Background of the KEYLYNK-007 trial for advanced solid tumours

Bookmark and Share
Published: 13 Jun 2020
Views: 4051
Rating:
Save
Dr Timothy Yap - MD Anderson Cancer Center, Houston, USA

Dr Timothy Yap talks to ecancer in an online interview for the ASCO virtual meeting 2020 about the KEYLYNK-007 trial, a phase 2 trial of the PARP inhibitor olaparib in combination with the PD-1 inhibitor pembrolizumab in patients with previously treated advanced solid tumours with homologous recombination repair mutations (HRRm) and/or homologous recombination repair deficiency (HRD).

Dr Yap outlines the trial design, and the reasons behind choosing olaparib in combination with pembrolizumab.

He also discusses how it could personalise treatment in the future.

This programme has been supported by an unrestricted educational grant from Pfizer.

The KEYLYNK-007 study is a phase II trial of the PARP inhibitor olaparib in combination with a PD1 inhibitor pembrolizumab in patients with previously treated advanced solid tumours with homologous recombination repair mutations and/or homologous recombination repair deficiency. This trial is unique in that it is a combination of both a molecularly targeted agent and an immunotherapy. It involves a novel combination strategy that is tumour agnostic and is instead focussed on personalising this promising combination through the molecular selection of patients.

Can you tell us about the trial design?

300 adult patients with previously treated advanced solid tumours will be enrolled. Patients should be ineligible for curative therapy and should have progressed on or should be intolerant to standard therapy. Patients should have tumours with homologous recombination repair mutations and/or homologous recombination repair deficiency and also have centrally confirmed measurable disease per RECIST version 1.1 or prostate cancer working group modified RECIST version 1.1 for patients with prostate cancer.

Eligible patients will be allocated into one of three subgroups based on biomarker status: those with BRCA mutations, those with other HRR mutations and those with HRD positivity. All patients will receive olaparib 300mg twice daily plus pembrolizumab 200mg every three weeks for up to 35 cycles, or approximately two years, until disease progression, unacceptable toxicity, current illness or withdrawal of consent.

Why was the combination of olaparib and pembro chosen for this study?

Both olaparib and pembrolizumab are already FDA approved drugs as monotherapy in different indications. For example, olaparib is approved in different settings in ovarian, breast, pancreas and recently in castration resistant prostate cancer while pembrolizumab is approved as monotherapy in different indications across multiple cancer types. Robust preclinical studies have indicated that this is a potentially synergistic combination and there are several hypotheses for this. For example, PARP inhibitors may lead to S-phase DNA damage which leads to an accumulation of cytosolic DNA which activates the cGAS-STING dependent innate immune response, priming of anti-tumour T-cells and also sees upregulation of PD-L1 expression. Early phase clinical trials of this combination have shown great promise with early signals of anti-tumour activity in different cancer types.

How do you hope this trial impacts clinical practice in the future?

We certainly hope it will personalise the way we select patients for modern day anti-cancer therapeutics by assessing patients based on their unique molecular characteristics and aberrations rather than use a one size fits all approach based on tumour type. We hope this promising combination of a molecularly targeted agent and immunotherapy will become a standard of care option across different cancers and benefit multiple patients in the future.