1. Nalley, Catlin

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Data from a phase Ib trial showed that treatment with RO7198457, a personalized cancer vaccine, in combination with the PD-L1 inhibitor atezolizumab was well-tolerated and clinically beneficial among patients with advanced solid tumors. These findings were presented at the AACR Virtual Annual Meeting II, held June 22-24 (Abstract CT301).

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"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," noted Juanita Lopez, MB, BChir, PhD, a consultant medical oncologist at The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, in a statement. "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."


Study Methods

RO7198457, which is a systemically administered RNA-lipoplex individualized neoantigen specific immunotherapy (iNeST), was designed to stimulate T-cell responses against neoantigens.


This messenger RNA (mRNA)-based cancer vaccine is manufactured on a per-patient basis, according to Lopez. The vaccine is produced by sequencing tumor and blood samples, identifying tumor-specific neoantigens. Up to 20 neoantigens are selected and the corresponding mRNA is created as part of the vaccine, which is then encapsulated in a liposomal formulation that can be administered via intravenous injection.


This first-in-human, phase Ib study takes a closer look at RO7198457 plus atezolizumab in patients with locally advanced or metastatic solid tumors. The primary objective was safety and tolerability. Secondary endpoints included maximum-tolerated dose, recommended phase II dose, pharmacodynamic activity, and preliminary anti-tumor activity.


Eligible patients are at least 18 years of age and have advanced or recurrent solid tumors, a life expectancy of 12 weeks or longer, and an ECOG performance status of 0 or 1.


The phase Ib trial also included a phase Ia dose-escalation where investigators were evaluating RO7198457 at five dose levels: 25 [mu]g, 38 [mu]g, 50 [mu]g, 75 [mu]g, and 100 [mu]g. Three doses (25 [mu]g, 38 [mu]g, and 50 [mu]g) were then tested in combination with 1,200 mg of atezolizumab every 3 weeks.


"Eight doses of RO7198457 were given in the induction phase in weekly and biweekly intervals, a boost in cycle 7, and followed by maintenance RO7198457 every 8 cycles thereafter," Lopez outlined during a press briefing prior to the conference. "Atezolizumab is administered on day 1 of each 21-day cycle."


To date, 144 patients with advanced solid tumors have been enrolled. The most common disease types include non-small cell lung cancer, melanoma, triple-negative breast cancer, and urothelial cancer. The median number of prior therapies was three, and nearly 40 percent of patients had received prior immunotherapy. Researchers reported that the majority of patients had low levels of PD-L1 expression on both the tumor and immune cells.


Key Findings

The researchers found that the combination is well-tolerated with the majority of adverse events (AEs) being grade 1/2. No dose-limiting toxicities were observed; however, seven patients discontinued treatment due to AEs related to study drugs.


AEs (occurring in >= 15% of patients) included infusion-related reaction (IRR)/cytokine release syndrome (CRS), fatigue, nausea, and diarrhea. "IRR/CRS were transient and reversible and presented primarily as grade 1-2 chills and fever," study authors noted.


Of 108 patients who had at least one tumor assessment, nine responded, according to Lopez, representing an overall response rate of 8 percent. The researchers reported one complete response in a colorectal cancer patient. Fifty-three patients (49%) had stable disease.


Among 63 patients whose peripheral blood have been evaluated to date, researchers observed ex vivo T-cell responses in nearly 73 percent. Lopez reported that the median number of neoantigen-specific responses per patient was 2.6 (range, 1-9), which were both CD4+ and CD8+ T-cell responses.


"In this trial, we show 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," Lopez said, in a statement. "While 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.


"We have established that RO7198457 in combination with atezolizumab was generally well-tolerated," she emphasized during the press briefing. "RO7198457 in combination with atezolizumab induced immune responses in the majority of patients, including preliminary data demonstrating the detection of neoantigen-specific T-cell responses within the tumor. The combination of RO7198457 and a checkpoint inhibitor is currently under investigation in randomized phase II clinical studies."


Expert Commentary

AACR president Elaine R. Mardis, PhD, shared her thoughts on the research during the press program. "Dr. Lopez and colleagues have conducted a phase Ib clinical trial with a very unique trial design, namely, combining a neoantigen mRNA-based vaccine that includes specific targets unique to each patient in combination with atezolizumab, an anti PD-L1 antibody-based drug.


"The unique trial design that they present combines dosing of the vaccine with dosing of the anti-PD-L1 antibody atezolizumab, and differs significantly from the handful of patients that have been described earlier in the peer reviewed literature, wherein neoantigen vaccines of different types-including mRNA vaccines-were given to patients, sometimes in combination with checkpoint blockade inhibitor therapy, but typically in the interval subsequent to the vaccine dosing, not concurrent with vaccine dosing," Mardis concluded.


Catlin Nalley is a contributing writer.