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Topics

FDA approval of sotorasib (Lumakras) plus panitumumab (Vectibix),

 and how it may affect the treatment paradigm for patients with 

G12C-mutant metastatic colorectal cancer (CRC).

Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California.

According to Fakih, the approval of this combination regimen is a “welcome step” for those with metastatic CRC harboring 

G12C mutations. Based on supporting data from the phase 3 CodeBreaK 300 trial (NCT05198934), sotorasib/panitumumab may prolong progression-free survival (PFS) and reduce disease burden in patients while offering improvements in other outcomes vs prior standards of care (SOC) like trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga).

Topline data at the time of the approval showed a median PFS of 5.6 months (95% CI, 4.2-6.3) with sotorasib at 960 mg plus panitumumab vs 2.0 months (95% CI, 1.9-3.9) in the SOC arm, in which patients were assigned to receive trifluridine/tipiracil or regorafenib (HR, 0.48; 95% CI, 0.30-0.78; 

= .005). Additionally, the overall response rate was 26% (95% CI, 15%-40%) vs 0% (95% CI, 0%-7%) in each respective arm.

Looking ahead, Fakih highlighted the potential next steps for research associated with the sotorasib combination as well as other novel therapeutic strategies in the gastrointestinal cancer space. For example, he described the phase 3 CodeBreaK 301 study (NCT06252649), which will evaluate sotorasib/panitumumab as frontline therapy when administered in combination with folinic acid, fluorouracil, and irinotecan (FOLFIRI) vs FOLFIRI plus bevacizumab (Avastin) in metastatic 

Other novel agents under development in the space include RAS inhibitors and immunotherapy regimens combining CTLA-4 inhibitors with anti–PD-L1 agents.

FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 12, 2025. https://shorturl.at/1WviB

Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301).

 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326

The approval of sotorasib plus panitumumab is a “welcome step” in KRAS G12C-mutated colorectal cancer, according to Marwan G. Fakih, MD.

Sotorasib Combo Approval May Address Novel Therapy Need in KRAS G12C+ CRC

®, Jagoda Misniakiewicz, PharmD, a clinical pharmacy specialist in the Clinical Pharmacy and Outcomes Sciences Department at Hollings Cancer Center of the Medical University of South Carolina, spoke about the use of fruquintinib (Fruzaqla) as a treatment option for those with metastatic colorectal cancer (CRC).

The FDA previously approved fruquintinib as a treatment for those with metastatic CRC

 and prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy and anti-VEGF therapy in November 2023.

Misniakiewicz detailed the agent’s mechanism of action as a potent, orally available small molecule kinase inhibitor and its potential to inhibit blood vessel growth, thereby yielding vascular regression, normalization, and construction. Additionally, the clinical benefit of switching from intravenous therapy to this oral treatment appears to extend to any patient who has progressed on prior therapy, although she noted that there are currently no specific biomarkers or tumor characteristics that would make patients suitable candidates for fruquintinib.

The discussion also focused on the efficacy and safety data supporting the clinical utility of fruquintinib in this patient population. Specifically, Misniakiewicz highlighted the “exciting” progression-free survival (PFS) findings from the 

 which may affirm fruquintinib as a “promising treatment option” for those with refractory disease.

According to previous findings from the FRESCO-2 trial published in 

the median PFS was 3.7 months (95% CI, 3.5-3.8) with fruquintinib plus best supportive care vs 1.8 months (95% CI, 1.8-1.9) with placebo plus best supportive care (HR, 0.32; 95% CI, 0.27-0.39; 

 Additionally, the median overall survival (OS) was 7.4 months (95% CI, 6.7-8.2) vs 4.8 months (95% CI, 4.0-5.8) in each respective arm (HR, 0.66; 95% CI, 0.55-0.80; 

 <.0001). PFS and OS benefits across various patient subgroups—in which investigators stratified patients based on previous treatment with trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga), 

 mutation status, and duration of metastatic disease—were comparable with those observed in the intent-to-treat population.

“The truth is that treatment options for metastatic [CRC] are limited, and the approval of fruquintinib will hopefully bridge that gap a little bit,” Misniakiewicz said. “Oral agents have changed the landscape of treatment for patients with cancer. Furthermore, targeted agents allow us to tailor therapy with the goal of improving clinical outcomes while minimizing off target toxicities; fruquintinib will hopefully allow us to do this in patients with metastatic colorectal cancer.”

Takeda receives U.S FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed June 6, 2024. https://bit.ly/3SwkD8U

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. 

. Published online June 15, 2023. doi:10.1016/S0140-6736(23)00772-9

Oncology pharmacist Jagoda Misniakiewicz, PharmD, discusses the potential efficacy and safety profile of fruquintinib in patients with metastatic CRC.

Optimizing Metastatic CRC Outcomes Following Fruquintinib Approval 

Through elaborate multidisciplinary collaboration, institutions with National Accreditation Program for Rectal Cancer (NAPRC) standards can deliver a “high level of care” in the surgical treatment of patients with rectal cancer, according to Steven Wexner, MD, PhD, and Arielle Kanters, MD.

, Wexner and Kanters detailed the history and advancement of the NAPRC as an interdisciplinary initiative to improve the outcomes of those undergoing surgery for rectal cancer.

Wexner is the chair in the Department of Colorectal Surgery and director of the Ellen Leifer Shulman & Steven Shulman Digestive Disease Center at Cleveland Clinic, Florida, the founding chair of the NAPRC for the American College of Surgeons Commission on Cancer, and part of the executive committee of the Commission on Cancer. Kanters is a colorectal surgeon, associate fellowship program director, and surgeon leader of the NAPRC program at Cleveland Clinic Main Campus.

Wexner spoke about the inspiration for developing the NAPRC as a mission to elevate the level of surgical outcomes in patients with rectal cancer across the United States to those he observed in European countries such as the United Kingdom and Scandinavia. He enlisted leaders from organizations including the Society of Surgical Oncology and the College of American Pathologists to outline and apply appropriate standards for surgical care in rectal cancer.

Additionally, Kanters highlighted how enforcing precise guidelines and compliance measures through the NAPRC program facilitates multidisciplinary efforts with colleagues who specialize in radiology and pathology. She stated that these principles help individuals develop their skills across each department, thereby maintaining a high level of treatment for patients with rectal cancer.

Journal of the American College of Surgeons

indicated that mortality and complication rates appeared to be lower for patients who received surgery for rectal cancer at NAPRC-accredited institutions compared with those who were treated at non-accredited practices.

Wexner and Kanters also discussed how potential advancements related to the use of neoadjuvant or adjuvant therapy may further improve patient outcomes in the field. Additionally, they spoke about updated research on immunotherapy and other modalities that they anticipate at the 

2024 American Society of Clinical Oncology (ASCO) Annual Meeting.

Harbaugh CM, Kunnath NJ, Suwanabol PA, Dimick JB, Hendren SK, Ibrahim AM. Association of National Accreditation Program for Rectal Cancer Accreditation with outcomes after rectal cancer surgery. 

. Published March 28, 2024. doi:10.1097/XCS.0000000000001064

Surgical oncologists from Cleveland Clinic discuss the National Accreditation Program for Rectal Cancer and its aim to improve patient outcomes.

Ensuring Quality Rectal Cancer Surgery at NAPRC-Accredited Institutions

 at John Theurer Cancer Center, Gregory Charak, MD, highlighted advancements in surgical treatment strategies for patients with colorectal cancer (CRC) as well as other ongoing challenges in the field.

Specifically, Charak, a board-certified colorectal surgeon at Palisades Medical Center and Hackensack University Medical Center of Hackensack Meridian Health, described how minimally invasive strategies such as laparoscopic and robotic surgery have become more prevalent in the field, which have appeared to confer improvements in pain and length of hospital stay for patients. Although these minimally invasive techniques are typically preferred in this population compared with open surgery, Charak stated that he would still employ the latter depending on factors such as tumor size.

Charak also discussed the rise in CRC incidence among younger populations, which has impacted how practices conduct screening. He highlighted that patients who are in their late 20s or 30s receive recommendations to undergo colonoscopy in the event of weight changes or blood appearing in their stool, noting that he would not hesitate to perform screening even if there’s a small but real possibility of disease.

Regarding other treatment modalities in this population, Charak emphasized the potential benefits of neoadjuvant therapy. Administering neoadjuvant treatment with agents including cytotoxic chemotherapy and immunotherapy, for example, may help achieve negative-margin resections, thereby yielding less morbidity for patients.

“It’s a very exciting time to be a surgical oncologist. [There are] tremendous new treatment modalities coming down the pike. Immunotherapy, in particular, is extremely exciting because it’s such an elegant way to treat cancer: to harness and augment the body’s own defense system to eliminate a cancer rather than using cytotoxic chemicals or invasive surgery,” Charak said. “It’s a beautiful thing. If we can get it to apply to more and more tumors and figure out how to make it work, it couldn’t be more exciting.”

Modern Surgical Oncology Shifts in Colorectal Cancer Practice

Gregory Charak, MD, discusses how modalities like laparoscopic surgery and neoadjuvant immunotherapy may benefit patients with colorectal cancer.

Leveraging Surgical Oncology Advances in Colorectal Cancer Care

In a recent discussion with CancerNetwork

, Joleen Hubbard, MD, research collaborator withMayo Clinic and deputy director for clinical research at Allina Health Cancer Institute in Minneapolis, Minnesota, discussed new opportunities for patients with colorectal cancer (CRC).

In the discussion, Hubbard highlighted the potential of trastuzumab deruxtecan-nxki (Enhertu; T-DXd) in patients with HER2-expressing metastatic CRC based on studies including the phase 2 DESTINY-CRC01 trial (NCT03384940), which assessed the efficacy and safety of the agent in those who progressed after 2 or more prior regimens.

These trials may play a role in continuing HER2 inhibition downstream after the 

 of trastuzumab (Herceptin) plus tucatinib (Tukysa) in patients with metastatic HER2-positive CRC.

Hubbard also discussed the phase 3 MOUNTAINEER-03 study (NCT03043313) and its effects in the CRC space.

 This trial assessed the safety and efficacy of frontline tucatinib and trastuzumab in patients with treatment-refractory, RASwild-type, HER2-positivemetastatic CRC. Primary endpoints for this analysis showed a clinically meaningful overall response rate of 38.1% and a median duration of response of 12.4 months. Additionally, the treatment combination was well tolerated.

She said she is “optimistic” that moving HER2-directed therapy to the first-line setting, as seen in the MOUNTAINEER-03 study, may help outcomes for patients with metastatic CRC.

“It’s a very exciting space,” Hubbard said. “Because it’s only 5% to 8% of patients [who have CRC], it may not get as much attention, but there’s 150,000 new cases of [CRC] diagnosed each year. So, 5% to 8% of that is a large number of patients [whom] we need to be looking at, studying, and potentially impact with these treatments.”

Yoshino T, Di Bartolomeo M, Raghav K, et al. Final results of DESTINY-CRC01 investigating trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer. Nat Commun. 2023;14(1):1-13. doi:10.1038/s41467-023-38032-4

Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. FDA. January 19, 2023. Accessed December 6, 2023. https://bwnews.pr/3Xpzbqn

Bekaii-Saab TS, Van Cutsem E, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. J Clin Oncol. Published online January 24, 2023.doi:10.1200/jco.2023.41.4_suppl.tps261

New studies and treatment options prove to be effective in treating metastatic CRC, notes Joleen Hubbard, MD. 

Joleen Hubbard, MD, Highlights The “Exciting Space” Of Metastatic CRC 

During an overview of the current standard of care for patients with colorectal cancer (CRC)

, Tanios S. Bekaii-Saab, MD noted that as molecular testing becomes more important, researchers are looking into how to best personalize therapy for optimal outcomes. He spoke with CancerNetwork

 program focused on testing and treatment options for patients with metastatic CRC. 

When discussing the future direction of CRC care strategies, it is possible that treatment will be tailored to the individual based on mutation status, such as 

 V600E, said Bekaii-Saab, leader of the Gastrointestinal Cancer Program and medical director of the Cancer Clinical Research Office, and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic.

Bekaii-Saab noted that his institution is investigating select treatments in earlier lines of therapy, as chemotherapy plus or minus a biologic is the current standard of care. He also highlighted the importance of a multidisciplinary team approach, as he knows working with radiologists, and surgeons is important to provide patients with the best care.

At the time of the interview, fruquinintib (Fruzaqla) was pending approval for patients with previously treated metastatic CRC. On November 8, 2023, 

 based on results from the phase 3 FRESCO-2 trial (NCT04322539).

 Investigators of the trial reported a median overall survival of 7.4 months (95% CI, 6.7-8.2) in the fruquintinib arm vs 4.8 months (95% CI, 4.0-5.8) in the placebo arm (HR, 0.66; 95% CI, 0.55-0.80; 

Fruquintinib will now join trifluridine/tipiracil (Lonsurf) or regorafenib (Stivarga) as part of the second-line landscape and beyond for patients with previously treated CRC, Bekaii-Saab explained.

In closing, he stated that he is optimistic about the future of CRC treatment, as there is the potential for the development of new targeted therapies, immunotherapies, and gene editing therapies that will lead to more personalized and effective treatments for CRC patients.

“The biggest takeaway from the discussion with my esteemed colleagues today relates to further understanding the complexities that have emerged with the availability of multiple targeted options in metastatic CRC,” he concluded.

Takeda receives U.S FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed November 8, 2023. https://bit.ly/3SwkD8U

Expert Insights Into Testing and Treatment for Metastatic Colorectal Cancer (mCRC)

Personalized therapy tailored for mutation status is something to expect in the coming years for colorectal cancer treatment, notes Tanios S. Bekaii-Saab, MD. 

Tanios S. Bekaii-Saab, MD, Speaks to Expanding Horizons in CRC Treatment 

Kristen K. Ciombor, MD, MSCI, an assistant professor in the Division of Hematology/Oncology in the Department of Medicine at the Vanderbilt University Medical Center, recently spoke at an 

 regarding updates in the world of metastatic colorectal cancer (CRC).

In this episode of the ONCOLOGY® On the Go Podcast, she discusses treatment updates, molecular testing options, and emerging targets in CRC. Ciombor also highlighted ongoing research in the space, including the phase 3 BREAKWATER (NCT04607421)

 trial and the phase 3 MOUNTAINEER-03 (NCT05253651)

 trial. She also discussed some of the most important presentations from the 

2023 European Society for Medical Oncology (ESMO) Congress

, including those covering the phase 2 MOUNTAINEER study (NCT03043313)

 and the phase 3 KEYNOTE-811 trial (NCT03615326).

 Additionally, she spoke about her work in the phase 2 ECOG-ACRIN trial (NCT04751370) assessing neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with microsatellite instability-high or mismatch repair deficient rectal cancer.

“I’m hoping that we see more treatment options for patients [and that] we identify more patient subtypes that we can target and find actionable alterations for,” Ciombor said.

Kopetz S, Grothey A, Yaeger R, et al. BREAKWATER: randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC). J Clin Oncol. Published online May 28, 2021. doi:10.1200/jco.2021.39.15_suppl.tps3619

Bekaii-Saab TS, Van Cutsem E, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. J Clin Oncol. Published online January 24, 2023. doi:10.1200/jco.2023.41.4_suppl.tps261

Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. Published online May 24, 2023. doi:10.1016/S1470-2045(23)00150-X 

Janjigian YY, Kawazoe A, Bai Y, et al. embrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424

Ciombor KK, Hong SC, Eng C, et al. EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors. J Clin Oncol. Published online June 2, 2022. doi:10.1200/jco.2022.40.16_suppl.tps3644

Expert Insights into Testing and Treatment for HER2-Positive Metastatic Colorectal Cancer (mCRC)

New treatment updates could help find more patient subtypes to target and treat in the world of CRC, according to Kristen K. Ciombor, MD, MSCI.

Multidisciplinary Care and New Treatment Options in CRC

In this episode of the ONCOLOGY On the Go Podcast, Arvind N. Dasari, MD, and Cathy Eng, MD, speak to data supporting fruquintinib (Elunate), a VEGFR-1, -2, and -3 inhibitor as a potential treatment for patients with metastatic colorectal cancer (CRC).

Arvind N. Dasari, MD, and Cathy Eng, MD, discuss clinical trial data that may support the FDA approval of fruquintinib in metastatic colorectal cancer, and how it may impact the standard of care.

Colorectal Cancer

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