Cancers of the digestive tract account for 338,090 new cases and 169,280 deaths annually in the United States. Although the overall mortality from these cancers is decreasing, this has been countered by an increase in the incidence of colorectal cancer in young adults. The rising incidence and poor clinical outcomes from hepatobiliary and pancreatic cancers are poignant reminders of the need for novel therapies.1
GUEST EDITORS
Kristen Spencer, DO, MPH
Milind M. Javle, MD
Dr. Spencer is Assistant Professor, Department of Medicine, Division of Medical Oncology, at Rutgers Cancer Institute of New Jersey. She is a member of the Gastrointestinal Cancers and Developmental Therapeutics Programs, where she specializes in the treatment of patients with hepatobilliary and pancreas cancers and on early-phase trials.
Dr. Javle is Professor, Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. He specializes in the treatment of hepatobiliary and pancreas cancers.
It has been a challenging year to say the least, but in spite of the obstacles posed by the COVID-19 pandemic, groundbreaking research resulting in potentially practice-changing breakthroughs for our most difficult-to-treat gastrointestinal cancers has persisted. Specifically, focuses on novel targeted and immunotherapy-based approaches have resulted in innovative options for our patients. This year’s Gastrointestinal Oncology Almanac will focus on these and other highlights in colorectal, gastroesophageal, hepatocellular, biliary tract, and pancreatic cancers, with additional attention paid to the impact of COVID-19 on cancer care delivery.
Immunotherapy Hits Prime Time for Advanced Cancers
Until recently, it has been widely recognized that immunotherapy-based approaches (with rare exceptions) have not been a home run in gastrointestinal cancers. However, a focus on combination strategies has resulted in profound strides in the treatment of advanced colorectal, gastroesophageal, and hepatocellular cancers.
In the KEYNOTE-177 trial, patients with treatment-naive microsatellite instability–high (MSI-H) advanced colorectal cancer received investigator’s choice chemotherapy (with or without bevacizumab or cetuximab) or pembrolizumab. During a plenary session at the ASCO20 Virtual Scientific Program, André et al reported the trial had met one of its co-primary endpoints, improving median progression-free survival from 8.2 to 16.5 months (hazard ratio [HR] = 0.6, P = .0002). Additionally, the duration of benefit persisted after patients progressed onto second-line therapy, with a second median progression-free survival not yet reached in the initial pembrolizumab arm vs 23.5 months in the initial chemotherapy arm. This was in spite of an effective crossover rate of almost 60% (36% of the patients crossed over, and 35 patients received anti–PD-1 or anti–PD-L1 therapy outside of the study). Importantly, 30% of the patients on the pembrolizumab arm progressed at the first restaging scan, highlighting that primary resistance is an issue even in the MSI-H population and a one-size-fits-all paradigm may not be appropriate. The overall survival analysis remains immature and likely will be impacted by the high crossover rate. We look forward to subsequent updates from this important study that establishes the importance of MSI testing and checkpoint inhibition in patients with colorectal cancer.2
The CheckMate 649 trial enrolled patients with treatment-naive advanced or metastatic, HER2-negative esophageal, gastroesophageal junction, and gastric cancers and randomly assigned them to nivolumab plus chemotherapy, nivolumab plus ipilimumab, or chemotherapy alone with either FOLFOX (fluorouracil, leucovorin, oxaliplatin) or XELOX (capecitabine plus oxaliplatin). At the European Society for Medical Oncology Virtual Congress 2020, Moehler et al reported the prespecified interim analysis of overall survival and the final progression-free survival for nivolumab plus chemotherapy vs chemotherapy alone. The combination of nivolumab plus chemotherapy significantly improved both median progression-free survival and median overall survival in patients with PD-L1 combined positive score (CPS) ≥ 5 and PD-L1 CPS ≥ 1. The median overall survival for all randomly assigned patients improved from 11.6 to 13.8 months (HR = 0.8, P = .0002). These data were encouraging, especially for patients with high CPS. In the PD-L1 CPS ≥ 5 population specifically, median overall survival was more than 14 months, setting a new benchmark for treatment of advanced disease.3
The benefit of checkpoint inhibitor–based strategies also extended to hepatocellular carcinoma as per the results from the IMbrave150 trial. Treatment-naive patients with advanced or metastatic hepatocellular carcinoma were randomly assigned 2:1 to atezolizumab plus bevacizumab or standard-of-care sorafenib. Randomization was stratified by geographic region, macrovascular invasion or extrahepatic spread of disease, alpha-fetoprotein (AFP) level, and Eastern Cooperative Oncology Group performance status. At the time of data cutoff, both co-primary endpoints had been met, with an improvement in median progression-free survival with atezolizumab plus bevacizumab from 4.3 months to 6.8 months (HR =0.59, P <.001) and overall survival (HR = 0.58, P < .001). Additionally, there was an improvement in objective response rate (27.3% vs 11.9%, P < .001) and 6-month duration of response (87.6% vs 59.1%) with the combination as compared with sorafenib. Importantly, the benefits were observed across subgroups, including geographic area, presence of macrovascular invasion or extrahepatic spread, and AFP level. A statistically significant improvement in quality of life was also noted, with longer median times to deterioration in overall quality of life, physical functioning, and role functioning.4 In an important update at the 2021 Gastrointestinal Cancers Symposium, median overall survival was demonstrated to be 19.2 months with atezolizumab plus bevacizumab vs 13.4 months with sorafenib (HR = 0.66, P = .0009), and the response rate with the combination was updated to 29.8%.5 This combination has been broadly accepted as a new reference standard for the first-line treatment of hepatocellular carcinoma.
FGFR Targeting of Value in Gastric Cancers
Bemarituzumab, a humanized IgG1 monoclonal antibody that selectively binds to FGFR2b, was evaluated in the randomized, placebo-controlled phase II FIGHT trial of patients with previously untreated, advanced gastric cancer that was not HER2-positive. All patients included had FGFR2b expression or had FGFR2 genetic amplifications. Of 910 patients, 275 (30%) were FGFR2b-positive. These patients were treated with modified FOLFOX6 and randomly assigned 1:1 to receive bemarituzumab 15 mg/kg or placebo every 2 weeks. The primary endpoint of progression-free survival was met, with an improvement in median progression-free survival from 7.4 months with placebo to 9.5 months with bemarituzumab (HR = 0.68, P = .07). Overall survival also improved in the bemarituzumab arm (HR = 0.58, P = .03). The response rate increased from 40% to 53%, with median duration of response of 7.1 months with placebo vs 12.2 months with bemarituzumab. An important toxicity noted was ocular: corneal events occurred in 67% of patients in the bemarituzumab arm, with 24% being grade 3 or higher, vs 10% in the placebo arm.
Targeted Therapy Steals the Show in Biliary Cancers
The current standard for the first-line treatment of advanced biliary tract cancers has not changed since the ABC-02 trial, which demonstrated that cisplatin plus gemcitabine resulted in a superior overall survival as compared with gemcitabine alone.6 With the advent of next-generation genomic sequencing and its widespread use gaining traction in biliary tract cancers, targeted therapies have emerged as a next exciting chapter in the field. The ClarIDHy trial was one of the first to demonstrate a benefit for targeted therapy in this devastating disease. Patients with previously treated advanced or metastatic IDH1-mutated cholangiocarcinoma (90% intrahepatic) were randomly assigned 2:1 to receive the oral small-molecule inhibitor of mutant IDH1 ivosidenib or placebo. This study met its primary endpoint with an improvement in median progression-free survival from 1.4 months to 2.7 months (HR = 0.37, P < .001). It also resulted in a greater disease control rate (53% vs 28%). Ivosidenib resulted in a nonsignificant improvement in median overall survival (10.3 months vs 7.5 months, HR = 0.79, P = .093), but when adjusted for the high rate of crossover at disease progression (70.5% of patients), median overall survival of the placebo group was determined to be 5.1 months, with a statistically significant HR of 0.49 (P < .0001). Importantly, there was a small difference in the rate of grade ≥ 3 adverse events (53% vs 37%), and side effects leading to treatment discontinuation were more common in the placebo group (8.5 vs 6.6%).7 Both the efficacy and tolerable safety profile make this an attractive option for patients with advanced/metastatic IDH1-mutated biliary tract cancers.
Genomic alterations in FGFR have been implicated in tumorigenesis, and pathogenic FGFR2 fusions are found in up to 14% of cholangiocarcinomas. Additionally, they have been demonstrated to be predictive of response to FGFR inhibition.8 A phase II study of the FGFR1–3 inhibitor infigratinib showed promising results in patients with previously treated advanced cholangiocarcinoma with FGFR2 gene fusions/rearrangements, FGFR1 and FGFR3 fusions/rearrangements, and FGFR mutations. Data from the FGFR2-fused/rearranged cohort showed a confirmed response rate of 23.1% lasting for a median duration of 5 months, and a disease control rate of 84.3%. The median progression-free survival was 7.3 months, and median overall survival was 12.2 months. Importantly, all subtypes of patients derived benefit, including heavily pretreated patients, and most treatment-related adverse events were grade 1 or 2. The response rate was higher in those patients who received only oneprior line of chemotherapy as compared with those who received two or more prior lines.9 Thus, infigratinib represents a new therapeutic option for FGFR2-altered cholangiocarcinoma.
Neoadjuvant Therapy in Pancreatic Cancer
SWOG S1505 sought to answer an important question in the management of patients with resectable pancreatic cancer. Patients were randomly assignedto modified FOLFIRINOX or gemcitabine plus nab-paclitaxel for 12 weeks preoperatively, followed by resection and then 12 weeks postoperatively. The study failed to meet its primary endpoint of 2-year overall survival by a “pick-the-winner” design, with 2-year overall survival rates of 41.6% in the modified FOLFIRINOX group (P = .42) and 48.8% in the gemcitabine plus nab-paclitaxel group (P = .12), neither of which met the prespecified threshold of 58% or more. Median overall survival and progression-free survival were also not significantly different between the two groups, and there were no significant differences in R0 resection rates between the arms. However, patients in the gemcitabine plus nab-paclitaxel group were somewhat more likely to have a node-negative resection (45% vs 40%). Importantly, the trial did not uncover any new or unexpected toxicities with either regimen.10 Although these results do not indicate the superiority of one regimen, the trial established the feasibility of the neoadjuvant approach for pancreatic cancer.
The 2021 Gastrointestinal Symposium thus highlighted significant developments in gastrointestinal cancers, several of which are likely to be practice changing. They include new clinical indications for checkpoint inhibitors and targeted agents including FGFR inhibitors. It has been the culmination of a year of progress under the most challenging conditions, and the benefit to our patients will be well worth the effort. Bravo!ν
DISCLOSURE: Dr. Spencer has served as a consultant or advisor to QED Therapeutics. Dr. Javle has served as a consultant or advisor to AstraZeneca, EMD Serono, Incyte, Merck, Mundi, OncoSil Medical, and QED Therapeutics and has held other relationships with Bayer, BeiGene, Incyte, Merck, Merck Serono, Novartis, Pieris Pharmaceuticals, QED Therapeutics, Rafael Pharmaceuticals, and Seattle Genetics.
REFERENCES
1. Siegel RL, Miller KD, Fuchs HE, et al: Cancer statistics, 2021. CA Cancer J Clin 71:7–33, 2021.
2. André T, Shiu KK, Kim TW, et al: Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med 383:2207-2218, 2020.
3. Moehler M, Shitara K, Garrido M, et al: LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): First results of the CheckMate 649 study. Ann Oncol 31(suppl 4):S1191, 2020.
4. Finn RS, Qin S, Ikeda M, et al: Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 382:1894-1905, 2020.
5. Finn, RS, Qin S, Ikeda M, et al: IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). J Clin Oncol 39(suppl 3):267, 2021.
6. Valle J, Wasan H, Palmer DH, et al: Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362:1273-1281, 2010.
7. Zhu AX, Macarulla T, Javle MM, et al: Final results from ClarIDHy, a global, phase III, randomized, double-blind study of ivosidenib (IVO) versus placebo (PBO) in patients (pts) with previously treated cholangiocarcinoma (CCA) and an isocitrate dehydrogenase 1 (IDH1) mutation. J Clin Oncol 39(suppl 3):266, 2021.
8. Javle MM, Sadeghi S, El-Khoueiry AB, et al: A retrospective analysis of post second-line chemotherapy treatment outcomes for patients with advanced or metastatic cholangiocarcinoma and FGFR2 fusions. J Clin Oncol 38(suppl 15):4591, 2020.
9. Javle MM, Roychowdhury S, Kelley RK, et al: Final results from a phase II study of infigratinib (BGJ398), an FGFR-selective tyrosine kinase inhibitor, in patients with previously treated advanced cholangiocarcinoma harboring an FGFR2 gene fusion or rearrangement. J Clin Oncol 39(suppl 3):265, 2021.
10. Sohal D, Duong MT, Ahmad SA, et al: SWOG S1505: Results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). J Clin Oncol 38(suppl 15):4504, 2020.
