RO7198457/Atezolizumab Shows Early-Phase Promise in Advanced Solid Tumors

Juanita Lopez, Ph

RO7198457, in combination with atezolizumab (Tecentriq), was found to be well tolerated in patients with locally advanced or metastatic disease, according to Juanita Lopez, PhD, who added that this ongoing research will provide a better understanding of how cancer interacts with the immune system.^1,2

In a phase 1/b study (NCT03289962), investigators evaluated the safety and efficacy of RO7198457, a neoantigen specific immunotherapy, in combination with atezolizumab in adult patients with locally advanced or metastatic disease, who had a life expectancy of at least 12 weeks and an ECOG performance status of 0 or 1. The most common tumors examined in the study included colorectal cancer, renal cell carcinoma, and melanoma. Notably, 40% of patients received prior immune checkpoint inhibitors.

The primary end point of the trial was safety and tolerability, while the key secondary end points including determining the maximum-tolerated dose (MTD), a recommended phase 2 dose, pharmacodynamic activity, and preliminary antitumor activity.

Part 1a of the trial was a dose-escalation phase where investigators evaluated RO7198457 at 5 different dose levels: 25 μg, 38 μg, 50 μg, 75 μg, and 100 μg. Following this, the 25 μg, 38 μg, and 50 μg doses were evaluated in combination with 1200 mg of atezolizumab every 3 weeks. Furthermore, in the induction phase, 8 doses of RO7198457 were administered in weekly and biweekly intervals. There was a boost in cycle 7, followed by RO7198457 maintenance every 8 cycles, according to Lopez. Atezolizumab was administered on day 1 of each 21-day treatment cycle.

Results presented during the AACR Virtual Annual Meeting showed that of 63 patients who had their peripheral blood evaluated, 73% had an ex vivo T-cell response with the treatment. Of the 108 patients who had, at minimum, 1 tumor assessment, 9 demonstrated a response: 1 patient had a complete response, while 53 patients had stable disease.

Moreover, regarding safety, the combination was found to be well tolerated. Most adverse effects (AEs) reported with this approach were grade 1/2 in severity and included infusion-related reaction, fatigue, cytokine release syndrome, influenza-like illness, and diarrhea. The MTD was not found.

In an interview with OncLive, Lopez, a consultant medical oncologist in the Phase I Drug Development Unit at the Royal Marsden and the Institute of Cancer Research, discussed early findings with RO7198457 in combination with atezolizumab in patients with locally advanced or metastatic malignancies.

OncLive: Could you provide some background on RO7198457 and what makes this agent so unique?

Lopez: We know that cancers have many what I refer to as “spelling” mistakes and these mistakes can be recognized by the immune system as foreign. One way to augment a response to immunotherapy would be to ramp up this recognition. We are trying to do this in the study by using a bioinformatics portal to analyze the tumor and then generating a vaccine based on RNA that we could give to the patient; this is a personalized form of immunotherapy.

What was the rationale for combining RO7198457 with atezolizumab in patients with locally advanced or metastatic solid tumors?

We had great preclinical data which demonstrated additive effects between the vaccine and immune checkpoint inhibitors; that ultimately served as the basis for the combination strategy.

What was the design of the trial and the goal of this research?

The goal was to establish the safety and tolerability of the combination therapy. In terms of the design, with the vaccine approach, phase 1a was an induction phase where patients received weekly doses. Following that induction phase, patients moved into the maintenance phase, where they received the vaccine every 8 cycles. The immune checkpoint inhibitor was given every 3 weeks.

Could you shed light on some of the findings from this research?

We established a safe dose for this combination; this was based on both the safety, as well as the immune readouts. Once a safe dose was established, we enrolled patients into expansion cohorts based on a number of tumor types that were of particular interest. Only 40% of these patients received prior immunotherapy.

This study was particularly successful in terms of getting the patient's immune system to recognize a tumor. We managed to generate tumor-specific immune cells in the majority of patients. In the patients analyzed thus far, 73% had a tumor-specific immune response, which was a particularly exciting finding.

With the numerous approvals for immune checkpoint inhibitors in different tumor indications, the sad story is that the majority of patients do not respond. We know that this is, in large part, because they don't have a tumor-specific immune response. Biologically, from a science viewpoint, I believe it’s very exciting that we demonstrated the generation of tumor-specific immune responses in the majority of patients.

Could you highlight some of the safety data with this regimen?

The combination is very safe. We did not reach the MTD and the safety profile was as expected. We wanted to wake up the immune system, generating an efficient response.Cytokine generation was expected and occurred about 3 to 4 hours after receiving the vaccine. Other AEs, such as fever and chills were reported; however, all in all, the combination was found to be safe.

What does the future look like for this agent?

Neoadjuvant vaccination strategies may be best for patients, especially early on when they have better immune health. Early on, their immune systems are less suppressed and can be activated. We're currently testing this [agent] in combination with immune checkpoint inhibitors in early-stage melanoma and in early-stage lung cancer in the adjuvant setting. These randomized studies are currently enrolling patients.

What is the take-home message regarding this research?

I believe this is very exciting. We are understanding how cancer interacts with the immune system and that enables us to create new combinations. Looking forward, we need to understand how cancer hides in the immune system. It’s unlikely [that it does it in] just 1 way; it is like a number of ways. Developing a better understanding of this will allow us to select combinations that will help us combat cancer.

References

1. Lopez JS, Camidge R, Iafolla M, et al. A phase Ib study to evaluate RO7198457, an individualized Neoantigen Specific immunoTherapy (iNeST), in combination with atezolizumabin patients with locally advanced or metastatic solid tumors. Presented at: 2020 AACR Virtual Annual Meeting II, June 22-24, 2020; Virtual. Abstract CT301.
2. Personalized cancer vaccine plus atezolizumab shows clinical activity in patients with advanced solid tumors. News release. AACR. June 22, 2020. Accessed August 28, 2020. https://bit.ly/3jpJ0jT.