved a partial response. At the time of the approval, the median duration of response had yet to be reached (range, 1.9-23.2+ months), with 83% of responders showing a sustained response ≥ 6 months.

Dr. Overman Discusses Progress With Immunotherapy in GI Cancer

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses next steps for the use of immunotherapy in the treatment of patients with metastatic colorectal cancer (mCRC).

Immunotherapy has had the most success in patients with tumors that express microsatellite instability-high (MSI-H) or mismatch repair deficiency (dMMR). These are types of DNA repair errors in a rare subset of patients that lead to various mutations, resulting in the increased immune response. Immunotherapy agent pembrolizumab (Keytruda) has a tumor agnostic indication for patients who express dMMR as it demonstrated good activity in this population, he adds. Ongoing trials are now looking to address the unanswered question of whether checkpoint inhibitors can move to the frontline setting.

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) has shown the most promise, but synergistic combinations are also being investigated, says Overman. For example, a combination comprised of a PD-1 inhibitor with a LAG3 inhibitor is currently being evaluated in the NCI-sponsored MATCH study.

Michael J. Overman, MD, associate professor, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, discusses next steps with immunotherapy in the treatment of patients with metastatic colorectal cancer.

Michael J. Overman, MD

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