Updated Data and Groundbreaking Research Lead to an Exciting 2023 ASCO GI

The 2023 Gastrointestinal Cancer Symposium (GI) hosted by the American Society of Clinical Oncology (ASCO) had its 25th anniversary, and the conference now covers multidisciplinary GI cancers. A few important studies presented will affect our treatment standards and are worth highlighting.

Colon Cancer

The big phase 3 study in the colon cancer space was the SUNLIGHT study (NCT04737187) comparing trifluridine/ tipiracil (Lonsurf) with or without bevacizumab (Avastin).¹ In total, 492 patients with metastatic colon cancer who had received 2 prior regimens, with all standard drugs, were randomly assigned 1:1 to trifluridine/tipiracil plus bevacizumab or trifluridine/tipiracil alone. The study was conducted mainly in Europe, with an enrollment rate of 64%, and only 3% were North American participants despite 10 centers being open for treatment. Additionally, 72% of participants had left-sided primary tumors, 70% had a RAS mutation, 72% had received prior bevacizumab, and 45% had an ECOG performance status of 0. The differences were quite substantial, with a major improvement in all efficacy parameters. The median overall survival (OS) was 10.8 months in the combination arm vs 7.5 months in the trifluridine/tipiracil arm (HR, 0.61; 95% CI, 0.49-0.77; P < .001), the median progression-free survival (PFS) was 5.6 months vs 2.4 months (HR, 0.44; 95% CI, 0.36-0.54; P < .001), the objective response rate was 6.3 months vs 0.9 months (P = .004), and the disease control rate was 77% vs 47% (P < .001), respectively.

Also, in colon cancer we saw interesting presentations on cell-free DNA (cfDNA) interference with circulating tumor DNA (ctDNA) detection based on more than 30,000 Natera tests, found the effects were minor and ctDNA can be drawn by week 2 postoperatively.² Continued data were reported on adjuvant therapy in a prospective trial for stage II colon cancer, with participants assigned to standard-of-care therapy or ctDNA-directed therapy.³ The ctDNA panel consisted of 15 common gene mutations, and only patients who tested positive for one of these in the tumor were eligible. In this study (N = 450 patients), for the ctDNA-directed treatment arm, only 15% received adjuvant chemotherapy and 62% of these received oxaliplatin. This can be compared with the standard-of-care control arm where 28% of patients were treated with adjuvant chemotherapy, with 90% of these receiving single agent fluropyrimidine and only 10% FOLFOX or CapeOX . The 3-year relapse-free survival (RFS) was equivalent and noninferior in the ctDNA arm, showing that even a suboptimal ctDNA test can be used to direct therapy resulting in almost half as many patients receiving adjuvant chemotherapy. Additionally, ctDNA-positive patients treated with chemotherapy had an 86% RFS rate at 3 years, compared with about 20% RFS without treatment in recent no-treatment ctDNA prospective trials. It is important to verify this experience with the phase 2/3 COBRA trial (NCT04068103) using a broader, a more commercially available test and with the phase 2/3 CIRCULATE-US trial (NCT05174169) for the treatment of stage III disease.

Hepatocellular Carcinoma

The phase 3 NRG/RTOG 1112 study (NCT01730937) should set a new standard for management of hepatocellular carcinoma (HCC).⁴ Patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C tumors and who are not eligible for local therapy were randomly assigned to sorafenib (Nexavar) with or without stereotactic body radiation therapy (SBRT) in 5 fractions. With 193 patients, this is the largest prospective randomized study of radiation in HCC. Patients had disease not amenable to resection or transarterial chemoembolization (TACE), fewer than 5 lesions, a sum of diameters less than 20 cm, and a Child-Pugh A score of 60,000 platelets or more. The median OS was improved with SBRT at 15.8 months in the sorafenib plus SBRT arm vs 12.3 months in the sorafenib alone arm (HR, 0.77; 1-sided P = .0554), and the median PFS was 9.2 months vs 5.5 months (HR, 0.55; 95% CI, 0.40-0.75; 2-sided P = .0001) with no major toxicity issues. SBRT may be a potential treatment option for patients who are not eligible for TACE or radiofrequency ablation and who have vascular invasion.

Biliary Cancer

The phase 3 S1815 trial (NCT03768414) enrolled 441 patients with biliary cancer to gemcitabine-cisplatin with or without albumin-bound nab-paclitaxel based on results from the phase 2 study.⁵ Patients were randomly assigned 2:1 to the combination regimen, and remarkably, patients were accrued in 2 years for this groundbreaking biliary cancer trial. Overall, the addition of nab-paclitaxel did not improve outcomes, but there was a substantial benefit in those with gallbladder cancer for both PFS and OS. Further hypotheses in this key study will carry the field forward.

Pancreatic Cancer

The phase 3 NAPOLI 3 trial (NCT04083235) was reported at the conference and again raised more questions than it answered.⁶ This study for metastatic first-line therapy of pancreatic cancer used reduced doses of NALIRIFOX (5-fluorouracil/leucovorin, oxaliplatin, liposomal irinotecan) vs gemcitabine/nab-paclitaxel. Although the NALIRIFOX regimen was somewhat better than gemcitabine/nab-paclitaxel (HR, 0.83; P = .04), this is largely due to an “overpowered” study of 770 patients. Another issue is whether NALIRIFOX is a real benefit over free irinotecan. The sponsor has never compared these 2 directly in any randomized trial, and there is no clear indication that NALIRIFOX is more effective or less toxic than free irinotecan. This is not like liposomal doxorubicin, which completely changed the toxicity profile of doxorubicin. This should not be considered a new reference regimen as stated by the presenters of the study. More data are needed here.

The trials and the movement forward continue. Your contributions to clinical trials can help.

References

1. Tabernero J, Prager GW, Fakih M, et al. Trifluridine/tipiracil plus bevacizumab for third-line treatment of refractory metastatic colorectal cancer: the phase 3 randomized SUNLIGHT study. J Clin Oncol. 2023;41(suppl 4):4. doi:10.1200/JCO.2023.41.3_suppl.4
2. Cohen SA, Kasi PM, Aushev VN, et al. Kinetics of postoperative circulating cell-free DNAand impact on minimal residual disease detection rates in patients with resected stage I-III colorectal cancer. J Clin Oncol. 2023;41(suppl 3):5. doi:10.1200/JCO.2023.41.3_suppl.5
3. Tie J. Circulating tumor DNA: prime time or jumping too soon? Presented at: 2023 Gastrointestinal Cancer Conference; January 19-22, 2023; San Francisco, CA.
4. Dawson LA, Winter KA, Knox J, et al. NRG/RTOG 1112: randomized phase III study of sorafenib vs. stereotactic body radiation therapy (SBRT) followed by sorafenib in hepatocellular carcinoma (HCC). J Clin Oncol. 2023;41(suppl 4):489. doi:10.1200/JCO.2023.41.4_suppl.489
5. Shroff RT, Guthrie KA, Scott AJ, et al. SWOG 1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. J Clin Oncol. 2023;41(suppl 4):LBA490. doi:10.1200/JCO.2023.41.3_suppl.LBA490
6. Wainberg ZA, Melisi D, Macarulla T, et al. NAPOLI-3: a randomized, open-label phase 3 study of liposomal irinotecan + 5-fluorouracil/leucovorin + oxaliplatin (NALIRIFOX) versus nab-paclitaxel + gemcitabine in treatment-naïve patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). J Clin Oncol. 2023;41(suppl 4):LBA661. doi:10.1200/JCO.2023.41.4_suppl.LBA661