Howard S. Hochster, MD, distinguished professor of medicine, associate director, Clinical Research, director, Gastrointestinal Oncology, Rutgers Cancer Institute, director, Oncology Research, RWJ Barnabas Health, discusses data from the phase 3 FRESCO-2 trial (NCT04322539) of fruquintinib (HMPL-013) plus best supportive care (BSC) in metastatic colorectal cancer (mCRC).

the FDA granted priority review to the new drug application for the highly selective and potent oral VEGF-targeted agent based on findings from the FRESCO-2 study

 The FRESCO-2 trial, which was conducted in the United States, confirmed findings from the phase 3 FRESCO trial (NCT02314819), which was conducted in China. In the FRESCO trial, the agent was shown to be an effective treatment alternative for patients in the third line or later line, following standard chemotherapy and targeted therapy.

FRESCO-2 enrolled patients with mCRC who were previously exposed to chemotherapy with fluoropyrimidine, oxaliplatin, or irinotecan; a VEGF inhibitor; or an EGFR inhibitor, provided they had 

 wild-type disease. The trial was double-blinded, except for instances in which patients developed uncontrollable hypertension. This rigorous methodology reinforces the credibility of the results. Notably, most patients on the trial who responded to the fruquintinib combination had been previously treated with regorafenib (Stivarga) or trifluridine/tipiracil (TAS-102; Lonsurf).

Results from the FRESCO-2 study showed that fruquintinib plus best supportive care produced superior overall survival (OS) and progression-free survival (PFS)benefit vs placebo and best supportive care. The median OS in the fruquintinib arm was 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, 0.662; 95% CI, 0.549-0.800; 

Data from subgroup analyses of the phase 3 FRESCO-2 trial

(NCT04322539) revealed that improved OS was observed regardless of the number of prior lines of therapy patients received or the type of prior treatment administered. Heavily pretreated patients with prior exposure to more than 4 prior lines of therapy experienced a median OS of 7.1 months (95% CI, 6.3-8.5) with fruquintinib (n = 214) vs 4.6 months (95% CI, 3.4-5.9) with placebo (n = 107; HR, 0.595; 95% CI, 0.453-0.781; 

 < .001). The agent was deemed tolerable, and its safety profile is consistent with previously reported data.

Positive outcomes from the FRESCO-2 trial have the potential to support any future FDA approval of fruquintinib in mCRC, Hochster says. The regulatory decision is anticipated to be made by November, 2023, and it is expected that an Oncologic Drugs Advisory Committee (ODAC) meeting will not be necessary, he notes. This suggests that patients may have access to this promising therapy in the near future. If approved, fruquintinib could provide patients who have exhausted other eligible therapies with another effective treatment option, Hochster concludes.

Videos

Howard S. Hochster, MD, discusses data from the phase 3 FRESCO-2 trial of fruquintinib plus best supportive care in metastatic colorectal cancer.

Dr Hochster on the FRESCO-2 Trial in mCRC

Howard S. Hochster, MD, distinguished professor of medicine, associate director for Clinical Research, director of Gastrointestinal Oncology, Rutgers Cancer Institute, and director of Oncology Research, RWJBarnabas Health, discusses the evaluation of trastuzumab (Herceptin) and pertuzumab (Perjeta) vs cetuximab (Erbitux) and irinotecan in HER2-amplified metastatic colorectal cancer (mCRC).

Findings from the phase 2 SWOG S1613 trial (NCT03365882) presented at the 2023 Gastrointestinal Cancers showed that trastuzumab/pertuzumab did not generate a superior progression-free survival compared with cetuximab/irinotecan. The median PFS was 4.4 months (95% CI, 1.9-7.6) among 26 patients treated with trastuzumab/pertuzumab vs 3.7 months (95% CI, 1.6-6.7) among 28 patients treated with cetuximab/irinotecan.

However, trastuzumab/pertuzumab generated an overall response rate of 31%, and rates grade 3 or high toxicities were 50% lower compared with cetuximab/irinotecan, showing the potential for trastuzumab/pertuzumab as a non-chemotherapy option for patients with 

 wild-type, HER2-amplified mCRC, Hochster says.

 wild-type, HER2-amplified mCRC who received up to 2 prior lines up therapy and did not receive prior cetuximab/panitumumab (Vectibix). Enrolled patients were randomly assigned to trastuzumab plus pertuzumab or cetuximab plus irinotecan, and patients in the cetuximab/irinotecan arm were allowed to cross over following disease progression.

With trastuzumab/pertuzumab representing a potential non-chemotherapy option for patients who have this biology, it is worth testing for HER2, since there is a subset of patients who may benefit from these HER2 drugs, Hochster notes.

FDA approval for tucatinib (Tukysa) plus trastuzumab for RAS wild-type HER2-positive mCRC

, based on the phase 2 MOUNTAINEER trial (NCT03043313). This approval also emphasized the importance of testing for HER2 overexpression, Hochster says.

Notably, trastuzumab/pertuzumab may provide more of benefit patients with HER2 amplification with a ratio greater than 5. Among those patients, the median PFS was 7.5 months (95% CI, 1.9-12.9) with trastuzumab/pertuzumab, compared with 3.5 months (95% CI, 1.5-6.8) for cetuximab/irinotecan. Because the patient numbers were small for this subset, the benefit for patients with a HER2 amplification ratio of more than 5 is still more of a hypothesis than a proven fact from this study, but it is important to be aware of when conducting HER2 testing, Hochster concludes.

Howard S. Hochster, MD, discusses the evaluation of trastuzumab and pertuzumab vs cetuximab and irinotecan in HER2-amplified metastatic colorectal cancer.

Dr. Hochster on Trastuzumab/Pertuzumab Vs Cetuximab/Irinotecan in HER2-Amplified mCRC 

Howard Hochster, MD, FACP, associate director for clinical research and director, Gastrointestinal Oncology, Rutgers Cancer Institute of New Jersey, director of oncology research, RWJBarnabas Health, discusses the safety analysis of TAS-102 (trifluridine/tipiracil; Lonsurf) in metastatic colorectal cancer (CRC) and metastatic gastric/gastroesophageal junction (GEJ) cancer.

These data, presented in a poster session at the 2019 ASCO Annual Meeting, relate to the use of TAS-102, which is now FDA approved in CRC and gastric/GEJ cancer. The approvals in CRC and gastric/GEJ cancer are based on the phase III RECOURSE and the phase III TAGS trials, respectively.

In the TAGS trial, TAS-102 led to a survival advantage for patients who had been previously treated with 1 or 2 prior regimens. In the RECOURSE trial, a survival advantage was seen among patients who had exhausted all standard chemotherapy drugs, explains Hochster. In this analysis, safety data from both studies were pooled and appeared consistent. The main toxicity was grade 2/3 neutropenia. There were low levels of febrile neutropenia and very little additional toxicity. These data suggest that the drug can be used in gastric/GEJ cancer as in CRC with similar toxicity management strategies, concludes Hochster.

Howard Hochster, MD, FACP, associate director for clinical research and director, Gastrointestinal Oncology, Rutgers Cancer Institute of New Jersey, director of oncology research, RWJBarnabas Health, discusses the safety analysis of TAS-102 in metastatic colorectal cancer and metastatic gastric/gastroesophageal junction cancer.

Dr. Hochster on the Safety Analysis of TAS-102 in CRC and Gastric/GEJ Cancer

Howard Hochster, MD, FACP, associate director for clinical research and director, Gastrointestinal Oncology, Rutgers Cancer Institute of New Jersey, director of oncology research, RWJBarnabas Health, discussed results from the SWOG S1513 study, which examined the use of second-line modified FOLFIRI with the PARP inhibitor ABT-888 (Veliparib) versus FOLFIRI alone in metastatic pancreatic cancer.

For the study, 123 patients were accepted. Of these patients, 108 were included in the analysis and 117 were biomarker evaluable. The most common grade 3/4 treatment-related adverse events for veliparib and FOLFIRI versus FOLFIRI alone were neutropenia (33% vs 20%), fatigue (19% vs 4%), and nausea (11% vs 4%). Median overall survival (OS) for the combination versus FOLFIRI alone was 5.1 months and 5.9 months, and the median progression-free survival was 2.1 months versus 2.9 months.

Nearly 30% of patients in the trial had DNA repair gene abnormalities; however, veliparib increased toxicity and did not improve OS when combined with FOLFIRI in biomarker unselected patients. In the future, 

and DNA damage-response biomarkers will be correlated with efficacy to inform patient selection for PARP inhibitor clinical trials.

Howard Hochster, MD, FACP, discusses results from the SWOG S1513 study, which examined the use of second-line modified FOLFIRI with PARP inhibitor ABT-888 (Veliparib) versus solely FOLFIRI in metastatic pancreatic cancer.

Howard Hochster, MD, FACP

Articles

Dr Hochster on the FRESCO-2 Trial in mCRC

Dr. Hochster on Trastuzumab/Pertuzumab Vs Cetuximab/Irinotecan in HER2-Amplified mCRC

Dr. Hochster on the Safety Analysis of TAS-102 in CRC and Gastric/GEJ Cancer

Dr. Hochster on SWOG S1513 Results in Pancreatic Cancer