Toxicity Considerations With Third-Line Treatment in KRAS Wild-Type mCRC

In a virtual Case-Based Roundtable event, Midhun Malla, MD, MS, associate professor of Medicine and section chief of GI oncology, University of Alabama at Birmingham, guided participants through the selection of third-line treatment for a patient with KRAS wild-type metastatic colorectal cancer (mCRC). Malla reviewed phase 3 trial data across approved treatment options in this setting and led a discussion that focused on how toxicity profiles, as much as efficacy data, drive treatment selection in third-line mCRC.

Register today to join a Case-Based Roundtable near you.

CASE SUMMARY

• 58-year-old female teacher was diagnosed with mCRC 3 years ago. The primary tumor was in the sigmoid colon with metastatic lesions in the liver and peritoneal implants.
• Controlled hypertension; Type 2 diabetes; History of deep vein thrombosis (DVT) 5 years ago
• Tumor genomics: MSS, RAS WT, BRAF WT, HER2 negative, low TMB
• FOLFOX/bevacizumab (Avastin) in the first-line with initial partial response; oxaliplatin discontinued after 3 cycles due to grade 2 peripheral neuropathy and diarrhea; continued on 5-FU/leucovorin plus bevacizumab; progression after 11 months of therapy
• FOLFIRI/cetuximab in the second-line with initial disease control; progression after 8 months of therapy; patient experienced grade 1 skin rash managed with topical treatments
• Currently: grade 1 fatigue worsening toward end of each treatment cycle and grade 1 myelosuppression; last imaging showed mixed response with no new lesions; ECOG PS = 1 (intermittently 2 for several days after each chemotherapy cycle)
• Labs: white blood cell 3.2 x10⁹/L; hemoglobin 10.2 g/dL; platelets 95 x 10⁹/L; ALT 65 U/L; AST 58 U/L
• Received trifluridine and tipiracil (Lonsurf) + bevacizumab as third-line therapy; currently on month 4 of treatment

EVENT RECAP

Malla and participants discussed how to select and sequence third-line therapy for patients with KRAS wild-type mCRC. Treatment options in the setting primarily consist of 3 FDA-approved regimens: trifluridine and tipiracil plus bevacizumab, fruquintinib (Fruzaqla), and regorafenib (Stivarga.) Each of these treatments has phase 3 supporting evidence; however, no head-to-head comparisons exist.

Malla walked through the major datasets in this setting. The phase 3 SUNLIGHT trial (NCT04737187) showed a median overall survival (OS) of 10.8 months with trifluridine/tipiracil plus bevacizumab vs 7.5 months with trifluridine and tipiracil alone HR, 0.61; 95% CI, 0.49-0.77; P < .001).¹ For fruquintinib, the phase 3 FRESCO trial (NCT02314819) established a median OS of 9.3 months vs 6.6 months with placebo (HR, 0.65; 95% CI, 0.51-0.83) in a third-line Chinese population of patients with mCRC.² The global FRESCO-2 trial (NCT04322539), which required prior exposure to trifluridine and tipiracil or regorafenib and therefore enrolled a later-line population than the patient under discussion, showed OS of 7.4 months vs 4.8 months (HR, 0.66; 95% CI, 0.49-0.77).³ Regorafenib in the phase 3 CORRECT trial (NCT01103323) mCRC produced a median OS of 6.4 months vs 5.0 months with placebo (HR, 0.77; 95% CI, 0.64-0.94).⁴

The panel noted that the efficacy differences across the trials, while modest, do seem to favor the SUNLIGHT data. And Mala also noted that the SUNLIGHT trial's use of an active comparator rather than placebo distinguished it from the fruquintinib and regorafenib trial datasets.

Overall, given the modest efficacy difference across the trials, much of the discourse focused on how the toxicity profiles for each of the treatments might affect patient selection. “I feel like I'm kind of running away from toxicity as opposed to trying to really run for being attracted toward the major efficacy of these agents," said Solly Chedid, Singing River Health System, Gulfport, Mississippi.

Some of the specific toxicities of note associated with the agents include myelosuppression with trifluridine and tipiracil, hand-foot syndrome and hepatotoxicity with regorafenib, and hypertension with fruquintinib. These toxicities carry their own clinical implications depending on the patient's comorbidities and prior toxicity burden.

Some of the participants explained their toxicity-based rationale for choosing regorafenib or fruquintinib. Thomas Reske, MD, PhD, associate professor of Clinical Medicine at LSU Health in New Orleans, chose regorafenib over trifluridine/tipiracil for a patient with borderline hematologic issues, citing the latter's myelosuppressive risk and his own success minimizing adverse events by starting at a low dose and gradually uptitrating as tolerated. Kameron Shahid, MD, Ochsner Health, also cited myelosuppression and cytopenias with his choice of fruquintinib.

However, Daniel Vaena, MD, highlighted key toxicity issues with regorafenib and fruquintinib:

"When it comes to an individual patient, to me, it's toxicity rather than focusing on the survival benefits. I've seen some of those third-line patients that are already starting to decline quite a bit get admitted with horrible complications from regorafenib or fruquintinib sometimes. These orals can sometimes be worse in terms of hypertension issues, the asthenia, the oral mucositis that you can see with some of those orals, if the patient’s performance status is declining, or if they have impending very large amount of intraabdominal disease. So I think you have to be very careful,” said Vaena MD, of Westminster Center in Memphis, Tennessee.

The issue of bevacizumab rechallenge was addressed with the selection of trifluridine and tipiracil plus bevacizumab. "I was questioning about the history of DVT and utility of bevacizumab, but it sounds like she rocked it in the first line, so probably able to rechallenge in third line,” said Ryan Griffin MD Ochsner Health. Malla expanded on the question of prior bevacizumab exposure and its effect on the SUNLIGHT benefit, noting that subgroup data showed a statistically significant OS benefit with trifluridine and tipiracil plus bevacizumab in the prior-bevacizumab subgroup.

Overall, the group consensus was that considering the benefit-risk profile in totality, trifluridine and tipiracil plus bevacizumab, with the optimal choice, with 80% of attendees making this choice. However, they agreed that the third-line treatment choice for each individual patient with mCRC must separately consider their tolerance for specific toxicities and their treatment goals.

REFERENCES:

1. Tabernero J, Prager GW, Fakih M, et al. Trifluridine plus tipiracil with or without bevacizumab for patients with refractory metastatic colorectal cancer (SUNLIGHT): a double-blind, randomised, phase 3 trial. N Engl J Med. 2023;388(18):1657-1667.

2. Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319(24):2486-2496.

3. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): a global, randomised, double-blind, placebo-controlled, phase 3 study. Lancet. 2023;402(10395):41-53.

4. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):303-312.