A recap of some of the most notable ASCO 2020 research results in the field of gastrointestinal cancer that may guide oncologists in their day-to-day work.
The 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program delivered many practice-influencing presentations in a virtual format. Here are some of the most notable research results in the field of gastrointestinal cancer that may guide oncologists in their day-to-day work.
Siena et al presented a phase 2, multicenter, open-label study of trastuzumab deruxtecan (T-DXd) in patients with HER2-expressing metastatic colorectal cancer (mCRC).1 T-DXd is an antibody–drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a topoisomerase I inhibitor payload. Early studies have shown promising activity in advanced HER2-expressing tumors. In this study, patients with RAS wild-type and HER2- overexpressing mCRC, who had disease progression after 2 or more prior regimens, were treated with T-DXd at 6.4 mg/kg every 3 weeks in 3 cohorts (A: immunohistochemistry [IHC] score of 3+ or IHC 2+ and positive by fluorescence in situ hybridization [FISH]; B: IHC 2+/FISH-negative; C: IHC 1+). Median duration of treatment was 3.5 months. The longest duration of treatment occurred in cohort A, with 4.8 months, and 38.5% of patients remaining on T-DXd treatment. In this cohort, the confirmed overall response rate (ORR) was 45.3%, including 1 complete response and 23 partial responses. The overall response in patients previously treated with anti-HER2 antibodies was 43.8%. The disease control rate (DCR) was 83.0%, median progression-free survival (PFS) was 6.9 months, and median overall survival (OS) had not been yet reached in this group. On the contrary, no responses were observed in cohorts B or C. Grade 3 or higher treatment-emergent adverse events (AEs) were reported in 61.5% of patients. The most common AEs were decreased neutrophil count (21.8%) and anemia (14.1%). Five patients (6.4%) had interstitial lung disease (two grade 2; one grade 3; two grade 5), which accounted for the only drug-related deaths. Overall, T-DXd at 6.4 mg/kg every 3 weeks demonstrated remarkable activity in patients with HER2-expressing mCRC who are refractory to standard therapies. T-DXd showed activity in patients with previous exposure to anti-HER2 and anti- EGFR antibody therapies; however, the efficacy seems to be limited to IHC 3+ patients. Testing for HER2 amplification in CRC should be considered standard of care. The trial results did not answer the question of whether to sequence trastuzumab followed by T-DXd versus upfront therapy with T-DXd, and it did not answer the question of whether RAS-mutated patients would benefit from HER2-targeted therapies. Interstitial lung disease, which caused 2 deaths, necessitates strategies for vigilant recognition and early intervention. The dose of TXd may need to be reevaluated.
Kopetz et al presented updated survival results from a randomized, 3-arm, phase 3 study of encorafenib plus cetuximab with binimetinib (triplet therapy) or without binimetinib (doublet therapy) versus investigator's choice of either irinotecan or FOLFIRI plus cetuximab (control) in previously treated patients with BRAF V600E–mutated mCRC.2 Primary end points were the OS and objective response rates for patients receiving triplet therapy versus those in the control group. A total of 665 patients were randomized to receive triplet (n = 224), doublet (n = 220), or control (n = 221) therapy. Median OS was 9.3 months for both the triplet and doublet groups vs 5.9 months for the control group. Confirmed ORR was 26.8% for the triplet, 19.5% for the doublet, and 1.8% for the control groups, respectively. Retrospective subgroup analyses suggested that some patients may benefit more from triplet than doublet therapy; however, both triplet and doublet therapy showed improved OS compared with control in all subgroups. Grade 3 or higher AEs were experienced by 65.8% of patients receiving triplet therapy, 57.4% of those receiving doublet therapy, and 64.2% of those in the control group. The updated analysis confirmed that encorafenib + cetuximab with or without binimetinib improved OS and ORR in previously treated patients with BRAF V600E–mutated mCRC, compared with standard chemotherapy. To address which patients would benefit from triplet vs doublet therapy will require study of the subset analysis; the triplet regimen is likely accompanied by additional AEs.
Lonardi et al presented data on first-line FOLFOX plus panitumumab versus fluorouracil/leucovorin (5FU/LV) plus panitumumab for up to 12 cycles followed by panitumumab maintenance until progressive disease in elderly patients with mCRC, RAS/BRAF wild type.3 Although guidelines recommend considering fluoropyrimidine monotherapy as an option for elderly patients, no randomized studies have ever explored the role of the combination with an anti-EGFR agent. In this prospective, open-label, multicenter phase 2 randomized trial, unresectable and previously untreated patients with RAS/BRAF wild type mCRC, 70 years or older, were randomized to receive FOLFOX + panitumumab (arm A) or 5FU/LV + panitumumab (arm B) for up to 12 cycles, followed by panitumumab maintenance until progressive disease. The primary end point was PFS in both arms. Stratification criteria were age (≤75 vs >75 years), ECOG performance status (0-1 vs 2) and geriatric assessment with G8 Score (≤14 vs >14). Median PFS was 9.6 months (95% CI, 8.8-10.9) in arm A compared with 9.1 months (95% CI, 7.7-9.9) in arm B. Response rates were 65% vs 57%, respectively. Grade 3-4 toxicities were neutropenia (9.8% vs 1.1%, respectively), diarrhea (16.3% vs 1.1%), stomatitis (9.8% vs 4.4%), neurotoxicity (3.3% vs 0%), fatigue (6.5% vs 4.4%), and skin rash (25.0% vs 24.2%). Panitumumab maintenance until progressive disease may be a reasonable option in elderly patients with mCRC, RAS/BRAF wild type; however, further investigations in phase 3 trials are needed for OS data.
Kanemitsu et allooked into the role of adjuvant FOLFOX6 after hepatectomy in patients with mCRC and liver-only metastasis.4 Eligible patients had histologically proven colorectal adenocarcinoma with an unlimited number of liver metastases. Patients were randomized to adjuvant modified FOLFOX6 for 12 cycles after surgery versus surgery alone. With a median follow-up period of 54 months, the 3-year disease-free survival (DFS) rate was 52.1% in the adjuvant chemotherapy group compared with 41.5% in the surgery-alone group (HR, 0.63). However, this did not translate into OS benefit. The 3-year OS was 86.6% with adjuvant chemotherapy vs 92.2% with surgery alone (HR, 1.35). The 5-year OS also did not favor the chemotherapy arm: 69.5% vs 83.0% for surgery alone. In patients with recurrence, median OS was worse with chemotherapy (38.4 months) compared with surgery alone (87.6 months). Similar to the results of the only other study on this topic, the EORTC 40983 trial, DFS did not correlate with OS. It seems that adjuvant FOLFOX6 is not beneficial in this setting.
Sohal et al presented data from a randomized phase 2 trial of perioperative chemotherapy with modified FOLFIRINOX (mFOLFIRINOX) versus gemcitabine (gem)/nab-paclitaxel for resectable pancreatic cancer.5 Standard of care for resectable pancreatic cancer is surgery followed by adjuvant chemotherapy. In this trial, resectable pancreatic cancer patients were randomized to 3 months of mFOLFIRINOX followed by surgery followed by 3 months of mFOLFIRINOX versus 3 months of gem/nab-paclitaxel followed by surgery followed by 3 additional months of gem/nab-paclitaxel. About 70% of patients underwent resection; less than 50%, however, were able to complete intended postoperative chemotherapy. Gem/nab-paclitaxel performed better than expected with pathologic complete response rates of 42% compared with 25% for mFOLFIRINOX. Gem/nab-paclitaxel produced better median DFS with 14.2 months, compared with mFOLFIRINOX at 10.9 months, but the difference did not reach statistical significance (P = 0.87). Median OS was 22.4 vs 23.6 months, respectively. OS at 2 years was 41.6% for mFOLFORINOX arm vs 48.8% for gem/nab-paclitaxel. Neither regimen`s 2-year OS estimate was statistically significantly higher than the a priori threshold of 40%. The intended target for OS at 2 years was 58%. Overall, there seems to be little evidence that either regimen improves survival compared with the historical standard.
In another study, Ghaneh et al presented data resulting from a 4-arm, prospective, multicenter, phase 2 trial comparing immediate surgery with surgery after 3 different neoadjuvant treatment regimens in patients with borderline resectable pancreatic cancer.6 Patients with borderline resectable pancreatic cancer generally have poor survival and low resection rates. Neoadjuvant therapy has been explored to improve the outcomes for these patients. The aim of this trial was to determine the feasibility and efficacy of immediate surgery; 2 cycles of neoadjuvant gemcitabine plus capecitabine; 4 cycles of neoadjuvant FOLFIRINOX; or 50.4 Gy capecitabine-based neoadjuvant CRT in 28 daily fractions over 5.5 weeks. Resected patients received adjuvant therapy, and follow-up continued for 12 months. Primary end points were recruitment rate and resection rate (R1/R0). Secondary end points included OS and toxicity. Recruitment rate was 20.74%. Resection rate was 62% for immediate surgery and 55% for the 3 neoadjuvant therapy groups (P = 0.668). The R0 resection rate on upfront-resected patients was 15%, compared with 23% for the neoadjuvant group (P = 0.721). The 1-year survival rate favored neoadjuvant treatment: 40% for immediate surgery vs 77% for neoadjuvant therapy.
Bi et al presented data from an open-label, randomized phase 2/3 trial of patients with unresectable or metastatic hepatocellular carcinoma with a Child-Pugh liver function score ≤7 and no prior systemic therapy.7 (The study included patients from China only, and the majority had hepatitis B infection.) Patients were randomized to receive oral donafenib (0.2 g) or sorafenib (0.4 g) twice daily until toxicity or progression. The primary end point was OS. Donafenib was associated with a significantly longer median OS than sorafenib (12.0 months vs 10.1 months, respectively; P = 0.0446). However, there were no significant differences in median PFS (3.7 vs 3.6 months, respectively), objective response rates (4.6% vs 2.7%) and DCR (30.8% vs 28.7%). Grade ≥3 AEs occurred in 57.4% and 67.5% of patients, respectively. Common AEs with donafenib included hand-foot skin reaction (50.5%), aspartate aminotransferase increase (40.5%), blood bilirubin increase (39.0%), platelet count decrease (37.8%), and diarrhea (36.6%). Donafenib significantly improved OS compared with sorafenib, with favorable safety and tolerability.
Safran et al presented data from an open-label, randomized phase 3 trial which included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5 cm of the stomach.8 Patients received chemoradiation therapy with weekly paclitaxel (50 mg/m2) and carboplatin AUC = 2 for 6 weeks in addition to radiation (50.4 Gy in 28 fractions), followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab (4 mg/kg the first week, followed by 2 mg/kg/weekly x 5 during chemoradiation, then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery, or standard chemoradiation therapy only. HER2 status was determined by IHC and gene amplification by FISH. At a median follow-up of 5.0 years, the estimated 2-, 3-, and 4-year DFS rates for the chemoradiation + trastuzumab group were 41.8%, 34.3%, and 33.1%, respectively, For the standard chemoradiation group, the rates were 40.0%, 33.4%, and 30.1%, respectively (P = 0.85). The median DFS was 19.6 months for the trastuzumab arm vs 14.2 months for the chemoradiation only arm (HR, 0.97), while the median OS was slightly less in the trastuzumab arm (38.5 months vs 38.9 months respectively, HR, 1.01). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab, including no increase in cardiac events. In summary, addition of trastuzumab to chemoradiation did not improve key outcomes of pathologic complete remission rate, DFS, and OS.