Tolerability and efficacy of durvalumab, either as monotherapy or in combination with tremelimumab, in patients from Asia with advanced biliary tract, esophageal, or head‐and‐neck cancer

Abstract

Background Agents targeting the programmed cell death‐1 pathway have demonstrated encouraging activity across multiple solid tumor types. The dose expansion phase of this phase I study evaluated the safety, tolerability, and antitumor activity of durvalumab monotherapy, and durvalumab plus tremelimumab (an anti‐cytotoxic T‐lymphocyte‐associated antigen 4 monoclonal antibody) combination therapy, in patients from Asia with biliary tract cancer (BTC), esophageal squamous cell carcinoma (ESCC), or head and neck squamous cell carcinoma (HNSCC). Methods Patients with advanced BTC, ESCC, or HNSCC with disease progression during or following ≥1 platinum‐based therapy received durvalumab monotherapy (10 mg/kg every 2 weeks) or durvalumab plus tremelimumab (durvalumab 20 mg/kg every 4 weeks [Q4W] plus tremelimumab 1 mg/kg Q4W for 4 doses, followed by durvalumab 20 mg/kg Q4W). The primary objective was safety and tolerability. Secondary objectives included antitumor activity. Results Durvalumab monotherapy was assessed in 116 patients (median age 63.5 years, 75.9% male) of whom, 42, 42, and 32 had BTC, ESCC, or HNSCC, respectively. Grade ≥3 treatment‐related adverse events (TRAEs) were reported in 19.0%, 9.5%, and 25.0% of patients with BTC, ESCC, and HNSCC, respectively. Objective response rate (ORR) was 4.8%, 7.1%, and 9.4% in BTC, ESCC, and HNSCC. Durvalumab plus tremelimumab was evaluated in 124 patients (median age 62.0 years, 79.8% male) of whom 65 had BTC and 59 had ESCC. Grade ≥3 TRAEs were reported in 23.1% and 13.6% of patients with BTC and ESCC. ORR was 10.8% and 20.3% in BTC and ESCC. There were two complete responses and 10 partial responses in ESCC, and seven partial responses in BTC. Conclusion In general, durvalumab monotherapy and durvalumab plus tremelimumab combination therapy displayed acceptable safety profiles consistent with published literature, and also demonstrated clinical benefit, in patients from Asia with BTC, ESCC, or HNSCC with disease progression on ≥1 prior treatment. ClinicalTrials.gov Identifier: NCT01938612.

Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment

“…The common CTLA-4 inhibitors currently in clinical trials mainly include ipilimumab and tremelimumab, and CTLA-4 inhibitors often combined with PD-1/PD-L1 inhibitors as dual immune blockade. As mentioned above, two clinical trials, CheckMate-648 and NCT01938612, have confirmed the efficacy and safety of combined CTLA-4 and PD-1 inhibitors as the immunotherapy of ESCC (176,184). Several ongoing clinical trials (NCT03416244, NCT03377400, NCT02658214 and NCT03212469) are eagerly awaited to further clarify safety and efficacy of CTLA-4 inhibitors in immunotherapy of ESCC.…”

“…The RATIONALE-302 is a phase III clinical trial comparing the efficacy of tislelizumab with chemotherapy (paclitaxel/docetaxel/irinotecan) in the second-line treatment of patients with advanced or metastatic ESCC, and the resulted demonstrated that tislelizumab significantly improved OS compared with chemotherapy (median 8.6 vs 6.3 months, P = 0.0001) with a manageable safety profile ( 183 ). The NCT01938612 is a phase I clinical trial to evaluate the safety, tolerability, and antitumor activity of durvalumab monotherapy, and durvalumab plus tremelimumab (anti-CTLA-4 monoclonal antibody) combination therapy in patients from Asia with ESCC as second-line and beyond treatment, which showed that both treatments displayed acceptable safety profiles clinical benefit ( 184 ). The results of phase Ib clinical trial KEYNOTE-028 showed that pembrolizumab demonstrated durable antitumor activity and manageable toxicity in patients with heavily pretreated, PD-L1-positive advanced ESCC [objective response rate (ORR): 30% (95% CI, 13%-53%); DoR: 15 months (range, 6-26 months); OS: 7.0 months (95% CI, 4.3-17.7 months); PFS: 1.8 months (95% CI, 1.7-2.9 months)] ( 185 ).…”

Different immune contextures underlie tumor site‐specific responses to immune checkpoint blockade in esophageal cancer

“…He subsequently received a combination of durvalumab plus tremelimumab (durvalumab 20 mg/kg, IV, on day 1, every 4 weeks; tremelimumab 1 mg/kg, IV, on day 1, every 4 weeks for an initial 4 cycles) for 10 cycles. 6 Follow-up computed tomography scans revealed heterogeneous tumor responses. A significant response was noted in tumors located in the liver, spleen, brain, and LN metastases, and a progressive enlargement of the esophageal tumor complicated with an esophagopulmonary fistula and lung abscess (Figure 1).…”

“…A 70‐year‐old man with metastatic ESCC had failed two lines of chemotherapy. He subsequently received a combination of durvalumab plus tremelimumab (durvalumab 20 mg/kg, IV, on day 1, every 4 weeks; tremelimumab 1 mg/kg, IV, on day 1, every 4 weeks for an initial 4 cycles) for 10 cycles 6 . Follow‐up computed tomography scans revealed heterogeneous tumor responses.…”

Reply to “Is there a role for combined anti–PD‐1/CTLA‐4 checkpoint blockade in the management of advanced biliary tract cancers?”

“…On a further review of the literature, it appears that most trials using the combination of anti-PD 1/L1 and anti-CTLA-4 antibodies report a much lower ORR for this rare cancer than noted in the CA209-538 trial (Table 1). [3][4][5][6] Interestingly, the median progression-free survival and overall survival across these studies are quite similar, and this suggests a limited benefit from dual immune checkpoint inhibitor therapy in an unselected patient cohort with advanced or metastatic biliary tract cancer.…”