Treatment Personalization Is Poised to Define New Era of mCRC Therapy

Kristen K. Ciombor, MD, MSCI

New combination regimens for patients with metastatic colorectal cancer (mCRC) who have experienced disease progression after frontline therapy are emerging that include tyrosine kinase inhibitors (TKIs), EGFR and VEGF inhibitors, and novel agents as components, expanding the treatment arsenal for clinicians beyond traditional chemotherapy-based approaches. Thus, an emphasis on molecular testing is needed to sift through these options in the second and third lines of therapy.

“We say ‘first, second, and third line,’ but treatment [today] for CRC is more of a continuum, and there’s not a one-size-fits-all approach,” Kristen K. Ciombor, MD, MSCI, said. “There are ways to personalize therapy, not only molecularly, but also based on tumor burden and patient performance status, goals, and preferences; we have to take all…those things into consideration. Getting molecular status early on is important because it used to be that we had [more] time to get these data, and now we’re making firstand second-line treatment decisions based on [them]. We have more and more treatment options that are biomarker selected in the second line after initial chemotherapy. It’s important to get those data early on so that you can counsel your patients [on] the best options.”

During a recent OncLive Peer Exchange^®, a panel of expert clinicians in the CRC field discussed recent findings from pivotal clinical trials that were primarily shared during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting. In the second-line setting, the panelists discussed findings from studies including the phase 3 CodeBreaK300 trial (NCT05198934) and the phase 2 MOUNTAINEER study (NCT03043313), which examined sotorasib (Lumakras) and tucatinib (Tukysa) plus trastuzumab (Herceptin), respectively. Then they highlighted regimens in the third line and beyond, such as regorafenib (Stivarga), trifluridine/tipiracil (Lonsurf; TAS-102) with or without bevacizumab (Avastin), and fruquintinib (Fruzaqla).

Second-Line Options Rapidly Expand With an Emphasis on Personalization

During the 2024 ASCO Annual Meeting, investigators presented findings from the overall survival (OS) analysis of CodeBreaK300. This multicenter, open-label trial examined the KRAS G12C inhibitor sotorasib at a daily dose of either 960 mg (n = 53) or 240 mg (n = 53) in combination with the EGFR inhibitor panitumumab (Vectibix) vs investigator’s choice of standard-of-care trifluridine/tipiracil or regorafenib in patients with KRAS G12C–mutated metastatic CRC (mCRC) who had not received a prior KRAS G12C inhibitor. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); OS and overall response rate (ORR) represented key secondary end points.¹

Updated findings showed that the median PFS in the sotorasib 960-mg arm was 5.8 months (95% CI, 4.2-7.5), and 4.0 months (95% CI, 3.7-5.9) in the sotorasib 240-mg arm, conferring respective 54% (HR, 0.46; 95% CI, 0.29-0.72) and 43% (HR, 0.57; 95% CI, 0.37-0.88) reductions in the risk of disease progression or death compared with the investigator’s choice arm (n = 54), which delivered a median PFS of 2.0 months (95% CI, 1.9-3.9). Additionally, at a median follow-up of 13.6 months, patients in both the sotorasib 960-mg arm (HR, 0.70; 95% CI, 0.41-1.18; 2-sided P = .20) and 240-mg arm (HR, 0.83; 95% CI, 0.49-1.39; 2-sided P = .50) experienced a trend toward an OS benefit vs the control arm.

In their conclusion, the study authors advocated for sotorasib at the 960-mg daily dose level in combination with panitumumab as the new SOC therapy for patients with chemotherapy-refractory KRAS G12C–mutated mCRC.

“The improvement in OS was not statistically significant, but that’s to be expected, given that this [study] was not powered for OS,” Marwan G. Fakih, MD, who presented the CodeBreaK300 data during the meeting, explained. “One thing we learned is that the ORR went up a little bit from the last report. The ORR was 30.0% [95% CI, 18.3%-44.3%] for sotorasib 960 mg plus panitumumab, and the responses are durable. The duration of response [DOR] was 10.1 months [95% CI, 3.1-12.9+] with sotorasib 960 mg plus panitumumab. [These are] exciting data [in] refractory disease, and hopefully [this regimen is] an option for patients with a KRAS G12C mutation who progressed on prior systemic chemotherapy.”

“When you [have a patient with] a RAS mutation, don’t just close it up and say, ‘I have [a patient with] a RAS mutation.’ You must know which RAS mutation it is and note that because you now have access to KRAS G12C inhibitors in this population,” John Marshall, MD, added.

For patients without the mutation, those with RAS wild-type, HER2-positive unresectable CRC or mCRC, tucatinib plus trastuzumab is available. The combination received accelerated approval in the setting following disease progression with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy in January 2023. During the 2024 ASCO Annual Meeting, investigators presented results from the final analysis of MOUNTAINEER, which supported the 2023 regulatory decision.^2,3

At a median follow-up of 32.4 months, patients who received the combination (n = 84) achieved a confirmed ORR of 39.3% (95% CI, 28.8%-50.5%), with a median DOR of 15.2 months (95% CI, 8.9-20.5). The median PFS and OS were 8.1 months (95% CI, 4.2-10.2) and 23.9 months (95% CI, 18.7-28.3), respectively.³

“The regimen remains active, and it’s been fully incorporated into National Comprehensive Cancer Network guidelines, [including] for initial therapy if you’re concerned about [the] tolerability of combination chemotherapy, because this regimen is quite well tolerated,” Al B. Benson III, MD, FACP, FACCC, FASCO, noted. “Some of the principal adverse effects [AEs] include fatigue, diarrhea, and nausea, as well as hypertension, as one would imagine with a TKI. Overall, it’s well tolerated, and its principal indication is for subsequent therapy along with the other HER2-targeted drugs. [We now have] multiple regimens to choose from in this population.”

To conclude their discussion of second-line treatment options, the panelists spotlighted 2 Chinese studies examining novel combination regimens, the phase 2 ZL-IRIAN study (NCT05229003) and another phase 2 study (ChiCTR2200059280). ZL-IRIAN evaluated irinotecan plus the novel TKI anlotinib with or without the PD-1 inhibitor penpulimab in patients with recurrent or metastatic BRAF wildtype colorectal adenocarcinoma. The other phase 2 study evaluated the VEGF inhibitor fruquintinib (Fruzaqla) in combination with investigator’s choice of chemotherapy, followed by maintenance therapy with fruquintinib.^4,5

In ZL-IRIAN, patients with mismatch repair– proficient (pMMR)/microsatellite stable (MSS) mCRC who received the doublet (n = 23) achieved an ORR of 39.1% and a disease control rate (DCR) of 87.0%. The median PFS was 9.57 months (95% CI, 25.69-66.99); the 6- and 12-month PFS rates were 72.44% and 37.19%, respectively.⁴

In the triplet arm (n = 21), which did not require pMMR/MSS status, the ORR was 38.1%, and the DCR was 90.5%. The median PFS was not reached; the 6- and 12-month PFS rates were 74.06% and 53.46%, respectively.

“This [trial’s evidence] shows that we’re still trying to move the needle, and that should be the constant pursuit here because we have not yet figured everything out,” Stacey Cohen, MD, commented. “[The ZL-IRIAN regimen] is an interesting combination using a mild chemotherapy backbone in MSS patients. It’s an interesting trial, [but] to me, it was more thought-provoking than practice changing at this point. The problem is that we don’t know how many of these patients had prior bevacizumab, and we don’t know if this is [superior to] full FOLFIRI [leucovorin calcium, fluorouracil (5-FU), and irinotecan] plus bevacizumab or FOLFIRI alone.”

In the other phase 2 study, which also examined patients with a pMMR/MSS phenotype, efficacyevaluable patients (n = 96) achieved a median PFS and OS of 6.9 months (95% CI, 5.2-8.6) and 20.1 months (95% CI, 13.7-26.3), respectively, at a median follow-up of 9.3 months. Additionally, the ORR among these patients was 26.0% (95% CI, 17.9%- 36.2%), with a median DOR of 11.3 months (95% CI, 8.6-14.0).⁵

“The toxicity profile looked similar to what we would expect with these drugs as we get to use them more in different lines of therapy,” Ciombor said. “[This regimen] doesn’t seem to be significantly better efficacy-wise [than other options], but what I wonder [is whether] it would be preferable for patients to [receive] fruquintinib maintenance as opposed to 5-FU plus bevacizumab maintenance. [However], one has to consider not just toxicity and efficacy, but financial toxicity as well, as it’s a more expensive drug.”

Multiple Regimens Display Promise in the Third Line and Beyond

As of May 2024, there are 4 FDA-approved treatment regimens for patients needing third- or later-line treatment: regorafenib, trifluridine/ tipiracil with or without bevacizumab, and fruquintinib. However, data regarding how to properly sequence these options are still emerging.⁶

“By the third line and beyond, patients [have received a good deal of treatment],” Ciombor said. “Patients sometimes are having cancer complications and certainly having chemotherapy complications at this point. They may be having more symptoms from increasing tumor burden and residual effects from prior chemotherapy, [such as] cytopenias, neuropathy, and diarrhea. All…those [factors] play a role in how we decide [on] and sequence further therapies.”

One notable study that enrolled patients with mCRC in the third line of treatment and beyond was the phase 3 SUNLIGHT trial (NCT04737187). SUNLIGHT evaluated trifluridine/ tipiracil with and without bevacizumab in patients who experienced disease progression following treatment with a maximum of 2 prior chemotherapy-based regimens. Data from SUNLIGHT supported the August 2023 FDA approval of trifluridine/ tipiracil plus bevacizumab in patients with mCRC who previously received fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF agent, and, if they had RAS wild-type disease, an anti-EGFR agent.^7,8

Findings from the primary analysis of SUNLIGHT demonstrated that patients in the combination arm (n = 246) experienced a median OS of 10.8 months (95% CI, 9.4-11.8) compared with 7.5 months (95% CI, 6.3-8.6) among those treated with trifluridine/tipiracil alone (HR, 0.61; 95% CI, 0.49-0.77; P < .001). The median PFS was 5.6 months (95% CI, 4.5-5.9) vs 2.4 months (95% CI, 2.1-3.2), respectively.⁷

During the 2024 Gastrointestinal Cancers Symposium (ASCO GI) and the 2024 ASCO Annual Meeting, multiple abstracts were presented that aimed to further define the role of the SUNLIGHT regimen based on the characteristics of patient subgroups.

At the ASCO GI meeting, Fakih and coauthors presented findings from a subgroup analysis that examined the effect of trifluridine/tipiracil in combination with bevacizumab vs trifluridine/ tipiracil alone in patients younger than 65 years, patients aged 65 to 74 years, and those of at least 75 years of age. The hazard ratios for OS were 0.65 (95% CI, 0.48-0.87), 0.64 (95% CI, 0.43-0.94), and 0.49 (95% CI, 0.27-0.90), respectively, all of which were in favor of the combination arm.⁹

“The hazard ratio is almost the same for all the subgroups; it didn’t matter if [the patient was] younger or older. [However] there were a few more AEs for the group of patients who were 65 to 74 [years of age],” Fakih said. “It was difficult to [arrive at] a conclusive answer regarding safety for such a small group. The take-home message is if the patient is fit, and satisfied the criteria for inclusion on SUNLIGHT, they benefited, irrespective of the age group.”

Then, during the 2024 ASCO Annual Meeting, investigators presented results from another analysis of SUNLIGHT that aimed to determine the effect of colorectal liver metastases on the efficacy of trifluridine/tipiracil with or without bevacizumab. Patients with colorectal liver metastases who received the combination (n = 194) experienced a benefit in OS (HR, 0.61; 95% CI, 0.48-0.77; P < .001) and PFS (HR, 0.44; 95% CI, 0.35-0.55; P < .001) compared with those who received trifluridine/tipiracil alone (n = 188). Patients without colorectal liver metastases experienced a similar OS (HR, 0.60; 95% CI, 0.35-1.0; P = .052) and PFS (HR, 0.38; 95% CI, 0.24-0.58; P < .001) benefit with the combination (n = 52) vs trifluridine/tipiracil monotherapy (n = 58).¹⁰

“In SUNLIGHT, the individuals with liver metastases did do somewhat less well, and that may simply be a prognostic factor,” Benson explained. “However, it did appear across the board that patients did benefit with the addition of bevacizumab compared with trifluridine/ tipiracil alone. At least with this regimen, I believe it’s still fine to offer [patients] trifluridine/ tipiracil and bevacizumab; they may not do as well overall, but it’s what we might expect when [these patients] have a poor prognosis.”

Investigators also examined fruquintinib in combination with best supportive care in the third line and beyond in the phase 3 FRESCO (NCT02314819) and FRESCO-2 (NCT04322539) trials. In the Chinese FRESCO study, patients with mCRC who received fruquintinib (n = 278) following disease progression after at least 2 standard chemotherapy regimens achieved a median OS of 9.3 months (95% CI, 8.18-10.45) vs 6.57 months (95% CI, 5.88-8.11) among those who received placebo (n = 138; HR, 0.65; 95% CI, 0.51-0.83; P < .001). Building on these findings, the global FRESCO-2 trial enrolled patients with mCRC who had exhausted all standard cytotoxic and targeted treatment options and experienced disease progression on or were intolerant to trifluridine/tipiracil and/or regorafenib. Patients who received fruquintinib (n = 461) achieved a median OS of 7.4 months (95% CI, 6.7-8.2) compared with 4.8 months (95% CI, 4.0-5.8) in the placebo arm (n = 230; HR, 0.66; 95% CI, 0.55-0.80; P < .0001).^11,12

“[FRESCO and FRESCO-2] are different patient populations,” Ciombor commented. “The FDA approved fruquintinib in mCRC in the third line and beyond, which gives us some options. I typically use trifluridine/tipiracil and bevacizumab prior to fruquintinib, with the exception being possibly in patients who have cytopenias who need to recover.”

During the ASCO 2024 meeting, investigators presented findings from a pooled analysis of FRESCO and FRESCO-2 that examined the effect of prior treatment sequences in the refractory setting. Patients in both studies who received prior trifluridine/tipiracil then regorafenib (HR, 0.532; 95% CI, 0.353-0.802), prior regorafenib then trifluridine/tipiracil (HR, 0.666; 95% CI, 0.432-1.025), prior trifluridine/tipiracil only (HR, 0.723; 95% CI, 0.557-0.938), and prior regorafenib only (HR, 0.772; 95% CI, 0.379-1.573) and patients who did not receive prior trifluridine/tipiracil or regorafenib (HR, 0.652; 95% CI, 0.512-0.829) all experienced an OS benefit with fruquintinib vs placebo. Patients in these subgroups also experienced a PFS benefit with fruquintinib, with respective hazard ratios of 0.313 (95% CI, 0.210- 0.467), 0.262 (95% CI, 0.161-0.396), 0.367 (95% CI, 0.287-0.470), 0.292 (95% CI, 0.139-0.611), and 0.262 (95% CI, 0.205-0.336).¹³

“We saw [additional] data out of ASCO [2024] about possibly the only potential role for regorafenib in the larger space, and that’s in what we call ‘regorafenib plus,’” Ciombor added. “Whether in combination with immune-oncology therapy or locoregional approaches, I believe it still deserves potential exploration. But as monotherapy, it has a limited role at this point.”

References

1. Fakih M, Salvatore L, Esaki T, et al. Overall survival (OS) of phase 3 CodeBreaK 300 study of sotorasib plus panitumumab (soto+pani) versus investigator’s choice of therapy for KRAS G12C-mutated metastatic colorectal cancer (mCRC). J Clin Oncol. 2024;42(suppl 17):LBA3510. doi:10.1200/ JCO.2024.42.17_suppl.LBA3510
2. FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. FDA. January 19, 2023. Accessed August 28, 2024. https://www.fda.gov/drugs/resources-informationapproved- drugs/fda-grants-accelerated-approval-tucatinibtrastuzumab- colorectal-cancer
3. Strickler JH, Cercek A, Siena S, et al. Final results of a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC (MOUNTAINEER). J Clin Oncol. 2024;42(suppl 16):3509. doi:10.1200/JCO.2024.42.16_suppl.3509
4. Wang C, Li W, Zhu X, Geng Q, Zhao X, Guo W. Irinotecan plus anlotinib or further in combination with penpulimab as secondline treatment of metastatic colorectal cancer (ZL-IRIAN). J Clin Oncol. 2024;42(suppl 16):3570. doi:10.1200/JCO.2024.42.16_ suppl.3570
5. Zhao W, Li J, Li L, et al. Efficacy and safety of fruquintinib plus investigator’s choice of chemotherapy as second-line therapy in metastatic colorectal cancer: updated results of a multicenter, single-arm, phase 2 trial. J Clin Oncol. 2024;42(suppl 16):3571. doi:10.1200/JCO.2024.42.16_suppl.3571
6. Barzi A, Bekaii-Saab T. Sequencing considerations in the thirdline treatment of metastatic colorectal cancer. Am J Manag Care. 2024;30(suppl 2):S31-S35. doi:10.37765/ajmc.2024.89546
7. Prager GW, Taieb J, Fakih M, et al; SUNLIGHT Investigators. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388(18):1657-1667. doi:10.1056/NEJMoa2214963
8. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. FDA. August 2, 2023. Accessed August 28, 2024. https://www.fda.gov/drugs/ drug-approvals-and-databases/fda-approves-trifluridine-andtipiracil- bevacizumab-previously-treated-metastatic-colorectalcancer
9. Taieb J, Prager GW, Fakih M, et al. Efficacy and safety of trifluridine/tipiracil in combination with bevacizumab in older and younger patients with refractory metastatic colorectal cancer: a subgroup analysis of the phase 3 SUNLIGHT trial. J Clin Oncol. 2024;42(suppl 3):111. doi:10.1200/JCO.2024.42.3_ suppl.111
10. Tabernero J, Prager GW, Taieb J, et al. Impact of colorectal liver metastases (CRLM) in patients with metastatic colorectal cancer (mCRC) receiving trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) in the phase 3 SUNLIGHT trial. J Clin Oncol. 2024;42(suppl 16):3584. doi:10.1200/JCO.2024.42.16_ suppl.3584
11. 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. doi:10.1001/jama.2018.7855
12. Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer (FRESCO-2): an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402(10395):41-53. doi:10.1016/S0140-6736(23)00772-9
13. Bekaii-Saab TS, Dasari A, Eng C, et al. Efficacy and safety of fruquintinib in patients with metastatic colorectal cancer according to prior treatment sequence in the refractory setting: results from FRESCO and FRESCO-2. J Clin Oncol. 2024;42(suppl 16):3579. doi:10.1200/JCO.2024.42.16_ suppl.3579