Colorectal cancer treatments show promise

New treatments for metastatic colorectal cancer (mCRC) over the past year continue to show advancements in precision medicine, including targeting the KRAS^G12C mutation (MT), microsatellite instability–high (MSI-H) status, or deficient mismatch repair (dMMR) status in locally advanced mCRC. Here are a couple of promising examples of the evolution of CRC treatment.

The recent publication of the overall survival (OS) analysis of the CodeBreaK 300 study showed a strong trend for improvement in OS in patients with KRAS^G12C–mutated, chemorefractory mCRC treated with sotorasib plus panitumumab versus the investigator’s choice (trifluridine/tipiracil or regorafenib).¹ Although not statistically significant, the trend suggests a potential 30% relative reduction in the risk of death in favor of sotorasib plus panitumumab (hazard ratio [HR], 0.70; 95% CI, 0.41–1.18).

“This is promising for an incurable disease with a critical unmet need for molecularly selected therapies providing survival benefits,” state the investigators.

The senior author, Marwan G. Fakih, MD, a professor in the Department of Medical Oncology and Therapeutics Research and the division chief of GI Medical Oncology at the City of Hope Comprehensive Cancer Center in Duarte, California, points out that although statistical significance was not seen, it is important to note that the study was not powered for that endpoint. “In addition, about a quarter of the patients on the control arm received KRAS^G12C inhibitors at progression, further confounding the overall survival endpoint.”

The finding builds on prior results showing significantly prolonged progression-free survival (PFS) with sotorasib plus panitumumab versus the investigator’s choice (median PFS, 5.6 vs. 2.0 months), which represents a 52% reduction in the risk of disease progression or death in favor of sotorasib plus panitumumab, as well as a high overall response rate with a 30% durable response.² These results supported the approval by the US Food and Drug Administration (FDA) of sotorasib and panitumumab for patients who have received prior oxaliplatin, irinotecan, and a fluoropyrimidine for KRAS^G12C mCRC and also provided support for the National Comprehensive Cancer Network guidelines on using sotorasib and panitumumab in the second- and third-line treatment of KRAS^G12C mCRC, says Dr Fakih.

The phase 3 CodeBreaK 300 trial included 160 patients with KRAS^G12C–mutated, chemorefractory mCRC who were randomly assigned to receive sotorasib (960 mg) and panitumumab (n = 53), sotorasib (240 mg) and panitumumab (n = 53), or the investigator’s choice (n = 54).

Commenting on the study, Cathy Eng, MD, the David H. Johnson Endowed Chair in Surgical and Medical Oncology and a professor of medicine, hematology, and oncology at Vanderbilt–Ingram Cancer Center in Nashville, Tennessee, says that she thinks providers are interested in this treatment option based on the PFS data alone if they are considering a KRAS^G12C inhibitor. “Given the rarity of KRAS^G12C MT in mCRC, I think providers will feel compelled to consider sotorasib if their patient is KRAS^G12C MT.”

The FDA recently approved nivolumab with ipilimumab for patients 12 years old or older who have unresectable or metastatic MSI-H or dMMR CRC.³

Approval was based on the CheckMate 8HW trial, a randomized, three-arm, open-label trial of immunotherapy-naïve patients with unresectable colorectal cancer or mCRC with a known MSI-H or dMMR status. Patients received nivolumab (240 mg every 3 weeks) and ipilimumab (1 mg/kg every 3 weeks) for a maximum of four doses followed by nivolumab (480 mg every 4 weeks), only nivolumab (240 mg every 2 weeks for 6 doses and then 480 mg every 4 weeks), or the investigator’s choice of chemotherapy.⁴

PFS was the main efficacy outcome and was assessed in two settings: (1) first-line treatment with nivolumab plus ipilimumab and (2) first-line treatment with chemotherapy. Two hundred fifty-five of the 303 patients had a centrally confirmed MSI-H/dMMR status. With the second-line treatment (nivolumab plus ipilimumab vs. nivolumab alone, or all lines), patients had significantly improved PFS compared to the chemotherapy arm (median PFS, not reached vs. 5.8 months; HR, 0.21; 95% CI, 0.14–0.32; p < .0001).

The analysis of nivolumab plus ipilimumab versus nivolumab (all lines) was conducted in 582 patients (of 707 patients) with a centrally confirmed MSI-H/dMMR status. Patients treated with nivolumab plus ipilimumab had significantly improved PFS in comparison with those treated with nivolumab alone (median PFS, not reached vs. 39.3 in the nivolumab arm; HR, 0.62; 95% CI, 0.48–0.81; p = .0003).

“The findings from CheckMate 8HW continue to be compelling and indicate the superiority of nivolumab plus ipilimumab versus chemotherapy as well as compared to nivolumab alone,” says Dr Eng, adding that there are no new safety signals, with the majority of toxicity for the combination occurring within the first 6 months.

“Obviously, standard precautions remain for immuno-oncology-based therapy, but although there were more grade 1 and 3 toxicities for the combination, there were small differences for 3 and 4 toxicities for the combination versus nivolumab alone,” she says.

For frail patients with multiple comorbidities, she says that it is not unreasonable to consider a single agent alone based on KEYNOTE-177. “Keeping in mind, single-agent immuno-oncology therapy still provides a benefit to patients with reported complete responses and still remains superior to chemotherapy alone,” Dr Eng adds.

“There is definitely more to come given the developments in multi-RAS inhibitors, as well as the role of possibly using immuno-oncology therapy in the neoadjuvant setting of microsatellite stable tumors,” says Dr Eng.