Selected Abstracts on Novel Treatments in Colon, Hepatocellular, and Biliary Tract Cancers

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The ASCO Post has reported on the pivotal trials presented at the 2020 Gastrointestinal Cancers Symposium in several issues. Featured here are the findings of several additional abstracts worthy of mention.

Intermittent Oxaliplatin in Stage II or III Colon Cancer

As adjuvant treatment for stage II or III colon cancer, the intermittent use of oxaliplatin in the CAPOX regimen (capecitabine/oxaliplatin) was as effective as standard CAPOX dosing while substantially reducing long-term peripheral neuropathy, Japanese investigators reported at the meeting.1 “Peripheral sensory neuropathy lasting for 1 year, the primary endpoint of the study, was significantly decreased in the intermittent arm, and efficacy could be comparable to continuous CAPOX in terms of the disease-free survival rate at 3 years after surgery,” said Masanori Nakamura, MD, of Konan Kosei Hospital, Konan, Japan.

The 200 patients in the trial had undergone curative resection of stage II or III colon cancer and were randomly assigned to either CAPOX with continuous use of oxaliplatin (8 cycles of CAPOX) or CAPOX with intermittent use of oxaliplatin (2 cycles of CAPOX followed by 4 cycles of capecitabine followed by 2 cycles of CAPOX). At a median follow-up of 39 months, efficacy outcomes were not compromised with the intermittent use of oxaliplatin. Disease-free survival at 3 years was 78% in the continuous arm and 82% in the intermittent arm (P = .49). Overall survival rates were 95% and 97%, respectively (P = .41), reported Dr. Nakamura.

Intermittent use of oxaliplatin was associated with significantly less grade 1 or 2 peripheral sensory neuropathy (33% vs 15%; P = .01), grade 1 or 2 hand-foot syndrome (29% vs 17%; P = .05), and all-grade neutropenia (16% vs 5%; P = .03). The incidence of neuropathy across the treatment period was, by the fourth cycle, 30% with intermittent use and 83% with continuous use (P < .01) and by the 8th cycle, 65% and 87%, respectively (P = .07). During follow-up, neuropathy persisted at 1 year in 19% of the intermittent arm and 58% of the continuous arm (P < .01); neuropathy was still worrisome at 3 years in 9% and 37%, respectively (P < .01).

“Oxaliplatin was successfully reintroduced in 93% of patients in the intermittent arm, and the overall treatment completion rate was significantly higher in the intermittent arm,” said Dr. Nakamura.

Cabozantinib/Ipilimumab/Nivolumab in Advanced Hepatocellular Carcinoma

The addition of cabozantinib to nivolumab plus ipilimumab showed activity in patients with advanced hepatocellular carcinoma, in the phase I/II CheckMate 040 study conducted in China.2 The downside was the relatively high rate of treatment-related adverse events.

Thomas Yau, MD

Thomas Yau, MD

One arm of CheckMate 040 evaluated nivolumab plus cabozantinib (doublet), whereas another arm added ipilimumab to nivolumab/cabozantinib (triplet). “Both combinations showed encouraging outcomes compared with single-agent nivolumab or cabozantinib,” said Thomas Yau, MD, of the University of Hong Kong.

The study enrolled 71 patients with advanced hepatocellular carcinoma with or without previous treatment with sorafenib. Patients were randomly assigned to nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg/d; n = 36) or nivolumab (3 mg/kg), cabozantinib (40 mg/d) and ipilimumab (1 mg/kg every 6 weeks; n = 35). Patients were treated until disease progression or intolerable toxicity.

The primary efficacy endpoint, overall response rate, was higher in the triplet arm. Responses were observed in 19% of the doublet arm and 29% of the triplet arm, by investigator assessment, and 14% and 31%, respectively, by blinded central review. Disease control was achieved by 75% and 83%, respectively; the median duration of response was 8.3 months with the doublet but was not reached with the triplet. More than two-thirds of both arms experienced a decrease in target lesion size.

With a median follow-up of 19 months, median progression-free survival was 5.4 months with the doublet and 6.8 months with the triplet; median overall survival was 21.5 months with the doublet but not reached with the triplet. The 15-month overall survival rates were 64% and 70%, respectively.

Although the triplet seemed to be more active than the doublet, it was associated with a numerically higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 47% of the nivolumab/cabozantinib arm and 71% of the triplet arm. Grade 4 toxicities were reported for eight patients (11.3%) altogether, including one patient who received the doublet and seven who received the triplet. Some of the more worrisome toxicities were elevations in liver enzymes, skin disorders, lipase elevations, diarrhea, and hypertension.

Dr. Yau considered the combinations “quite promising,” but he added that longer duration of follow-up “may be necessary to better assess the true benefit-risk ratio of both the doublet and triplet combinations in patients with advanced hepatocellular carcinoma.”


Combination Therapy With Ramucirumab or Merestinib in Biliary Tract Cancer

Juan W. Valle, MD

Juan W. Valle, MD

In a global randomized phase II study of advanced biliary tract cancer in the first-line setting, neither ramucirumab nor merestinib, when added to gemcitabine and cisplatin, added benefit, according to Juan W. Valle, MD, of the University of Manchester and The Christie NHS Foundation Trust, United Kingdom.3

As background, Dr. Valle noted that the vascular growth factor (VEGF)/VEGF receptor signaling pathway is an important mediator of tumor angiogenesis and likely contributes to the pathogenesis and progression of invasive biliary tract cancer. Dysregulation of MET, AXL, elF4E, and ROS kinase pathways also supports tumorigenesis and angiogenesis, potentially contributing to resistance to cisplatin. The study evaluated the efficacy of ramucirumab (anti-VEGFR2) or merestinib (a tyrosine kinase inhibitor that targets MET and other oncoproteins) in terms of progression-free survival when added to standard treatment.

The study enrolled 309 patients from 75 sites in 18 countries onto the 2-arm study. Arm A randomly assigned patients (in a 2:1 ratio) to cisplatin/gemcitabine plus either the intravenous drug ramucirumab or placebo, whereas arm B randomly assigned patients (also in a 2:1 ratio) to cisplatin/gemcitabine plus either the oral drug merestinib or placebo. The placebo arms were pooled in the comparative analysis.

Median progression-free survival was not improved on either investigational arm: 6.5 months with ramucirumab, 7.0 with merestinib, and 6.6 with placebo. Similarly, overall survival was 10.5, 14.0, and 13.4 months, respectively. There was a trend, in fact, for the ramucirumab arm to have worse survival than the placebo arm (hazard ratio = 1.33; P = .0870). All treatments were well tolerated, and toxicity was consistent with prior reports.

“Translational biomarker work is ongoing, and preliminary evaluation suggests that sample size may be a limiting factor for the identification of potentially predictive biomarkers,” Dr. Valle said. “Alterations in genes of interest (such as MET, ROS1) were infrequent and consistent with previously reported prevalence.”

One positive finding, he added, was that “in this randomized phase II study, the use of a shared control arm allowed two-thirds of patients to access a novel therapy.” 

DISCLOSURE: Dr. Nakamura reported no conflicts of interest. Dr. Yau has received honoraria from and has consulted or advised for Bristol-Myers Squibb (the sponsor of his study) and MSD Oncology. Dr. Valle has received honoraria from Ipsen; has served as a consultant or advisor to Agios, AstraZeneca, Debiopharm Group, Delcath Systems, Genoscience Pharma, Incyte, Ipsen, Keocyt, Merck, Mundipharma EDO, Novartis, NuCana BioMed, PCI Biotech, Pfizer, Pieris Pharmaceutica, QED, Servier, and Wren Laboratories; and has received travel funds from Celgene, Nucana, and Pfizer.


1. Nakamura M, Nakayama G, Ishigure K, et al: Randomized phase II trial of CAPOX with continuous vs intermittent use of oxaliplatin as an adjuvant chemotherapy after curative resection of stage II/III colon cancer (CCOG-1302 study). 2020 Gastrointestinal Cancers Symposium. Abstract 95. Presented January 25, 2020.

2. Yau T, Zagonel V, Santoro A, et al: Nivolumab + ipilimumab + cabozantinib combination therapy in patients with advanced hepatocellular carcinoma: Results from CheckMate 040. 2020 Gastrointestinal Cancers Symposium. Abstract 478. Presented January 24, 2020.

3. Valle JW, Bai LY, Orlova R, et al: Ramucirumab or merestinib or placebo plus gemcitabine and cisplatin as first-line treatment for advanced or metastatic biliary tract cancer: A randomized, double-blind, phase II study. 2020 Gastrointestinal Cancers Symposium. Abstract 477. Presented January 24, 2020.