Patient Goals and Characteristics Play an Outsized Role in Determining First-Line Treatment for mCRC

Selecting the optimal frontline treatment regimen for patients with unresectable metastatic colorectal cancer (mCRC) requires careful consideration of multiple patient and treatment characteristics according to a presentation by Kristen K. Ciombor, MD, MSCI, at the 7th Annual School of Gastrointestinal Oncology^® (SOGO^®), hosted by Physicians’ Education Resource^®, LLC (PER^®).¹

“We have a lot of [treatment] options nowadays, which is great, but sometimes it can be overwhelming,” said Ciombor, an associate professor of medicine at Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. “It is not just biology [that we are considering] anymore. We have learned a lot about colorectal cancer and the different factors that will predict how well each of these options will work. But we [must] keep the patient in mind: performance status, comorbidities, their own goals and preferences, as well as the [effect] the treatment has on them.”

Ciombor began her presentation by outlining some of the primary decision drivers in terms of choosing a first-line therapy for patients with mCRC. Driving factors consisted of tumor characteristics, including clinical presentation and RAS/BRAF mutation status, patient characteristics, such as age and organ function, and the characteristics of the given treatment, including toxicity profile and effect on patient quality of life. Ciombor noted that often patient and treatment characteristics become even more important when choosing later lines of therapy.²

Intensive Chemotherapy Remains the Primary Option

In a review of past clinical trials, Ciombor highlighted those evaluating the intensive chemotherapy regimens FOLFOXIRI (5-fluorouracil, folonic acid, oxaliplatin, and irinotecan), FOLFIRI (5-fluorouracil, folonic acid, and irinotecan) in patients with mCRC. These included the following: the phase 3 GONO trial (NCT01219920) and a phase 3 trial from the Hellenic Oncology Research Group evaluating FOLFOXIRI vs FOLFIRI, and the phase 3 TRIBE (NCT00719797) and phase 2 OLIVIA (NCT00778102) trials, which added bevacizumab (Avastin) to intensive chemotherapy. As expected, response rates across the trials tended to increase with the addition of more chemotherapy, although this was often accompanied by an increase in toxicity. However, median overall survival (OS) and median progression-free survival (PFS) often favored the triplet regimens, which Ciombor identified as an important consideration when selecting a treatment regimen.³

Building on the PFS findings from TRIBE, the phase 3 TRIBE2 study (NCT02339116) compared FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen at disease progression (arm A; n = 340) with FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab at disease progression (arm B; n = 339). Patients received intensive treatment for up to 8 cycles and were deescalated to maintenance therapy. The primary end point of the trial was second PFS (PFS2).⁴

Patients in arm B experienced a median PFS2 of 19.2 months (95% CI, 17.3-21.4) compared with 16.4 months (95% CI, 15.1-17.5) in arm A (HR, 0.74; 95% CI, 0.63-0.88; P < .001). The median OS was 27.4 months (95% CI, 23.7-30.0) in arm B vs 22.5 months (95% CI, 20.7-24.8) in arm A (HR, 0.82; 95% CI, 0.68-0.98; P = .032).

“We saw that the PFS was statistically superior in the FOLFOXIRI arm,” Ciombor said. “The updated results also confirmed an [OS] advantage.”

Biologics and Tumor Sidedness

Ciombor moved into a discussion of the different biologic and doublet combinations available for mCRC, noting that due to the varying overall response rates (ORRs), PFS, and OS date, clinicians should take into account patient-specific factors when making a decision.

Using tumor sidedness as an example, Ciombor focused on an analysis of the phase 3 CALGB/SWOG 80405 trial (NCT00265850), in which investigators compared the addition of cetuximab (Erbitux) with the addition of bevacizumab with first-line doublet chemotherapy and found no difference in terms of OS or PFS.

However, a subgroup analysis showed that primary tumor sidedness appeared to have an effect on OS. Patients with left-sided tumors had a superior median OS in both the bevacizumab and cetuximab groups, 31.4 months (95% CI, 28.3-33.6) and 36.0 months (95% CI, 32.6-40.3), respectively. Among patients with right-sided tumors, the median OS was 24.2 months (95% CI, 17.9-30.3) and 16.7 months (95% CI, 13.1-19.4).⁵

“We still do not understand why this is completely,” Ciombor said. “[But] this is important and has changed how we think about primary tumor sidedness and where the tumor originates. It is something to certainly keep in mind.”

Single-agent and Doublet Regimens

In a review of data from doublet vs single-agent chemotherapy regimens, Ciombor said that doublet regimens often displayed better response rates vs single-agent regimens, but OS was not necessarily always superior in favor of the doublet regimens.

“That’s an important point that factors in patient tumor burden and their goal [of treatment],” Ciombor said. “At the end of the day, OS is clearly a better long-term end point, but response rate can have its role too, depending on the patient.”

In the Japanese RESPECT trial (UMIN000008866) the addition of oxaliplatin to fluoropyrimidine plus bevacizumab was evaluated in elderly patients with mCRC. Patients were randomized to receive oxaliplatin plus fluoropyrimidine and bevacizumab (n = 126) or fluoropyrimidine plus bevacizumab (n = 125). To be eligible for the trial, patients needed to be between the ages of 70 to 74 years with an ECOG performance score of 2, or at least 75 years with an ECOG performance score of 0 to 2.⁶

Results from the trial showed that patients treated with the oxaliplatin combination experienced a median PFS of 10.0 months (95% CI, 9.0-11.2) compared with 9.4 months (95% CI, 8.3-10.3) among those who did not receive oxaliplatin (HR, 0.837; 95% CI, 0.648-1.033; P = .086). The median OS was 19.7 months (95% CI, 15.5-25.5) and 21.3 months (95% CI, 18.7-24.3), respectively (HR, 1.054; 0.810-1.372). However, a difference in ORR was observed; patients who had oxaliplatin added to their treatment regimen had an ORR of 47.7% compared with 29.5% in those patients who were not treated with oxaliplatin.

“Look for the patients who need a response, that may be the portion of patients who would benefit more from doublet therapy,” Ciombor said. “But other [individuals who are] 70 [years] and above can avoid the toxicities of oxaliplatin. This is definitely a discussion to be had with your patients based on their goals and preferences.”

In the phase 2 TASCO1 trial (NCT02743221), trifluridine/tipiracil plus bevacizumab (TT-B) was compared with capecitabine plus bevacizumab (C-B) as first-line therapy for patients with mCRC who are not candidates for intensive therapy. Patients were randomized 1:1 and were stratified by RAS status, ECOG performance score, and region. The median age of patients in the TT-B group (n = 77) was 73 years (range, 43-83) and 75.5 years (range, 33-91) in the C-B arm (n = 76).⁷

Data from the trial showed that the median PFS for patients in the TT-B cohort was 9.23 months (95% CI, 7.59-11.56) vs 7.82 months (95% CI, 5.55-10.15) in the C-B group (HR, 0.71; 0.48-1.06). The median OS was 22.31 months (95% CI, 18.00-23.69) and 17.67 (95% CI, 12.58-19.81), respectively (HR, 0.78; 0.32-0.98).

In light of the findings from TASCO1, the phase 3 SOLSTICE study (NCT03869892) was initiated to compare TT-B with C-B in patients with treatment-naïve mCRC who are not eligible for standard doublet chemotherapy regimens. Patients were randomized to the TT-B group (n = 426) or the C-B group (n = 430) and were stratified based on ECOG performance status, tumor localization, and the reason for not being eligible for intensive therapy. The primary end point was PFS.⁸

Results from the trial showed that T-B was not superior to C-B in terms of PFS; the median PFS was 9.4 months (95% CI, 9.1-10.9) compared with 9.3 months (95% CI, 8.9-9.8), respectively (HR, 0.87; 0.75-1.02; P = .0464). Ciombor noted that the disease control rate for both regimens was relatively high, at 86.4% (95% CI, 82.76%-89.5%) and 85.1% (95% CI, 81.40%-88.40%), respectively. “The disease control rate was quite high in these patients [and] that’s something we always think about and worry about…we want to control their disease above anything, [and these data showed] a very high proportion [of patients] who had disease control despite having less intensive therapy,” Ciombor said.

References

1. Ciombor KK. Where do we begin? Optimizing frontline regimens in (unresectable) metastatic CRC. Paper presented at 7th Annual School of Gastrointestinal Oncology; March 26, 2022. Accessed April 1, 2022. bit.ly/3LLQDiC
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4. Cemolini C, Antoniotti C, Rossini D, et al. Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial. Lancet Oncol. 2020;21(4):497-507. doi:10.1016/S1470-2045(19)30862-9
5. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance).J Clin Oncol. 2016;34(suppl 15):3504. doi:10.1200/JCO.2016.34.15_suppl.3504
6. Hamaguchi T, Takashima A, Mizusawa J, et al. A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT). J Clin Oncol. 2022;40(suppl 4):10. doi:10.1200/JCO.2022.40.4_suppl.010
7. Van Cutsem E, Danielewicz I, Saunders MP, et el. Phase II study evaluating trifluridine/tipiracil + bevacizumab and capecitabine + bevacizumab in first-line unresectable metastatic colorectal cancer (mCRC) patients who are noneligible for intensive therapy (TASCO1): results of the final analysis on the overall survival.J Clin Oncol. 2021;39(suppl 3):14. doi:10.1200/JCO.2021.39.3_suppl.14
8. Andre AT, Falcone Y, Shparyk R, et al. Trifluridine/tipiracil plus bevacizumab vs capecitabine plus bevacizumab as first line treatment for patients with metastatic colorectal cancer (MCRC) ineligible for intensive therapy: the phase III randomized solstice study. Ann Oncol. 2022;33(2):229-230. doi:10.1016/j.annonc.2021.11.006