PROs Offer More Insight on Tolerability of Adavosertib and Gemcitabine to Guide Phase 3 Trial

In patients with platinum-resistant epithelial ovarian cancer and other malignancies with high replication stress, treatment with the WEE-1 inhibitor adavosertib combined with gemcitabine may be a viable treatment approach after progression-free survival (PFS) improvement was shown with the combination in a phase 2 clinical trial. Also, its good tolerability has been supported by patient-reported outcomes (PROs) data.

In the randomized, placebo-controlled study, patients received either gemcitabine monotherapy or adavosertib with gemcitabine until disease progression or unacceptable toxicity. The primary analysis of the trial showed that the combination achieved a median PFS of 4.6 months (95% CI, 3.6-6.4) compared with 3.0 months (95% CI, 1.8-3.8) in the placebo plus gemcitabine group (HR, 0.55; 95% CI, 0.35-0.90]; log-rank P =.015). In terms of safety and tolerability, the primary analysis showed that the most common grade 3 or higher adverse events (AEs) were hematological or related to fatigue. There were also neurological AEs observed in 62% of the adavosertib/gemcitabine arm versus 30% of the control arm. The combination did not cause any deaths during the study.

Results of the exploratory analysis of PROs from the phase 2 study showed a similar tolerability profile. The findings were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

In an interview with Targeted OncologyTM, Ainhoa Madariaga, MD, a Medical Oncology fellow at the Princess Margaret Cancer Centre in Canada, explained the similarities between the primary and exploratory analyses of adavosertib and gemcitabine as it relates to toxicity.

Targeted OncologyTM: What previous discoveries led to this analysis?

Madariaga: The initial findings of the study were published in the Lancet this year. This is our randomized phase 2, placebo-controlled study where patients with platinum-resistant or refractory ovarian cancer were receiving either gemcitabine, dynamic placebo, or gemcitabine and adavosertib. There was also an exploratory arm in the study where we do the patients with non-high-grade serous histologies, and they received the gemcitabine and adavosertib treatment.

The rationale of this study is that in platinum-resistant and refractory disease, outcomes are poor, and treatment options are limited. Exploiting the cell cycle vulnerability is one of the ways that we can maybe overcome resistance. We know that in high-grade serous ovarian cancer over 99% of women have deep alterations in TP53 in their tumors. TP53 relates to alterations in the G1S checkpoint, and therefore more dependent G2M checkpoint. This is adavosertib is very promising because it is a WEE-1 inhibitor and inhibiting that with the adavosertib can create an escape of the G2 checkpoint and increase replication. Together, this can promote tumor cell mitosis and apoptosis.

In preclinical data, we also saw that there was a synergy between the other adavosertib and gemcitabine, and that's that that was the main rationale of this study.

Without the novel regimen, what options are available for patients with platinum-resistant epithelial ovarian cancer and what are response like with these therapies?

In platinum-resistant disease, the standard of care treatments includes single-agent chemotherapy that can be weekly paclitaxel, gemcitabine, or topotecan. The responses are quite low at around 10% to 15%. The response rates can be increased a little bit sometimes if we add bevacizumab (Avastin). Besides that, some patients that have BRCA mutations and haven't received PARP inhibitors before are also able to receive a PARP inhibitor in the platinum-resistant setting.

In terms of AEs, the AEs related to chemotherapy are well known by the patients generally hematological toxicity, vomiting, and in some cases, neuropathy. But trying to add a new targeted therapy or new agents that can be oral may be good for patients and may help us find other ways to treat them. They may decrease some of the symptomatic AEs and make sure that they spend less time in the hospital.

Can you provide detail on the initial study results? How did you design the PROs analysis based on the initial analysis?

We included 124 patients, and the results of the study showed that those patients receiving that I've also heard they've had higher progression-free survival and overall survival. Again, this is a randomized phase 2 study, so more research is needed.

During my presentation at the ASCO Annual Meeting, I discussed the assessment of the tolerability or patient self-reported symptomatic toxicity of the treatment. We were aiming to compare the group of patients who received adavosertib with gemcitabine with those who received placebo and gemcitabine.

The tool that we used to choose different toxicities that we think are the most relevant for the study treatment that we're assessing was Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Besides that, patients can include free text or verbiage to express any other symptoms that we didn't ask them about.

Can you discuss the results of the PROs analysis?

In the phase 2 trial, the main grade 3/4 toxicity was hematological toxicity, which in most cases doesn't cause any symptoms. We also saw quite a lot of fatigue in patients that were receiving adavosertib, especially those that were receiving the level 30 dose.

As part of the PRO-CTCAE, we asked patients 9 different questions and allowed the free text. We were trying to look at the toxicity longitudinally instead of at a certain time point with a percentage of on that time point. Longitudinally, we observed patients in the first 3 cycles of treatment. We use a tool that is called incremental area under the curve in 12 weeks to try to assess the toxicity over time. This is for patients that have more AEs at the beginning, so that will be adjusted when we look at AEs over time.

We detected that those patients receiving adavosertib did have some more difficulty swallowing and some more mucositis and fatigue, compared with those that were receiving gemcitabine and placebo. We also assessed the high scores of toxicity, scores of 3 or 4, to see if there was an impact in like high-grade of toxicity. We found that especially in cycle 1, day 15 of treatment, there was higher severity, and the highest score of severity was fatigue. No other significant alterations in the highest core toxicity were detected when we compare the 2 arms of treatment.

What do you think is most significant about these findings and your group prepare to design another clinical trial?

PRO-CTCAE gives us an overview of the patient's health, reports the tolerability, and can give us some information on the AEs that maybe were not recorded by the clinicians.

It's a great tool to see which AEs we should be looking at in a larger phase 3 trial, for example. It also gives us a good overview of the assessment of the patient’s perception of the toxicity. Overall, these findings are like the findings of the report.

_Reference:

_{Lheureux S, Cristea MC, Bruce JP, et al. Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021;397(10271): 281-292. doi: 10.1016/S0140-6736(20)32554-X}