Combining Reqorsa® Gene Therapy with Tagrisso® (osimertinib) in NSCLC

The Acclaim-1 clinical trial is an open-label, multi-center Phase 1/2 clinical trial evaluating the Company’s lead drug candidate, REQORSA, in combination with AstraZeneca’s Tagrisso® (osimertinib) in patients with late-stage non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations whose disease progressed after treatment with Tagrisso.

In January 2020, we received Fast Track Designation from the U.S. Food and Drug Administration for use of REQORSA in combination with TKI Tagrisso for the treatment of NSCLC patients with EGFR mutations whose tumors progressed after treatment with Tagrisso.

The Phase 1 dose escalation portion of the Acclaim-1 trial has been completed. The Phase 2a expansion portion of the study is expected to enroll approximately 33 patients who have previously received only Tagrisso treatment, to determine toxicity profiles of patients with different eligibility criteria, as well as efficacy and other endpoints. There will be an interim analysis following the treatment of 19 patients. 

The Phase 2b randomized portion of the study is expected to enroll approximately 74 patients to be randomized 1:1 to receive either REQORSA and Tagrisso combination therapy or platinum-based chemotherapy. The primary endpoint of the Phase 2b portion of the trial is progression-free survival, which is defined as time from randomization to progression or death. An interim analysis will be performed at 28 events.

Phase 1 Dose Escalation

While the Phase 1 portion of the Acclaim-1 study was designed primarily to assess safety, we believe promising efficacy results were also observed.  The reported results showed no Dose Limiting Toxicities (DLTs), established a Recommended Phase 2 Dose (RP2D) of 0.12 mg/kg (the highest dose level administered in the trial) and provided data showing early efficacy of REQORSA in combination with Tagrisso. 

Of the 12 patients treated with escalating doses of REQORSA and standard doses of Tagrisso, all of whom had progressed on Tagrisso containing regimens, three patients, as of data from January 2024, had experienced prolonged time to progression, including one with continuing partial response. 

Specifically, one patient at the 0.06 mg/kg dose level, previously treated with carboplatin, pemetrexed, and Tagrisso, had a partial remission by investigator evaluation and treatment is now ongoing in the trial after 28 cycles, which is approximately 19.5 months. 

A second patient at the 0.12 mg/kg dose level who was previously treated with cisplatin, pemetrexed, carboplatin, and Tagrisso has stable disease and is continuing to receive REQORSA after 14 cycles, or approximately 10 months. 

And a third patient who was at the 0.09 mg/kg dose level, previously treated with Tagrisso, had stable disease and received 14 cycles, over approximately 10 months before disease progression occurred. 

The extended PFS of each of these patients is consistent with long-term PFS seen in several patients in prior early stage clinical trials of REQORSA and is not expected with treatment with Tagrisso alone after progression on Tagrisso. 

REQORSA administration was generally well tolerated and there were no DLTs.  The administration was associated with a delayed infusion-related reaction of muscle aches, fever and chills in some patients, which we believe is similar to reactions seen with the administration of antibodies routinely used in oncology treatment. This was managed with prophylactic steroids, acetaminophen and diphenhydramine, and symptoms decreased with repeat cycles.  

We believe this new mechanism and novel approach targeting lung cancer, which comes with a strong safety profile and early signs of efficacy, is paving new ground in the fight against lung cancer.

AACR 2021: Reqorsa^® + Tagrisso Reduce Tumor Growth in Tagrisso Resistant Tumors

In 2021, research collaborators presented preclinical data at the American Association of Cancer Research (AACR) annual meeting on REQORSA in combination with Tagrisso in EGFR mutant NSCLC.

Preclinical data showed that REQORSA in combination with targeted therapy osimertinib (Tagrisso) demonstrated synergistic antitumor efficacy in EGFR mutant osimertinib resistant NSCLC tumors in H1975-OsiR isogenic tumors. Researchers also found that the upregulation of PDK1 was associated with osimertinib resistance.

For more information, please review the poster presented at AACR 2021, titled, “Overcoming resistance to osimertinib by TUSC2 gene therapy in EGFR mutant NSCLC.”