Lumakras Combo May Replace SOC in Third-Line Treatment for mCRC

Dr. Marwan Fakih discussed the FDA approval of Lumakras with Vectibix for third-line KRAS G12C-mutated metastatic colorectal cancer and its future implications.

On Jan. 16, the Food and Drug Administration (FDA) approved Lumakras (sotorasib) with Vectibix (panitumumab) for adults with KRAS G12C-mutated metastatic (spreading) colorectal cancer (mCRC), as determined by an FDA-approved test, who have received previous fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, according to the drug’s manufacturer, Amgen.

This approval was based on the phase 3 CodeBreaK 300 trial.

CURE® recently spoke with the lead study investigator of the trial, Dr. Marwan G. Fakih, a Professor of Medical Oncology at City of Hope in Duarte, California and co-director of the Gastrointestinal Cancer Program at City of Hope, to discuss the drug approval’s future implications.

Future Implications for Patients

According to the news release from Amgen, the KRAS G12C mutation occurs in about 3% to 5% of colorectal cancers, as per an FDA-approved biomarker test. This highlights the critical role of comprehensive biomarker testing in mCRC. Detecting an actionable mutation allows eligible patients to receive targeted therapy, potentially improving treatment responses.

“In this day and age, every single patient with metastatic colorectal cancer should have upfront what we call next generation sequencing of their treatment, meaning full profiling of the genetic alterations of their cancer. I think it's not acceptable not to know if a patient has a KRAS mutation, and it's not acceptable not to know what is that mutation,” said Fakih.

This combination appears to be highly effective, according to Fakih. The study showed a 30% major shrinkage rate, referred to as the objective response rate, meaning more than 50% of the tumor disappeared with therapy. About half of the patients continued to benefit from ongoing responses or disease control beyond 5.7 months. For those who responded, the major shrinkage lasted, on average, more than 10 months.

“So the key here is that you can get some durable benefits in patients, and that those benefits appear to be better than the third-line treatment. So, I think this should replace any other third-line treatment, and other third-line treatments should move on to the fourth line in the KRAS G12C-[mutated] population,” said Fakih.

This combination may also compete with, and potentially be favored over, second-line chemotherapy in some patients, as stated by Fakih. Second-line chemotherapy for metastatic KRAS-mutated colorectal cancer does not show as high an objective response rate as Lumakras and Vectibix. It may also be preferred due to its safety profile. However, this is an individualized decision that should be made by the physician and patient.

Fakih also discussed a current study that is exploring the combination’s use in first-line treatment. “There has been a first line clinical trial that looked at FOLFURI, which is a standard chemotherapy used in the first line in combination with [Lumakras] and [Vectibix], and showed favorable responses that exceeded what one would expect historically.”

If the study yields positive results, it could make this option available as a first-line treatment for patients, which would have an even greater impact than what has been observed so far in third-line treatment, according to Fakih.

How and Why is it Safe?

“The KRAS inhibitor, [Lumakras], is actually very well tolerated. And the side effects are typically what we call grade 1 side effects, or grade 2 side effects, meaning they're mild side effects. So, for example, mild fatigue, mild anemia, minimal elevations in liver enzymes and so on,” said Fakih.

Lumakras is considered very safe because it specifically targets cells with the KRAS G12C mutation. The drug does not bind to normal KRAS, only to the mutated form, which is present only in cancer cells, and provides a safety advantage.

Additionally, according to Fakih, the side effects observed with the combination were primarily associated with Vectibix, an agent targeting the EGFR protein. The side effect profile was generally manageable, often presenting as skin rash or minor decreases in electrolytes like magnesium and potassium. Most toxicities were dermatological and have established treatment approaches, such as ointments, lotions or oral antibiotics. The phase 3 trial did not reveal any major surprises, and the combination was well-tolerated, with side effects consistent with those typically seen with Vectibix.

“I'm 100% certain this will not be the last progress in the coming few years, but I would look at this as a message of hope for patients who don't have many options in their treatment,” Fakih concluded.

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