Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie, head, Medical Oncology Department, St. Antoine Hospital, Paris, discusses the efficacy of trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin) in patients with metastatic colorectal cancer (mCRC) and the safety profiles of the 2 arms of the phase 3 SOLSTICE trial (NCT03869892).

Dr Andre on Efficacy With TAS-102 Plus Bevacizumab in mCRC

The SOLSTICE trial evaluated the efficacy and safety of TAS-102 in combination with bevacizumab vs bevacizumab in combination with capecitabine (Xeloda) in treatment-naïve patients with unresectable mCRC who were unfit for intensive chemotherapy. In this trial, patients in the TAS-102 arm achieved a median progression-free survival (PFS) of 9.4 months (95% CI, 9.1-10.9) vs 9.3 months (95% CI, 8.9-9.8) in those in the capecitabine arm, missing the trial’s primary end point (HR, 0.87; 95% CI, 0.75-1.02). Overall survival (OS), the trial’s key secondary end point, was also not met. The median OS was 19.74 months (95% CI, 18.04-22.40) in the TAS-102 arm vs 18.59 months (95% CI, 16.82-21.39) in the capecitabine arm (HR, 1.06; 95% CI, 0.90-1.25).

Conversely, the phase 3 SUNLIGHT trial (NCT04737187), which investigated TAS-102 plus bevacizumab vs TAS-102 alone in patients with pretreated mCRC, demonstrated positive results with the TAS-102 combination in the third-line setting. In this trial, patients in the bevacizumab arm achieved a median OS of 10.8 months compared with 7.5 months in those in the TAS-102 monotherapy arm (HR, 0.61; 95% CI, 0.49-0.77; 

 < .001). In addition, the median PFS was 5.6 months with the combination vs 2.4 months with the monotherapy (HR, 0.44; 95% CI, 0.36-0.54; 

The findings from SUNLIGHT and SOLSTICE indicate that although TAS-102 plus bevacizumab should be the third-line standard of care in mCRC, this regimen was not superior to capecitabine plus bevacizumab in the first-line mCRC setting, and therefore should not be used as a first-line regimen, Andre says.

Dr Andre on the Safety Profiles of TAS-102 Plus Bevacizumab and Capecitabine Plus Bevacizumab in mCRC

In the SOLSTICE trial, the most common toxicities in the TAS-102 and capecitabine arms, respectively, were neutropenia (54% vs 1%) and hand-foot syndrome (0% vs 15%), Andre explains. The toxicity profiles may differ between the 2 arms because of differences in the bevacizumab dosing schedule, Andre notes. In the TAS-102 arm, patients received TAS-102 at 35 mg/m

 twice daily on days 1 through 5 and 8 through 12 plus bevacizumab at 5 mg/kg on days 1 and 15 of each 28-day cycle. In the capecitabine arm, patients received capecitabine at 1000 mg/m

 twice daily on days 1 through 14 plus bevacizumab at 7.5 mg/kg on day 1 of each 21-day cycle.

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Thierry Andre, MD, discusses the efficacy of trifluridine/tipiracil plus bevacizumab in patients with metastatic colorectal cancer and the safety profiles of the 2 arms of the phase 3 SOLSTICE trial.

Dr Andre on the SOLSTICE Trial in mCRC

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), head, Medical Oncology Department, St. Antoine Hospital, Paris, discusses negative overall survival results and updated safety data from the phase 3 SOLSTICE trial (NCT03869892) in metastatic colorectal cancer (mCRC).

The SOLSTICE study investigated the efficacy of trifluridine/tipiracil (TAS-102; Lonsurf) plus bevacizumab (Avastin) vs capecitabine (Xeloda) and bevacizumab for patients with unresectable mCRC who were ineligible for intensive chemotherapy in the first-line setting, Andre says. Previously reported efficacy results from this trial were negative, as the study did not meet its primary end point of improved progression-free survival (PFS) with the experimental regimen. Patients who received the trifluridine/tipiracil regimen had a median PFS of 9.4 months (95% CI, 9.1-10.9) vs 9.3 months (95% CI, 8.9-9.8) with the control (HR, 0.87; 95% CI, 0.75-1.02; 

Analysis of the key secondary end point of overall survival (OS), as well as updated safety data, were presented at the 2023 ASCO Annual Meeting, Andre continues. Ultimately, the trifluridine/tipiracil regimen failed to produce a significant improvement in OS vs capecitabine and bevacizumab in this population, he states. Median OS with the experimental regimen was 19.74 months (95% CI, 18.04-22.40) vs 18.59 months (95% CI, 16.82-21.39) with the control regimen (HR, 1.06; 90% CI, 0.90-1.25), he expands. Both regimens also produced a similar likelihood of survival at different time points.

Notably, the study identified several factors correlated with a higher OS, including age 70 years or younger, 

left-sided primary disease, surgical resection of the primary tumor, 1 to 2 metastatic sites, lack of liver metastasis, a neutrophil-to-lymphocyte ratio lower than 3, Charlson Comorbidity Index score of 0 vs 1 to 2 or 1 to 2 vs 3 or higher, and ECOG performance status of 0 vs 1 and 1 vs 2. However, no significant treatment effect was identified with the experimental regimen vs control after adjusting for these prognostic factors.

Disclosures: Dr Andre reported serving as a consultant or in an advisory role for Amgen, Aptitude Health, Astellas Pharma, AstraZeneca/MedImmune, Bristol-Myers Squibb, GamaMabs Pharma, Gilead Sciences, GlaxoSmithKline, Gritstone Bio, Kaleido Biosciences, MSD Oncology, Nordic Bioscience, Pierre Fabre; Seagen, SERVIER, Tesaro, Transgene; he received honoraria from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Merck Serono, Pierre Fabre, Roche/Genentech, Sanofi, Seagen, SERVIER, Ventana Medical Systems; he received funding for travel-related expenses from MSD Oncology; he disclosed uncompensated relationships with the Adjuvant Colon Cancer End Points (ACCENT) Collaborative Group, ARCAD Foundation, and Gercor.

Thierry Andre, MD, discusses negative overall survival results and updated safety data from the phase 3 SOLSTICE trial in metastatic colorectal cancer.

Dr Andre on Survival Results From the SOLSTICE Trial in mCRC

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discusses the rationale for the phase 3 KEYNOTE-177 trial in metastatic colorectal cancer (mCRC).

The standard treatment for patients with mCRC is chemotherapy plus cetuximab (Erbitux), panitumumab (Vectibix), or bevacizumab (Avastin), says Andre. However, patients with microsatellite instability—high (MSI-H) mCRC receive limited benefit from this regimen in terms of progression-free survival and response rates compared with patients with microsatellite stable disease.

As such, KEYNOTE-177 randomized patients with MSI-H/mismatch repair deficient mCRC to pembrolizumab (Keytruda) versus standard of care chemotherapy with or without bevacizumab or cetuximab as first-line therapy.

Phase 2 data suggested that previously treated patients with MSI-H tumors can derive survival benefit from pembrolizumab, explains Andre.

Additionally, MSI-H mCRC is associated with a high tumor burden and neoantigen load and therefore is thought to be responsive to immunotherapy, concludes Andre.

Thierry Andre, MD, discusses the rationale for the phase 3 KEYNOTE-177 trial in metastatic colorectal cancer.

Dr. Andre on the Rationale for the KEYNOTE-177 Trial in mCRC

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discusses the future of immunotherapy for patients with metastatic colorectal cancer (mCRC).

The CheckMate-142 study of nivolumab (Opdivo) with ipilimumab (Yervoy) reported that of 119 patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) mCRC, the overall response rate was 55% and disease control rate was 80% at 12 weeks. The 9-month progression-free survival was 76%, and the ORR was 87%.

This trial not only established a possible new standard of care for these patients, but indicates that using select patient populations is the future of testing immunotherapy in cancer, says Andre. It is not beneficial to treat all patients, he adds, but the success of combinations might allow for larger populations to benefit from immunotherapy.

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discusses the future of immunotherapy for patients with metastatic colorectal cancer.

Dr. Andre Discusses the Future of Immunotherapy in mCRC

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discusses the results of the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC).

In the first report of the full cohort from the CheckMate-142 study at the 2018 Gastrointestinal Cancer Symposium, investigators conclude that the combination of nivolumab and ipilimumab built on the efficacy reported with nivolumab monotherapy. This resulted in enhanced clinical benefit with a manageable safety profile.

Patients on the study received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab monotherapy at 3 mg/kg every 2 weeks.

Of 119 patients with dMMR/MSI-H mCRC, the overall response rate was 55% and disease control rate was 80% at 12 weeks, says Andre. Additionally, the 9-month progression-free survival was 76%, and the overall response rate was 87%. This combination may represent a new standard of care for this population of patients.

Thierry Andre, MD, professor of medical oncology, University Pierre et Marie Curie (UMPC), and Head of the Medical Oncology Department in St. Antoine Hospital, Assistance Publique Hôpitaux de Paris, discusses the results of the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer.
 

Thierry Andre, MD

Articles

Dr Andre on the SOLSTICE Trial in mCRC

Dr Andre on Survival Results From the SOLSTICE Trial in mCRC

Dr. Andre on the Rationale for the KEYNOTE-177 Trial in mCRC

Dr. Andre Discusses the Future of Immunotherapy in mCRC

Dr. Andre on Nivolumab Plus Ipilimumab in dMMR/MSI-H mCRC