ASCO 2017 Report — Gastrointestinal Cancer
ASCO 2017 Report — Gastrointestinal Cancer
- David H. Ilson, MD, PhD
Key trials in colorectal, gastric, pancreatic, and hepatocellular cancer
- David H. Ilson, MD, PhD
At this year's annual meeting of the American Society of Clinical Oncology (ASCO 2017), held June 3–7 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Associate Editor David H. Ilson, MD, PhD, reviews key presentations on new gastrointestinal cancer treatments. All meeting abstracts can be viewed in the ASCO meeting library).
Duration of Colon Cancer Therapy: 3 or 6 Months?
A plenary session presentation of the IDEA trial by Shi and colleagues (abstract LBA1) released pooled international data from six phase III trials comparing the use of 3 versus 6 months of capecitabine plus oxaliplatin or FOLFOX chemotherapy for more than 10,000 patients with stage III colon cancer. Of these, 72% had N1 disease, 28% N2 disease, 79% were T1-2 or 3, and 21% were T4. The primary endpoint, disease-free survival (DFS), was designed to show noninferiority for 3 versus 6 months of treatment, allowing a 12% relative risk increase with shorter therapy.
Completion of all treatment cycles was higher with 3 months of therapy (86%–90%) versus 6 months (65%–71%). Grade 2 neurologic toxicity was reduced from 32%–36% to 12%–14% with shorter therapy, and grade 3-4 neurotoxicity was reduced from 9%–16% to 3%. There was a 0.9% difference in 3-year DFS, which did not meet the criteria for noninferiority. However, low-risk T1-3 N1 disease achieved near equivalence with 3 months of therapy; DFS in low-risk patients differed by only 0.2%.
By regimen, FOLFOX failed to demonstrate noninferiority with 3 months of therapy in either high- or low-risk stage III disease, whereas 3 months of capecitabine plus oxaliplatin achieved noninferiority and a benefit clearly noninferior for low-risk T1-3 N1 disease. For T4 N2 disease, capecitabine and oxaliplatin noninferiority could not be proven.
Three other trials — the study by Andre and colleagues from France (abstract 3500), the TOSCA study by Sobrero and colleagues from Italy (abstract 3501), and the SCOT study by Iveson and colleagues from the U.K. (abstract 3502) — generally supported the results of the IDEA trial.
The Andre study failed to demonstrate noninferiority of 3 versus 6 months of FOLFOX therapy for either low- or high-risk stage III disease, with an 8% inferior disease-free survival for high-risk stage III disease and a 2% inferior disease-free survival for low-risk stage III disease. Data from the SCOT trial indicated noninferiority for 3 versus 6 months of capecitabine plus oxaliplatin in either low- or high-risk stage III disease. Collectively, data from the three trials support the use of 3 months of adjuvant chemotherapy for low-risk stage III disease with a potential preference for capecitabine and oxaliplatin. For high-risk stage III disease, 6 months of therapy remains the standard of care. Any decision to truncate adjuvant therapy needs to be reviewed with patients, given the overall small differences in outcomes in most of the data sets presented in this series.
Vitamin D of Modest Benefit in Metastatic Colon Cancer
Ng and colleagues conducted a randomized phase II trial (SUNSHINE; abstract 3506) in which 139 treatment-naive patients with metastatic colon cancer received FOLFOX plus bevacizumab with or without high-dose vitamin D3. Vitamin D supplementation modestly improved progression-free survival (PFS) from 11.2 to 13.1 months, with an equivalent response rate of 55% and a suggestion of improvement in disease control from 84% to 96%.
Vemurafenib Improves Survival in Metastatic Colorectal Cancer
In the SWOG S1405 trial (abstract 3505), Kopetz and colleagues evaluated the effect of adding the BRAF inhibitor vemurafenib to standard cetuximab plus irinotecan in 92 patients with BRAF-mutant metastatic colorectal cancer (CRC).
Vemurafenib significantly improved PFS from 2.0 to 4.3 months (HR, 0.48). A higher response rate (16% vs. 4%) and a higher rate of disease control (67% vs. 22%) were also achieved. Patients crossing over to vemurafenib treatment at progression achieved a 17% response and a PFS of 5.8 months. Overall survival (OS) improved with vemurafenib from 5.9 to 9.6 months.
Radiotherapy Ineffective for Liver Metastases from CRC
A salient negative trial (FOXFIRE) by Sharma and colleagues (abstract 3507) assessed adding selective internal radiotherapy (SIRT) using yttrium-90 resin microspheres to first-line FOLFOX chemotherapy, with a permissible added use of bevacizumab, for patients with liver metastases from metastatic CRC and limited extra hepatic disease. The addition of SIRT failed to improve OS or PFS.
Prognostic Factors in Metastatic CRC
Two studies updated results of the CALGB/SWOG 80405 trial (NEJM Oncol Hematol Aug 2014) of first-line chemotherapy with either bevacizumab or cetuximab in patients with exon 12 and 13 KRAS wild-type metastatic CRC.
In the first study, Venook and colleagues showed that a right-sided primary tumor was an independent prognostic and predictive factor for worse outcome (abstract 3503). The data also suggested a better survival benefit for bevacizumab versus cetuximab combined with chemotherapy in right-sided tumors.
In the second study, Innocenti and colleagues used DNA mutational analysis to confirm that the presence of a BRAF mutation has an adverse effect on OS (abstract 3504) and that OS was similar between MSI-high versus MSI-stable patients. The data also indicated that OS might be improved in patients with ≥8 versus <8 mutations (HR, 0.67; P=0.02).
Perioperative Chemotherapy for Gastric Cancer: A New Standard
A practice-changing trial conducted by Al-Batran (FLOT4-AIO; abstract 4004) compared FLOT (docetaxel, oxaliplatin, and 5-FU) versus standard ECF (epirubicin, cisplatin, and 5-FU) in 716 patients with gastric or gastroesophageal (GE) junction cancer treated with surgery. Of these, 56% had GE junction cancers, 44% had distal gastric cancers, 70%–75% had T3 disease, and 78%–81% had node-positive disease. Most (90%) completed preoperative chemotherapy, and 94%–97% proceeded to surgery.
Patients treated with FLOT versus ECF had a higher rate of curative resection (84% vs. 77%; P=0.011). OS was improved with FLOT (50 vs. 35 months; P=0.012), with an improvement in projected 5-year overall survival from 36% to 45%. PFS was also improved from 18 to 30 months (P=0.004). These results establish FLOT as a potential new standard of care in the perioperative chemotherapy management of resectable gastric and GE cancer.
Pembrolizumab Active in Advanced Gastric Cancer
The KEYNOTE-059 study by Bang and colleagues (abstract 4012) evaluated pembrolizumab plus 5-FU and cisplatin in 259 patients with chemotherapy-refractory gastric cancer. Of these, an equal number had gastric and GE junction cancers, 57% tested positive for PD-L1 expression, and 52% received ≥2 prior chemotherapy regimens.
The response rate was 11.6%, and the disease control rate was 27%. A higher response was observed in PD-L1–positive versus negative patients (15.5% vs. 6.4%); more responses were seen in patients receiving third-line versus fourth-line treatment (15.4% vs. 6.4%). Most patients progressed early with a median PFS of 2 months, with a median OS of 5.6 months and a 12-month OS rate of 23.4%. In seven patients who tested MSI high, a 57% response rate was observed. These results substantiate a signal of activity for immune checkpoint inhibitors in advanced gastric cancer.
Capecitabine Bests Observation for Biliary Tract Cancer
The practicing-changing BILCAP study by Primrose and colleagues (abstract 4006) evaluated the use of adjuvant capecitabine for 6 months versus observation in 447 patients after biliary cancer resection. Half of patients had intrahepatic or hilar cholangiocarcinoma versus either gallbladder or common bile duct cholangiocarcinoma. A negative margin resection was present in 62%–63% of patients, and 46%–48% had node-positive disease.
OS was similar with treatment versus observation (51.1 and 36.4 months, respectively, HR, 0.81), but was significantly improved when the analysis was adjusted for prognostic factors (HR, 0.70; P=0.007). Relapse-free survival was improved from 17.6 to 24.6 months with adjuvant chemotherapy (HR, 0.76; P=0.039). No quality-of-life detriment was observed with adjuvant chemotherapy.
No Improvement with SIRT for Locally Advanced HCC
In another key negative trial (SIRveNIB) Chow and colleagues compared yttrium microsphere SIRT versus standard sorafenib in 182 patients with locally advanced hepatocellular carcinoma (HCC) (abstract 4002). OS was similar for SIRT versus sorafenib (8.8 and 10.0 months, respectively), as was time to tumor progression (6.1 and 5.3 months). Because 52 patients randomized to SIRT could not be treated, the study potentially favored the SIRT population due to enhanced patient selection, but SIRT still did not improve survival outcome.
Lenvatinib Effective for Unresectable HCC
Cheng and colleagues (abstract 4001) compared the use of standard sorafenib versus lenvatinib, a newer-generation multitargeted TKI in nearly 1000 international patients with unresectable HCC. Hepatitis B was the most common cause of liver disease (48%–53%) followed by hepatitis C (19%–27%).
Noninferiority for OS for lenvatinib versus sorafenib was achieved (13.6 vs. 12.3 months; HR, 0.92). PFS was significantly improved with lenvatinib (7.4 vs. 3.7 months; HR, 0.66; P<0.00001). A higher response rate was also observed for lenvatinib (24.1% vs. 9.2%). Rates of treatment-related adverse events were similar between therapies, with more hypertension with lenvatinib (23% vs. 14%) and more hand-foot reaction with sorafenib (11% vs. 3%).
Editor Disclosures at Time of Publication
Disclosures for David H. Ilson, MD, PhD at time of publication Consultant / Advisory board Amgen; Eli Lilly–ImClone; Bayer; Merck; Bristol-Myers Squibb; Roche-Genentech; Pieris; Astellas