AN APPROACH using an RNA-based personalized cancer vaccine called RO7198457 in combination with the PD-L1 inhibitor atezolizumab has shown a preliminary benefit, according to an early study in patients with advanced solid tumors. The novel combination was well tolerated, and 8% of patients showed a response to therapy, while almost 50% had stable disease. Of note, the combination generated immunogenicity, and the hope is that studying it in less-advanced cancers will result in higher response rates. These results were presented during the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting II.¹

“Many cancers are able to successfully avoid the immune system, and we are only starting to understand the myriad ways in which cancers can do this. Because many mutations are not shared between cancers, a personalized treatment approach that targets individual tumor neoantigens may be a viable immunotherapeutic strategy for numerous patients with cancer,” explained lead author Juanita Lopez, MB, BChir, PhD, Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. “We saw that the combination was generally well tolerated, and the approach induced an immune response in the majority of patients, including within the tumor,” she noted.

“We saw that the combination was generally well tolerated, and the approach induced an immune response in the majority of patients, including within the tumor.”

— Juanita Lopez, MB, BChir, PhD

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About the Vaccine

RO7198457 IS an mRNA-based cancer vaccine manufactured separately for each patient through a labor-intensive process. Tumor and blood samples are sequenced to identify tumor-specific neoantigens, which are an attractive target for cancer immunotherapy because they may be recognized as foreign by the immune system. After selecting up to 20 tumor neoantigens, the corresponding mRNA is generated, forming the backbone of the vaccine, which is then encapsulated in a liposomal formulation to enable intravenous administration, she explained.

Once the vaccine is administered, it works in two ways: one is to stimulate the innate immune system and the second is to encode the neoantigens, which are expressed, processed, and displayed on antigen-presenting cells, with the goal of stimulating an antitumor immune response.

Study Details

DR. LOPEZ EXPLAINED that a study found monotherapy with the vaccine was tolerable with a manageable safety profile, and about one-third of 31 patients treated with the vaccine  had stable disease. The present phase Ib study enrolled 144 patients with advanced solid tumors (non–small cell lung cancer [NSCLC], melanoma, triple-negative breast cancer, and urothelial cancer).

The idea was to boost the immune response using atezolizumab along with the vaccine. The vaccine was administered in weekly doses for the first 6 weeks, and then the next two doses were given every 2 weeks. Atezolizumab at 1,200 mg was given on day 1 of each 21-day cycle. A booster dose of the vaccine was given during the seventh cycle of atezolizumab and then along with a maintenance dose of the vaccine every 24 weeks after the induction phase.

The median number of prior therapies was 3 (range = 1–11), and about 40% had received prior immunotherapy. Low levels of PDL1 were found in the majority of patients: 93% in tumor cell assays and 79% in immune cell assays.

The median number of vaccine doses was 8, and 16% of patients discontinued the treatment due to progressive disease before completing 6 weeks of therapy.

The majority of adverse events were grade 1 or 2. Infusion-related reactions and cytokine-release syndrome were reported in 15% or more of patients but were transient and reversible. No dose-limiting toxicities were identified, but seven patients (5%) discontinued treatment due to treatment-related adverse events.

“We saw modest activity in these patients with heavily pretreated, advanced cancer,” Dr. Lopez said.

In 108 evaluable patients, 9 responded (overall response rate of 8%). One patient with colorectal cancer had a complete response, and 53 patients (49%) had stable disease.

Evaluation of the peripheral blood showed neoantigen-specific T-cell responses induced by the vaccine in 73% of patients. Forty-six had ex vivo responses that mostly involved CD4 and CD8 T cells.

“In this trial, we showed that we were able to generate tumor-specific immune responses in the majority of evaluable patients using a personalized cancer vaccine approach in combination with immune checkpoint blockade. Although the clinical response rate overall was low, this is likely because many of the patients treated in our study had very advanced disease and were heavily pretreated,” Dr. Lopez said.

Due to the small sample size and lack of a control arm, direct comparisons with single-agent atezolizumab were not possible. The combination strategy is also being explored earlier in the course of disease in randomized phase II trials of patients with melanoma and early-stage NSCLC.

‘Unique Design’

“THESE AUTHORS used a novel design, combining a neoantigen RNA-based vaccine unique to each patient with atezolizumab,” said AACR Past President Elaine R. Mardis, PhD, Nationwide Children’s Hospital, Columbus, Ohio. “This study differs from other neoantigen vaccine studies in the schedule of giving the vaccine with an immune checkpoint inhibitor. Other studies have primarily dosed with neoantigen vaccine alone, wherein a handful of patients also received an immune checkpoint blockade immunotherapy, whereas this study gives the vaccine with the anti–PD-L1 agent at intervals. We really don’t know the best sequence when combining the vaccine with an immune checkpoint inhibitor, and it is important to have trials that evaluate different therapeutic sequencing schedules.” 

DISCLOSURE: The study was funded by Genentech and BioNTech. Dr. Lopez has received research funding from Roche, Basilea Pharmaceutica, and Genmab; and has served in a consulting or advisory role for Basilea Pharmaceutica and Genmab. Dr. Mardis has reported financial relationships with Qiagen, Pact Pharma, Moderna, and Interpreta.

REFERENCE

1. Lopez JS, Camidge R, Iafolla M, et al: A phase Ib study to evaluate RO7 198457, an individualized neoantigen specific immunotherapy in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. 2020 AACR Virtual Annual Meeting II. Abstract CT301.