Single Priming Dose of Tremelimumab Plus Durvalumab Shows Encouraging Clinical Activity, Safety in Advanced HCC

A regimen comprised of a single 300-mg priming dose of tremelimumab and 1500 mg of durvalumab (Imfinzi) every 4 weeks (T300+D) yielded favorable efficacy and an acceptable safety profile in patients with advanced HCC, according to results from the phase 2 multi-arm Study 22 presented during the 2021 HCC-TAG Congress.¹

T300+D yielded a median overall survival (OS) of 18.7 months (95% CI, 10.8-27.3) and an 18-month OS rate of 52.0% (95% CI, 38.9%-63.6%). Tremelimumab, given as a monotherapy at 750 mg every 4 weeks for 7 doses every 12 weeks thereafter, resulted in the second highest median OS of the doses examined, at 15.1 months (95% CI, 11.3-20.5). A 1500-mg dose of single-agent durvalumab every 4 weeks led to a median OS of 13.6 months (95% CI, 8.7-17.6), while 75 mg of tremelimumab for 4 doses plus durvalumab at 1500 mg every 4 weeks (T75+D) yielded a median OS of 11.3 months (95% CI, 8.4-15.0). The 18-month OS rates in these additional dosing cohorts were 45.7% (95% CI, 32.8%-57.7%), 35.3% (95% CI, 25.0%-45.8%), and 34.7% (95% CI, 24.4%-45.2%).

Moreover, patients in the T300+D arm experienced an overall response rate (ORR) of 24.0% (95% CI, 14.9%-35.3%); this was comprised of a complete response (CR) rate of 1.3%, a partial response (PR) rate of 22.7%, and a stable disease rate of 21.3%. With durvalumab monotherapy, the ORR was 10.6% (95% CI, 5.4%-18.1%), while it was 7.2% (95% CI, 2.4%-16.1%) with single-agent tremelimumab, and 9.5% (95% CI, 4.2%-17.9%) with T75+D arm. The median duration of response (DOR) was not yet reached in those who received T300+D, but it was 11.17 months in the durvalumab monotherapy arm, 23.95 months in the tremelimumab monotherapy arm, and 13.21 months in the T75+D arm.

“This single priming dose of tremelimumab combined with durvalumab showed promising clinical activity in a predominantly second-line HCC population,” Katie Kelley, MD, an associate professor of clinical medicine, Department of Medicine (Hematology/Oncology) and affiliated faculty of the Cancer Immunotherapy Program at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center said during a presentation on the data. “Across all arms, the T300+D regimen demonstrated the most favorable efficacy along with safety and tolerability.”

The combination of CTLA-4 inhibition and PD-1/PD-L1 inhibition could work to enhance antitumor activity in patients with advanced HCC because the agents target 2 complementary immune mechanisms, Kelley noted. Regimens that incorporate higher doses of a CTLA-4 inhibitor plus a PD-(L)1 inhibitor have been linked with increased OS in patients with solid tumors at the cost of increased toxicity and the need for steroid use, according to Kelley.^2-4

Based on these previous findings, investigators set out to examine whether a single priming dose of tremelimumab with durvalumab would improve immune-mediated activity in patients with HCC while minimizing toxicities.

“Study 22 was a multicenter, international study [conducted] in 3 parts. Part 1 is a safety cohort that has reported [data] previously,” Kelley said. “The phase 2 portion of the study [was] comprised of parts 2 and 3.”

The trial enrolled patients with unresectable HCC who had Child–Pugh A liver function and fresh or archival tumor tissue biopsy specimens available for evaluation. Patients also needed to have progressed on, been intolerant to, or refused treatment with prior sorafenib (Nexavar).

In part 2a of the trial, patients were randomized to single-agent durvalumab (n = 40), tremelimumab monotherapy (n = 36), or T75+D (n = 39). In part 2b, patients were allocated to T300+D with a safety run in (n = 10). In the third part of the trial, patients were randomized to T300+D (n = 65), durvalumab monotherapy (n = 64), tremelimumab monotherapy (n = 33), and T75+D (n = 45).

The primary end point of the study was safety, with key secondary end points that included OS, ORR, and DOR. Investigators performed multiphase imaging at 8 weeks, examined circulating immune cells, and assessed PD-L1 status.

In the overall patient population, the median age was 63.5 years. The majority of patients were male and more than half were Asian. Additionally, 43.4% of all patients resided in Asia excluding Japan, while 56.6% of all patients resided in the rest of the world, including Japan. Moreover, 51.7% of all patients had progressed on, 15.7% were intolerant to, and 32.7% refused treatment with sorafenib.

“The majority of patients had either viral hepatitis B or C virus as the etiology of liver disease,” Kelley said. “Across the 4 arms, [there was] a slightly higher proportion of hepatitis B virus–positive [patients]. The majority of patients in all 4 arms had BCLC advanced-stage HCC and one can see that nearly 80% [of patients] across this study as a whole had macrovascular invasion or extrahepatic spread.”

Additional efficacy data indicated that patients in the T300+D, durvalumab monotherapy, tremelimumab monotherapy, and T75+D arms experienced a median progression-free survival of 2.17 months (95% CI, 1.91-5.42), 2.07 months (95% CI, 1.84-2.83), 2.69 months (1.87-5.29), and 1.87 (95% CI, 1.77-2.43), respectively. The disease control rates were 45.3%, 37.5%, 49.3%, and 36.9%, respectively.

On average, 37.1% of patients across all arms went on to receive subsequent therapy, including systemic therapy (31.4%), TKIs (29.0%), chemotherapy (5.1%), immunotherapy (4.6%), investigational agents (1.1%), radiation (7.4%), or cancer-related surgery (2.1%).

Moreover, a pharmacodynamic biomarker analysis indicated that T300+D is able to drive an acute expansion of CD8-positive lymphocytes, which was found to be associated with response.

“We examined peripheral blood using flow cytometry for 26 different lymphocyte populations at baseline, as well as on treatment,” Kelley explained. “At baseline, no significant difference [was observed] between the 4 treatment arms. On day 15, however, the 4 treatment arms showed intriguing differences, in particular the T300+D priming dose arm had the highest level of…lymphocyte population per portion. This is a population comprised predominantly of CD3-, CD8-, and Ki67-positive T cells, which are proliferative when activated. This population of proliferative, activated T cells also correlates with response status.”

Across the treatment arms, the absolute count of these T cells proved to be highest in patients who experienced a CR or PR, according to Kelley. The count was highest of all in the complete and partial responders of the T300+D arm.

Regarding safety, grade 3 or 4 treatment-related AEs (TRAEs) occurred in 19.8% to 43.5% of patients across the 4 treatment arms. Serious TRAEs occurred in 10.9% to 24.6% of all patients. “TRAEs that led to treatment discontinuation were quite low for an advanced HCC study and ranged from 6.1% to 13.0%,” Kelley noted. Steroid requirement for TRAEs ranged from 9.9% to 26.1%.

The most common any-grade AEs observed in the T300+D arm included increased aspartate aminotransferase (AST; 16.2%), increased alanine aminotransferase (ALT; 14.9%), and increased amylase (14.9%), with common grade 3 or higher AEs including increased AST (12.2%), increased amylase (6.8%), and increased lipase (6.8%). Other symptomatic any-grade AEs included pruritus (32.4%), rash (32.4%), and fatigue (10.8%); grade 3 or higher symptomatic events comprised rash (2.7%), diarrhea (1.4%), and maculopapular rash (1.4%).

“Relatively low rates of AST and ALT increase [were observed], with grade 3 or higher [AEs reported] in less than or equal to 12% [of patients] across the 4 arms,” Kelley said. “Other key events, such as diarrhea, occurred with low incidence in the grade 3 or higher range. It was highest in [the] tremelimumab monotherapy [arm]. Rash and pruritus were the most prevalent AEs but were most commonly grade 1 or 2.”

Additionally, investigators reported on immune-mediated AEs that required either endocrine or steroid therapy. Patients in the T300+D arm most frequently experienced any-grade diarrhea (6.8%), hypothyroidism (5.4%), colitis (4.1%), and pneumonitis (1.4%); grade 3 immune-mediated AEs included increased AST (4.1%), colitis (2.7%), increased ALT (2.7%), and pneumonitis (1.4%).

“Again, we see that the majority of AEs were grade 1 or 2, and [the number of] grade 3 or 4 [effects] was low [across all arms],” Kelley noted.

T300+D and durvalumab are going to be further examined in comparison with sorafenib in the first-line treatment of patients with HCC as part of the ongoing phase 3 HIMALAYA study (NCT03298451).

References

1. Kelley KR, Masatoshi K, Harris W, et al. Study 22: a randomized, phase 2 trial of durvalumab and tremelimumab in advanced HCC. Presented at: 2021 Annual HCC-TAG Conference; March 25-27, 2021; Virtual. Accessed March 26, 2021.
2. Yau T, Kang YK, Kim TY, et al. Nivolumab (NIVO) + ipilimumab (IPI) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2019;37(suppl 15):4012-4012. doi:10.1200/JCO.2019.37.15_suppl.4012
3. Naumann RE, Oaknin A, Meyer T, et al. Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: results from CheckMate 358. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394
4. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30(21):2691-2697. doi:10.1200/JCO.2012.41.6750