Dr Foote on the Ongoing Debate Over Upfront EGFR Inhibitor Use in CRC

“I’m using [EGFR inhibitors] more and more up front now for my patients, especially if they’re young and they're healthy, and especially if I think we need a [to achieve a] big response that enables something else, like surgery. If they have a lot of symptoms from their cancer, and I want to shrink it quickly to make them feel better, then I would include EGFR inhibitors in my frontline [treatment approach]."

Michael Foote, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the ongoing debate regarding the use of EGFR inhibitors in the frontline setting or in subsequent lines of therapy for patients with metastatic colorectal cancer (CRC).

The phase 3 PARADIGM study (NCT02394795) demonstrated that using the EGFR inhibitor panitumumab (Vectibix) in the first-line treatment of patients with 

wild-type, left-sided CRC provides a survival benefit of 3.6 months compared with standard first-line therapy. However, only approximately half of the patients in the panitumumab and bevacizumab arms went on to receive subsequent treatment with bevacizumab and panitumumab, respectively. For example, 41.8% of the patients in the control arm who received chemotherapy plus bevacizumab (Avastin) did not subsequently receive an EGFR inhibitor, despite evidence from other studies confirming their survival benefit, Foote reports. This raises questions about whether the observed benefit with panitumumab would remain if all patients had received the agent in subsequent lines of therapy, he states.

A practical challenge in real-world treatment settings is that patients may become too ill to tolerate subsequent therapy, underscoring the importance of administering effective treatments earlier in the disease course, Foote notes. Delivering EGFR inhibitors upfront can ensure patients receive this active therapy, as delaying treatment may render some patients ineligible due to disease progression or declining performance status, Foote says.

Globally, many oncologists incorporate EGFR inhibitors into the first-line setting for patients with 

 wild-type, left-sided tumors, particularly when a strong response is needed for symptom control or to enable surgical intervention, Foote continues. However, concerns about adverse effects, such as rash, and the lack of definitive evidence that upfront use is superior, lead some centers to reserve EGFR inhibitors for later lines of therapy, he explains. Ultimately, the decision is individualized, with factors such as patient age, health status, tumor burden, and treatment goals influencing the choice, Foote says. Increasingly, younger and healthier patients, or those requiring a robust response, are considered candidates for upfront EGFR inhibitor use, he concludes.

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Michael Foote, MD, discusses the use of EGFR inhibitors in the first vs subsequent lines of therapy for patients with metastatic colorectal cancer.


Michael Foote, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the use of tucatinib (Tukysa) plus trastuzumab (Herceptin) compared with chemotherapy in the management of 

-amplified metastatic colorectal cancer (mCRC).

Although mutations in HER2 can occur in mCRC, they are unlikely to be responsible for the initiation of HER2-positive cancer, Foote clarifies. Instead 

 amplification has been implicated as the oncogenic driver and is therefore a clinically actionable target for treatment approaches, Foote says.

On January 19, 2023, the FDA granted accelerated approval to tucatinib and trastuzumab for the treatment of patients with 

 wild-type HER2-positive unresectable or metastatic colorectal cancer who progressed on prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This approval was based on efficacy data from the phase 2 MOUNTAINEER study (NCT03043313).

In this combination, trastuzumab works by binding to the extracellular HER2 receptor, Foote explains. Meanwhile, the TKI tucatinib operates intracellularly by inhibiting kinase signaling pathways, thereby preventing proliferation, he details.

According to data from the primary analysis of the MOUNTAINEER study, the combination of tucatinib and trastuzumab is well tolerated, and adverse effects (AEs) were deemed manageable, Foote reports. The combination regimen has a similar safety profile to that of chemotherapy, with the most common AE being diarrhea, followed by fatigue. However, the treatment discontinuation rate with the combination regimen is lower than that of chemotherapy, Foote states.

Notably, median overall survival (OS) with the combination in patients who were heavily pretreated and displayed resistance to chemotherapy was 2 years, Foote adds. This is substantially longer than the OS rate with chemotherapy, as chemotherapy resistance often develops within a few months of treatment initiation, Foote notes. Moreover, the overall response rate was 38.1%, and the median duration of response was 12.4 months in patients treated with the combination, Foote concludes.

Micheal Foote, MD, discusses the use of tucatinib plus trastuzumab compared with chemotherapy in the management of HER2-amplified metastatic colorectal cancer.

Dr Foote on the Use of Tucatinib Plus Trastuzumab in HER2-Amplified mCRC

Micheal Foote, MD, medical oncologist, assistant attending physician, Memorial Sloan Kettering Cancer Center, discusses the quest to determine optimal sequencing of current therapeutics in the third-line setting and beyond for metastatic colorectal cancer (mCRC).

Findings from the phase 3 SUNLIGHT trial (NCT04737187), which is examining the use of trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin) as a third-line treatment in patients with refractory mCRC were presented at the 2023 Gastrointestinal Cancers Symposium. Results demonstrated that the combination improved overall survival (OS) and disease control vs TAS-102 alone in this patient population, in all clinically relevant subgroups.

Based on these findings, the combination of TAS-102 and bevacizumab will likely continue as a standard third-line treatment after all acceptable targeted therapies have been exhausted, according to Foote. After patients have progressed on this regimen, they may receive regorafenib (Stivarga), followed by fruquintinib (Inrebic), Foote says. Attempts to create a definitive guideline on the optimal sequence of TAS-102 vs regorafenib in this setting are ongoing, he notes.

The emergence of fruquintinib may have addressed the need for a novel therapeutic option in the fourth line and beyond, Foote adds. In June 2020, the FDA granted a fast track designation to fruquintinib based on findings from the phase 3 FRESCO-2 study (NCT04322539). In this trial, treatment with fruquintinib resulted in a statistically significant improvement in OS, as well as progression-free survival, which served as a key secondary end point. The agent was deemed tolerable, and its safety profile was consistent with previously reported data.

Notably, a significant amount of the population in FRESCO-2 who responded to fruquintinib had previously progressed on TAS-102 and regorafenib, Foote emphasizes. This indicates that the regimen may be an optimal choice for these patients in later lines, he explains. The potential utility of fruquintinib in earlier lines of treatment is also an area of interest for continued research, Foote adds. The agent’s safety profile may be favorable compared with other VEGF inhibitors, which makes it an attractive option for further investigation in this space, he concludes.

Micheal Foote, MD, discusses the quest to determine optimal sequencing of current therapeutics in the third-line setting and beyond for metastatic colorectal cancer.

Michael Foote, MD

Articles

Dr Foote on the Ongoing Debate Over Upfront EGFR Inhibitor Use in CRC

Dr Foote on the Use of Tucatinib Plus Trastuzumab in HER2-Amplified mCRC

Dr. Foote on the Quest to Determine Optimal Sequencing in Late-line mCRC