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Bartlett Family Professor of Gastrointestinal Oncology
Chief, Solid Tumor Services
Director, Gastrointestinal Oncology Program
Weill Cornell Medical College
New York, New York
Manish A. Shah, MD, has disclosed that he has received funds for research support from Bristol-Myers Squibb and Merck.
Assistant Professor of Medicine
Chief, Section of GI Medical Oncology
Director, UACC Clinical Trials Office
The University of Arizona Cancer Center
Rachna Shroff, MD, has disclosed that she has received consulting fees from AstraZeneca, Boehringer Ingelheim, CAMI, Clovis, Genentech, Incyte, Merck, QED Therapeutics, Servier, Taiho, and Zymeworks and funds for research support from Bayer, Bristol-Myers Squibb, Exelixis, IMV, Loxo, Merck, Novocure, NuCana, Pieris, QED Therapeutics, Rafael, Seagen, and Taiho.
In this commentary, Manish A. Shah, MD, and Rachna Shroff, MD, highlight key studies in the management of gastric, biliary, hepatocellular, and rectal cancers presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) and share their perspectives on the clinical implications of these findings.
Gastric Cancer Studies
The randomized, double-blind phase III KEYNOTE-590 trial compared the PD-1 inhibitor pembrolizumab plus chemotherapy (CT; 5-fluorouracil and cisplatin) vs CT alone as first-line treatment of patients (N = 749) with treatment-naive, locally advanced, unresectable, or metastatic advanced esophageal adenocarcinoma, esophagogastric junction adenocarcinoma, or esophageal squamous cell carcinoma (ESCC). At the first interim analysis of 22.6 months, the addition of pembrolizumab to CT resulted in a significant improvement in overall survival (OS) and progression-free survival (PFS).
At ASCO GI 2022, we saw results presented with updated efficacy, safety, and quality-of-life metrics with a median follow-up of 34.8 months. The confirmed overall response rate (ORR) was higher in the pembrolizumab plus CT vs CT alone (45.0% vs 29.3%), as was the duration of response (8.3 vs 6.0 months). Compared with CT alone, pembrolizumab plus CT maintained a superior survival in the overall population and in patients with ESCC (HR: 0.73), ESCC PD-L1 CPS ≥10 (HR: 0.59), and PD-L1 CPS ≥10 (HR:0.64). In patients with adenocarcinoma, OS was also improved in the pembrolizumab plus CT vs CT alone (HR: 0.73). Of importance, the rates of grade ≥3 adverse events (AEs) were comparable in both treatment arms (72% vs 68%), and there were no significant differences in quality of life with the addition of pembrolizumab to CT. This study confirms the initial efficacy of the addition of pembrolizumab in esophageal cancer. Additionally, patients received the therapy while maintaining their quality of life. This was a practice changing study and pembrolizumab is now approved for the treatment of esophageal cancer that has a PD-L1 combined positive score (CPS) ≥10.
Updates from the randomized phase III CheckMate 649 trial were also presented at ASCO GI 2022. The CheckMate 649 trial enrolled 2031 patients with untreated, unresectable, advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma and unknown HER2 status. Patients were randomized to receive nivolumab plus CT (XELOX or FOLFOX), nivolumab plus ipilimumab, then nivolumab or CT alone. Initial results of this trial showed that nivolumab plus CT prolonged OS and PFS in patients with PD-L1 CPS ≥5, making nivolumab the first PD-1 inhibitor to show superior OS benefit in this patient population, which led to FDA approval. In the updated analysis, the median PFS2 (time to progression after subsequent therapy, initiation of second subsequent systemic therapy, or death, whichever is earlier) was 12.2 months vs 10.4 months (HR: 0.75) for nivolumab plus CT vs CT alone, respectively. Moreover, 41% vs 44% of patients in the nivolumab plus CT arm vs the CT-alone arm received subsequent therapy. Of importance, the median OS benefit with nivolumab plus CT vs CT alone was improved among patients with a PD-L1 CPS ≥10 (15.0 months vs 10.9 months; HR: 0.66; 95% CI: 0.56-0.77). There were no new safety signals identified with this longer follow-up. Most immune-related AEs were grade ≥2, and grade 3/4 events were infrequent in both arms. This study also confirmed the efficacy of the addition of nivolumab to chemotherapy in patients with gastroesophageal adenocarcinoma. The study also confirms that most patients (eg, 55% to 60%) do not receive subsequent therapy. This study also provides the strongest evidence to suggests that it’s very important to initiate therapy with the best treatment options available.
PD-1 Blockade in DNA Mismatch Repair Deficient, Locally Advanced Rectal Cancer
Neoadjuvant therapy with induction CT and chemoradiation (chemoRT) is the standard of care for locally advanced rectal cancer. However, patients with mismatch repair deficient (MMRd) colorectal cancer have a poor response to neoadjuvant CT. At ASCO GI 2022, Lumish and colleagues presented results from an ongoing, prospective, single-arm phase II study evaluating PD-1 blockade with dostarlimab in 13 patients with locally advanced MMRd rectal cancer. The coprimary objectives of the study are ORR, pathologic complete response, or clinical complete response with or without chemoRT. Investigators report that the ORR was 100% in patients with at least 3 months of evaluation; 7 of 13 (54%) patients who completed induction therapy achieved a 100% clinical complete response and were undergoing observation without chemoRT or surgery. To date, there have been no serious AEs and the rate of progressive disease is 0%. Investigators suggest that these findings represent a new paradigm for the treatment of MMRd, locally advanced rectal cancer.
This is a very early look at a very exciting paradigm of giving immunotherapy to patients with locally advanced rectal cancer that is MMRd. Most patients ─indeed virtually all in this small series─ had a complete response to immunotherapy. These data, if they uphold, will likely be practice changing.
Oh and colleagues presented interim analysis results from the randomized phase III TOPAZ-1 trial evaluating the combination of durvalumab plus gemcitabine and cisplatin-based CT (GemCis) vs GemCis in patients with biliary tract cancer (BTC). The trial enrolled 685 patients with untreated, unresectable locally advanced, recurrent, or metastatic BTC. The primary endpoint was OS. Secondary endpoints were PFS, ORR, and safety. The primary endpoint was met with a median OS of 12.8 months vs 11.5 months (P = .021; HR: 0.80; 95% CI: 0.66-0.97) with durvalumab plus GemCis vs GemCis alone. Durvalumab plus GemCis also improved median PFS when compared with GemCis alone (7.2 vs 5.7 months; HR: 0.75; 95% CI 0.64-0.89; P = .001). The rates of grade 3/4 treatment-related AEs (62.7% vs 64.9%) and discontinuation rates (8.9% vs 11.4%) were comparable between treatment arms. TOPAZ-1 is the first randomized trial to report positive results for immunotherapy plus CT as first-line treatment in BTC.
This is a potentially practice-changing study and the first one to demonstrate an OS improvement over gemcitabine and cisplatin in more than a decade. The HR of 0.8, although statistically significant, does not tell the whole story, as there is a notable difference in 2-year and 3-year OS rates with a tail to the durvalumab Gem/Cis. That being said, 55% of patients enrolled were from Asia, and thus it will be important to ascertain which subset of patients is truly benefiting from the immunotherapy arm. In addition, given that the practice in the United States is not to stop GemCis at 6 months, it will be important to see how this treatment gets integrated into the traditional front-line management approach for BTC.
The randomized, multicenter phase III HIMALAYA trial is evaluating the combination of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC) with no previous systemic therapies (N = 1179). In the report presented at ASGO GI 2022, investigators reported data for a single priming dose of tremelimumab added to regular-interval durvalumab (STRIDE), durvalumab monotherapy, or sorafenib. With STRIDE, there was a significant improvement in OS when compared with sorafenib (median OS: 16.4 vs 13.8 months; HR: 0.78; 95% CI: 0.65-0.92; 2-sided P = .0035). The OS benefit was maintained across all prespecified subgroups, some of which included macrovascular invasion, and extrahepatic spread. Single-agent durvalumab was noninferior to sorafenib, with a median OS of 16.6 months (95% CI: 14.1-19.1) compared with 13.8 months (95% CI: 12.3-16.1) and an HR of 0.86 (95% CI: 0.73-1.03). Of importance, there were no new safety signals identified in this trial. The rate of grade 3/4 treatment-related AEs was 25.8% with the STRIDE arm vs 12.9% with durvalumab monotherapy vs 36.9% with sorafenib. The HIMALAYA trial is the first to evaluate monotherapy and combination immunotherapy long-term follow-up in a diverse group of patients with unresectable HCC.
This study shows the utility of a dual immunotherapy combination in the treatment of advanced HCC. It has the potential to become a standard of care in newly diagnosed patients with Child-Pugh A cirrhosis. It is of particular interest because it does not contain an anti-VEGF treatment component, which is clinically relevant in HCC patients with cirrhosis who could be at risk of bleeding. The STRIDE regimen involves a 1-time dose of tremelimumab followed by durvalumab, which also adds to an ease of administration. The immune-related AEs and steroid use were fewer than in early studies with nivolumab and ipilimumab, suggesting that this dual immunotherapy combination may be better tolerated. Integration of the STRIDE regimen into clinical care is likely, and it will become another option for patients outside of bevacizumab and atezolizumab. Because the control arm in this study was sorafenib, it is difficult to know how it truly compares against the bevacizumab and atezolizumab combination, but it clearly provides another option for patients with advanced HCC.
The phase III KEYNOTE-394 trial evaluated pembrolizumab plus best supportive care (BSC) vs BSC alone as second-line treatment in patients enrolled in Asia with advanced HCC and progressive disease after treatment with sorafenib or oxaliplatin-based CT. At the final analysis presented at ASCO GI 2022, the median OS with pembrolizumab plus BSC vs BSC alone was 14.6 months vs 13.0 months (HR: 0.79; 95% CI: 0.63-0.99; P = .0180), and the median PFS was 2.6 months and 2.3 months, respectively. The ORR was also improved with pembrolizumab plus BSC vs BSC alone (13.7% vs 1.3%), as well as the median duration of response (23.9 vs 5.6 months). In this trial, the rate of treatment-related AEs was higher with pembrolizumab plus BSC vs BSC alone (66.9% vs 49.7%); the rate of grade 3-5 AEs was also higher with pembrolizumab plus BSC vs BSC alone (14.4% vs 5.9%). Three treatment-related deaths were reported in the pembrolizumab plus BSC arm, and no deaths were reported in the BSC arm. Compared with BSC alone, the addition of pembrolizumab to BSC improved ORR, PFS, and OS. The safety profile was in line with that reported in KEYNOTE-224 and KEYNOTE-240. The final analysis showed that pembrolizumab plus BSC treatment was efficacious and well tolerated, and it introduces this regimen as another treatment option for patients after sorafenib therapy. Finally, how this treatment fits into the treatment algorithm with bevacizumab and atezolizumab remains to be seen.
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