Brief Update on Clinical Trials of New Treatments in Gastrointestinal Cancers

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The 2019 ASCO Annual Meeting provided attendees with an abundance of clinically relevant abstracts in gastrointestinal cancers. Briefly featured here are clinical trial updates on pembrolizumab in the second-line treatment of hepatocellular carcinoma (KEYNOTE-240 trial), laparoscopic vs open resection of colorectal cancer liver metastases, rivaroxaban thromboprophylaxis in patients with pancreatic cancer (CASSINI trial), and active symptom control with or without chemotherapy for biliary tract cancer (ABC-06 trial).

Pembrolizumab in Second-Line Treatment of Hepatocellular Carcinoma

In a phase III study that followed the approval of pembrolizumab for previously treated patients with hepatocellular carcinoma, the risk of death was reduced by 22%, but the study did not meet the prespecified efficacy boundary for statistical significance, reported Richard S. Finn, MD, of the University of California, Los Angeles.1

“These results are consistent overall with those of KEYNOTE-224, further supporting second-line therapy with pembrolizumab in patients with hepatocellular carcinoma.”
— Richard S. Finn, MD

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Pembrolizumab received accelerated approval based on the results of the KEYNOTE-224 trial, a phase II study in patients with advanced hepatocellular carcinoma in the second-line setting. The current study, KEYNOTE-240, was a randomized, placebo-controlled, phase III study of pembrolizumab versus best supportive care in 413 patients with previously treated advanced hepatocellular carcinoma. The dual primary endpoints were overall survival and progression-free survival.

After a median follow-up of 13.8 months, pembrolizumab produced a numerical improvement in overall survival from 10.6 months on the placebo arm to 13.9 months with pembrolizumab; hazard ratio [HR] = 0.0781; P = .0238) and progression-free survival (HR = 0.775; P = 0.0186) vs placebo. However, these differences did not meet significance per the prespecified statistical plan.

Responses were observed in 18.3% of patients treated with pembrolizumab and 4.4% of patients treated with placebo (P = .00001). The median duration of response was 13.8 months with pembrolizumab.

“These results are consistent overall with those of KEYNOTE-224, further supporting second-line therapy with pembrolizumab in patients with hepatocellular carcinoma,” Dr. Finn concluded. He said a similar phase III study, KEYNOTE-394, is ongoing in the Asia-Pacific region.

Additional Commentary

William P. Harris, MD

William P. Harris, MD

Study discussant William P. Harris, MD, of the University of Washington School of Medicine, Seattle, commented that although statistical significance was not met in the KEYNOTE-240 trial, pembrolizumab did produce favorable, clinically relevant outcomes, and he will continue to prescribe it in the second-line setting, especially to patients with poor tolerance to tyrosine kinase inhibitors. He suggested that future investigators “consider reassessment of statistical assumptions, given there are third-line options,” and noted the need for immunotherapy trials to “capture the tail of the curve.” He also hopes the U.S. Food and Drug Administration will not withdraw approval of pembrolizumab for this indication, pending results of the KEYNOTE-394 trial.

Laparoscopic vs Open Surgery for Liver Metastases

In the randomized OSLO-COMET trial, resection of colorectal liver metastases by laparoscopy proved to be as safe and as effective as open surgery.2 The study of 280 patients was conducted in Norway, where the laparoscopic technique is frequently performed. It is a parenchyma-sparing surgery that leaves a maximum amount of healthy liver. In the United States, just 22% of resections are performed laparoscopically.

“We think more hospitals should establish a laparoscopic liver surgery program.”
— Åsmund Avdem Fretland, MD

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Despite the increasing use of laparoscopic liver surgery, this is the first randomized study to compare long-term oncologic outcomes and safety, said Åsmund Avdem Fretland, MD, of Oslo University Hospital.

After the laparoscopic resection, patients lived a median of 80 months, compared with 81 months after open surgery. For laparoscopic vs open surgery, respectively, survival rates were 94% and 93% at 1 year, 71% and 71% at 3 years, and 56% and 57% at 5 years. Respective recurrence-free survival rates were 53% and 54% at 1 year, 34% and 39% at 3 years, and 29% and 31% at 5 years. The median recurrence-free survival was 19 and 16 months, respectively, Dr. Fretland reported.

Laparoscopic surgery was associated with fewer complications, shorter hospital stays, and better quality of life, without an increase in cost.3 “Laparoscopy was better tolerated and was cost-effective, and survival and the chance for recurrence were also the same,” Dr. Fretland said. “[Laparoscopy] was better for the patients, and we think more hospitals should establish a laparoscopic liver surgery program.”


Rivaroxaban Thromboprophylaxis in Patients With Pancreatic Cancer

Rivaroxaban significantly reduced the incidence of venous thromboembolism, compared with placebo, in ambulatory patients with pancreatic cancer who received the anticoagulant as prophylaxis in the CASSINI study.4 The study screened 1,080 patients at high risk for venous thromboembolism, identifying 841 and randomly assigning them to rivaroxaban at 10 mg/d or placebo for up to 180 days. Of these patients, 273 had pancreatic cancer.

A composite of symptomatic deep-vein thrombosis, asymptomatic proximal deep-vein thrombosis, any pulmonary embolism, and venous thromboembolism–related death served as the primary efficacy endpoint. Major bleeding was the primary safety endpoint.

Venous thromboembolism was observed in 3.7% of the rivaroxaban arm and 10.1% of the placebo arm (HR = 0.35; P = .03), with a number needed to treat of 16. Treatment with rivaroxaban did not increase major bleeding events, which occurred in 1.5% and 2.3%, respectively. Effects on all-cause mortality did not significantly differ between the arms.

“[Rivaroxaban thromboprophylaxis] has a favorable risk/benefit ratio and convenient once-daily oral administration.”
— Saroj Vadhan-Raj, MD

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Saroj Vadhan-Raj, MD, of The University of Texas MD Anderson Cancer Center, concluded there is benefit for rivaroxaban thromboprophylaxis in patients with pancreatic cancer initiating systemic therapy. The treatment has a favorable risk/benefit ratio and convenient once-daily oral administration, Dr. Vadhan-Raj noted.

Second-Line FOLFOX Treatment of Biliary Tract Cancer

Chemotherapy combined with active symptom control improved overall survival in patients with advanced biliary tract cancer whose disease progressed on cisplatin/gemcitabine, compared with active symptom control alone.5 Active symptom control included every 4-week assessments for symptom control and early detection as well as treatment of biliary-related complications.

“The intervention provided a clinically meaningful 31% reduction in the risk of death and a clinically meaningful increase in 6-month and 12-month overall survival,” said Angela Lamarca, MD, PhD, of The Christie NHS Foundation Trust/Institute of Cancer Sciences at the University of Manchester in the United Kingdom.

Angela Lamarca, MD, PhD

Angela Lamarca, MD, PhD

Although advanced biliary tract cancer is often managed with palliative care alone, evidence does support the use of cisplatin/gemcitabine as first-line chemotherapy. Without prospective trials, the role of chemotherapy in the second-line setting is unclear, noted Dr. Lamarca. “This is the first prospective phase III study evaluating the benefit of chemotherapy after cisplatin/gemcitabine in patients with advanced cancer.”

The phase III, open-label ABC-06 study, conducted at 20 sites in the United Kingdom, enrolled 162 patients with biliary tract cancers whose disease progressed after first-line cisplatin/gemcitabine. Patients were randomly assigned to active symptom control or the same plus modified FOLFOX (oxaliplatin, leucovorin, fluorouracil) for up to 12 cycles. The median follow-up was 21.7 months.

For overall survival, modified FOLFOX was significantly favored over active symptom control, yielding a median survival of 6.2 months, vs 5.3 months (HR = 0.69; P = .031). The respective survival rate was 50.6% vs 35.5% at 6 months and 25.9% and 11.4% at 12 months, Dr. Lamarca reported, noting that survival in the control arm was better than anticipated.

“The benefit was consistent across all exploratory subgroups, but those with a poorer prognosis seemed to benefit the most from modified FOLFOX, including patients who were platinum-resistant or -refractory, had low albumin, or had metastatic disease,” added Dr. Lamarca. Patients in the active treatment arm had more grade ≥ 3 fatigue, neutropenia, and infections.

“Modified FOLFOX combined with active symptom control should become the standard of care in the second-line setting,” she concluded. Quality of life, health economics, and translational research are ongoing.


New Benchmark?

The study’s discussant, William P. Harris, MD, of the University of Washington School of Medicine, Seattle, said the findings from the ABC-06 trial suggest that in the second-line setting, FOLFOX “is the new benchmark.” However, he added, “molecularly targeted options and clinical trials remain appealing.” 

DISCLOSURE: Dr. Finn has served as a consultant or advisor for AstraZeneca, ­Bayer, Bristol-Myers Squibb, Eisai, Exelixis, Genentech/Roche, Lilly, Merck, Novartis, Pfizer; has received institutional research funding from Bayer, Bristol-Myers Squibb, Eisai, Merck, Novartis, Pfizer, and Roche/Genentech; and has been compensated for expert testimony by Novartis. Dr. Harris has served as a consultant or advisor for Bayer, Bristol-Myers Squibb, Eisai, Exelixis, and NeoTherma Oncology; has received travel expenses from Eisai; and has received institutional research funding from Agios, Arqule, Bayer, BMS, BTG, Eisai, Halozyme, and Merck. Dr. Fretland has received honoraria from Olympus Medical Systems. Dr. Vadhan-Raj has received honoraria from Tesaro; has served as a consultant or advisor for Amgen, BeyondSpring Pharmaceuticals, Dara BioSciences, Enzychem Lifesciences, Hospira, Janssen, Novartis, Pfizer, Sandoz, and Shionogi; has received research funding from American Regent, Janssen, Amgen, and Tesaro; and has received institutional funding from American Regent, Amgen, Janssen, and Tesaro. Dr. Lamarca has received honoraria from Eisai and Nutricia; has served on the speakers bureau for Ipsen, Merck, and Pfizer; has received research funding from Ipsen; and has received travel/accommodations/expenses from Abbott Nutrition, Advanced Accelerator Applications, Bayer, Celgene, Delcath Systems, Ipsen, Mylan, Novartis, Pfizer, and Sirtex Medical. Dr. Lamarca also has an immediate family member who has received honoraria from Nutricia; has spoken on the speakers bureau for Ipsen, Novartis, and Pfizer; has received research funding from Ipsen; and has received travel/accommodations/expenses from Ipsen and NanoString Technologies.


1. Finn RS, Ryoo BY, Merle P, et al: Results of KEYNOTE-240: Phase 3 study of pembrolizumab vs best supportive care for second line therapy in advanced hepatocellular carcinoma. 2019 ASCO Annual Meeting. Abstract 4004. Presented June 2, 2019.

2. Fretland AA, Aghayan D, Edwin B, et al: Long-term survival after laparoscopic versus open resection for colorectal liver metastases. 2019 ASCO Annual Meeting. Abstract LBA3516. Presented June 3, 2019.

3. Fretland AA, Dagenborg V, Bjørnelv GM, et al: Laparoscopic versus open resection for colorectal liver metastases: The OSLO-COMET randomized controlled trial. Ann Surg 267:199-207, 2018.

4. Vadhan-Raj S, McNamara MG, Venerito M, et al: Rivaroxaban thromboprophylaxis in ambulatory patients with pancreatic cancer: Results from a prespecified subgroup analysis of the CASSINI study. 2019 ASCO Annual Meeting. Abstract 4016. Presented June 3, 2019.

5. Lamarca A, Palmer DH, Wasan HS, et al: ABC-06: A randomised phase III, multi-centre, open-label study of active symptom control (ASC) or ASC with oxaliplatin/5-FU chemotherapy for patients with locally advanced/metastatic biliary tract cancers previously treated with cisplatin/gemcitabine chemotherapy. 2019 ASCO Annual Meeting. Abstract 4003. Presented June 2, 2019.