TOPAZ-1: Significant results from the Phase III study demonstrating durvalumab in combination with gemcitabine plus cisplatin improves OS and PFS in patients with advanced BTC

The results of the double-blind, randomized Phase III TOPAZ-1 (NCT03875235)1 trial were presented at American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium 2022. The trial investigated the addition of immunotherapy to standard chemotherapy to improve the prognosis of patients with advanced biliary tract cancer (BTC). BTC is a rare, heterogenous cancer that is often diagnosed once the disease has reached advanced stages in progression, making for a poor prognosis2.

TOPAZ-1 is the first Phase III clinical trial to exhibit an improved overall survival (OS) for patients with advanced BTC in the first-line setting using the PD-L1 immune checkpoint inhibitor, durvalumab, plus the standard chemotherapy combination gemcitabine plus cisplatin (GemCis). Importantly, this was achieved without any serious adverse effects.

The primary endpoint was OS and secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety.

In total, 685 patients previously untreated for unresectable locally advanced, recurrent, or metastatic BTC were randomized to receive GemCis with either durvalumab (n=341) or placebo (n=344). Durvalumab plus GemCis demonstrated a significantly improved OS compared to placebo plus GemCis (HR, 0.80; 95% CI, 0.66-0.97, p=0.021) as well as significantly improved PFS (HR, 0.75; 95% CI, 0.64–0.89; p=0.001). ORR was 26.7% with durvalumab and 18.7% with placebo.

During the trial, 62.6% of patients receiving durvalumab and 64.9% of patients receiving placebo experienced grade 3-4 treatment-related adverse events. This led to the discontinuation of any study medication for 8.9% of patients receiving durvalumab and 11.4% of patients receiving placebo.

Overall, the results of the TOPAZ-1 trial showed durvalumab plus GemCis to be a significantly superior treatment for patients with advanced BTC compared to GemCis alone, demonstrating a markedly improved OS and PFS with reasonable safety. These results highlight a plausible new standard of care regimen of durvalumab plus GemCis in the first-line setting for patients with advanced BTC.

HIMALAYA: Promising results for patients with unresectable hepatocellular carcinoma when combining a single dose of tremelimumab plus regular intervals of durvalumab in comparison to sorafenib

There is a high unmet need for patients with unresectable hepatocellular carcinoma (uHCC) who face poor prognosis due to sparse treatment options. The upregulation of CTLA-4 and PD-L1 immune checkpoints in HCC offer the rationale for treating patients with the anti‐CTLA‐4 and anti‐PDL1 antibodies tremelimumab and durvalumab, respectively3.

Having demonstrated promising clinical activity with limited toxicity in a Phase II study (NCT02519348)4, the Phase III HIMALAYA (NCT03298451)2 clinical trial was initiated. HIMALAYA was an open-label, randomized, multicenter trial investigating tremelimumab and durvalumab for the treatment of patients with uHCC in the first-line setting.

1171 patients were randomized to receive either the STRIDE regimen (Single Tremelimumab Regular Interval Durvalumab) (n=393), durvalumab alone (n=389) or the standard of care (SOC), sorafenib (n=389). The primary objective was overall survival (OS) for STRIDE versus sorafenib and the secondary objective was OS noninferiority of durvalumab and sorafenib. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) as per RECIST 1.1, duration of response (DoR), and safety.

Results showed that STRIDE exhibited significantly improved OS in comparison to sorafenib (HR, 0.78; 96% CI, 0.65–0.92; p=0.0035) and durvalumab demonstrated superior OS noninferiority compared to sorafenib (HR, 0.86; 96% CI, 0.73–1.03). ORR was greater for STRIDE (20.1%) and durvalumab (17.0%) than for sorafenib (5.1%). 36.9% of patients receiving sorafenib experienced grade 3-4 treatment-related adverse events, compared to 25.8% and 12.9% of patients receiving STRIDE and durvalumab, respectively. This lead to treatment discontinuation of 11% of patients receiving sorafenib, 8.2% of patients receiving STRIDE and 4.1% of patients receiving durvalumab.

In conclusion, the results show the STRIDE regimen is a notably improved treatment option for patients with uHCC, both in terms of efficacy and safety and therefore a promising new first-line SOC for this patient population.



The GERCOR NEONIPIGA study: encouraging rates of pCR observed in patients with localized MSI/dMMR oeso-gastric adenocarcinoma following neoadjuvant nivolumab plus ipilimumab.

For patients with resectable gastric cancer or gastroesophageal junction adenocarcinoma (GEJ) the only curative option is radical surgery and perioperative chemotherapy is often ineffectual for those with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR). The GERCOR NEONIPIGA (NCT04006262)5 single-arm Phase II study investigated an immunotherapeutic perioperative approach treating patients with resectable MSI/dMMR OGA with nivolumab plus ipilimumab in the neoadjuvant setting and adjuvant nivolumab following surgery.

32 patients were treated in this Phase II trial, 16 of which had gastric cancer and 16 had OGA. The primary endpoint was pathological compete response (pCR). During the course of neoadjuvant treatment, 32% of patients experienced grade 3-4 adverse events.  29 patients underwent surgery and 2 patients had complete endoscopic response with tumor-free biopsies.

The overall surgical morbidity rate was 54% and post-operative mortality occurred in 1 patient due to cardiovascular adverse event at post-operative day 3. All of the patients who underwent surgery had microscopically margin-negative resection (R0) and 59% had pCR, defined by TRG 1a according to Becker grade, and 14% had TRG 1b as per Becker grade. 1 patient had 10-50% of residual tumor, TRG 2, and 7 patients had more than 50% of residual tumor, TRG 3, according to Becker grade, measured by local pathological assessment. After a median follow-up of 10.9 months, 30 patients were progression-free, 1 patient had metastatic relapse and 1 patient died without relapse.

The encouraging results from the GERCOR NEONIPIGA study show that nivolumab and ipilimumab is viable in the neoadjuvant setting and associated with a promising pCR rate in patients with MSI/dMMR resectable OGA.

KEYNOTE-590: Pembrolizumab plus chemotherapy demonstrates long-term superiority compared with chemotherapy alone in patients with advanced oesophageal cancer

The randomized, double-blind, Phase III KEYNOTE-590 (NCT03189719)6 study investigated pembrolizumab chemotherapy compared to chemotherapy alone in patients with untreated, advanced or metastatic adenocarcinoma or esophageal squamous cell carcinoma (ESCC) or Siewert type esophagogastric junction adenocarcinoma (EGJ). The results with an additional 12-month follow-up were reported at the American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Symposium 2022.

749 patients were randomized to receive either pembrolizumab or placebo for up to 2 years plus chemotherapy. The primary endpoints were overall survival (OS) in patients with ESCC PD-L1 combined positive score (CPS) of ≥10, and investigator-assessed overall survival (OS) and progression-free survival (PFS) in accordance with RECIST 1.1 in patients with ESCC, PD-L1 CPS of ≥10, and for all patients. Secondary endpoints included overall response rate (ORR), duration of response (DOR), safety and health-related quality of life (HRQoL). HRQoL was assessed in 711 treated patients.

After a median follow-up of 34.8 months, median OS was greater for patients receiving pembrolizumab and chemotherapy compared to chemotherapy alone in patients with ESCC and a CPS ≥10 (HR 0.59; 95% CI, 0.45-0.76), ESCC (HR 0.73; 95% CI, 0.61-0.88), patients with a CPS ≥10 (HR 0.64; 95% CI, 0.51-0.80), and in all patients (HR 0.73, 95% CI, 0.63-0.86). In patients with adenocarcinoma, the OS HR was 0.73 (95% CI, 0.55-0.99). At 24 months, the OS rate was 26.3% for all patients receiving pembrolizumab plus chemotherapy compared to 16.1% in those receiving chemotherapy alone.

The median PFS was superior in patients receiving pembrolizumab in combination with chemotherapy versus chemotherapy alone in patients ESCC (HR 0.65; 95% CI, 0.54-0.78), those with a CPS ≥10 (HR 0.65; 95% CI, 0.54-0.78), and in all patients (HR 0.64; 95% CI, 0.55-0.75).

The rate of PFS in all patients was 11.6% compared to 3.3% for pembrolizumab plus chemotherapy and chemotherapy alone, respectively, ORR was 45% versus 29.3%, respectively and a median DOR of 8.3 versus 6 months was achieved, respectively. 20% of patients receiving pembrolizumab versus chemotherapy had a response duration ≥24 months compared to 6% of patients receiving chemotherapy alone. Grade 3-5 treatment-related adverse events occurred in 72% of patients receiving the combination treatment versus 68% in those receiving chemotherapy which led to treatment discontinuation in 21% versus 12%, respectively.

These results of the 12-month follow-up of KEYNOTE-590 demonstrated pembrolizumab plus chemotherapy continued to provide superior OS, PFS and ORR compared to chemotherapy alone in the first-line setting, with a reasonable safety profile and steady HRQoL for patients with untreated, advanced esophageal and EGJ cancer.


  1. Oh, D., Chen, L., He, A., et al., 2019. A phase III, randomized, double-blind, placebo-controlled, international study of durvalumab in combination with gemcitabine plus cisplatin for patients with advanced biliary tract cancers: TOPAZ-1. Annals of Oncology, 30, p.v319.
  2. Imfinzi plus chemotherapy significantly improved overall survival in 1st-line advanced biliary tract cancer in TOPAZ-1 Phase III trial at interim analysis [Internet]. 2022 [cited 25 January 2022]. Available from:
  3. Abou-Alfa, G., Chan, S., Furuse, J., et al., 2018. A randomized, multicenter phase 3 study of durvalumab (D) and tremelimumab (T) as first-line treatment in patients with unresectable hepatocellular carcinoma (HCC): HIMALAYA study. Journal of Clinical Oncology, 36(15_suppl), pp.TPS4144-TPS4144.
  4. Kelley, R., Sangro, B., Harris, W., et al., 2021. Safety, Efficacy, and Pharmacodynamics of Tremelimumab Plus Durvalumab for Patients With Unresectable Hepatocellular Carcinoma: Randomized Expansion of a Phase I/II Study. Journal of Clinical Oncology, 39(27), pp.2991-3001.
  5. Andre, T., Tougeron, D., Piessen, G., et al., Henriques, J., Cohen, R., Lefevre, J. and Svrcek, M., 2022. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in patients (pts) with localized microsatellite instability-high (MSI)/mismatch repair deficient (dMMR) oeso-gastric adenocarcinoma (OGA): The GERCOR NEONIPIGA phase II study. Journal of Clinical Oncology, 40(4_suppl), pp.244-244.
  6. Sun, J., Shen, L., Shah, M., et al., 2021. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. The Lancet, 398(10302), pp.759-771.

Written by Esther Drain