FDA Grants Fast Track Status to Novel Gene Therapy Plus Pembrolizumab for Late-Stage NSCLC

The FDA has granted a fast track designation to a combination comprised of the immunogene therapy quaratusugene ozeplasmia (REQORSA) and pembrolizumab (Keytruda) for use in patients with histologically confirmed, unresectable, stage III or IV non–small cell lung cancer (NSCLC) who experienced disease progression following treatment with pembrolizumab.¹

The product utilizes Genprex, Inc.’s proprietary ONCOPREX Nanoparticle Delivery System, which is believed to be the first systemic gene delivery platform leveraged for cancer in humans, according to the clinical-stage gene therapy company.²

Quaratusugene ozeplasmia is comprised of the tumor suppressor gene, TUSC2, which is encapsulated in a nanoparticle composed from lipid molecules with a positive electrical charge. The product is intravenously administered, and was designed to target cancer cells, which are known to generally have a negative charge. Once the product is taken into the cancer cell, the gene is expressed into a protein that can restore select defective functions that arise in the cancer cell.

The gene therapy has a multimodal mechanism of action in that it can disrupt cell-signaling pathways that are responsible for the replication and proliferation of cancer cells; it can also re-establish pathways for apoptosis and modulate the immune system so that it responds against cancer cells.

Additionally, the pan-kinase inhibitor simultaneously inhibits the EGFR and AKT pathways both in vitro and in vivo. When a cancer cell takes up the TUSC2-containing nanoparticle, it is reprogrammed to die. It is known that resistance to existing targeted agents and checkpoint inhibitors can develop when alternate bypass pathways are activated. The multimodality activity of the gene therapy allows it to block emerging bypass pathways and reduce the probability of drug resistance.

“We are thrilled to receive a second fast track designation from the FDA for REQORSA in patients with late-stage NSCLC, this time in combination with the checkpoint inhibitor pembrolizumab,” Rodney Varner, president and chief executive officer at Genprex, stated in a press release. “This fast track designation is an important step in our efforts to accelerate clinical development of REQORSA and another validation of the potential of REQORSA to treat the unmet medical need of patients with late-stage NSCLC.”

In the first quarter of 2022, the company expects to launch the open-label, multicenter, phase 1/2 Acclaim-2 trial (NCT05062980), which will evaluate the safety and efficacy of the gene therapy in combination with pembrolizumab in patients with previously treated NSCLC.³

The trial will enroll patients aged 18 years and older who have histologically or cytologically documented NSCLC with locally advanced or metastatic stage IV disease who derived clinical benefit from prior pembrolizumab/platinum-based chemotherapy for at least 3 months and then subsequently progressed.

To be eligible for enrollment, patients need to have an ECOG performance status of 0 or 1, have acceptable organ function and stable cardiac condition with a left ventricular ejection fraction of greater than 40%.

Patients who are unable to tolerate pembrolizumab treatment, who have hypersensitivity to docetaxel or polysorbate 80, or who at risk for tumor lysis syndrome, will be excluded. Other exclusion criteria include having previously received systemic chemotherapy or monoclonal antibodies for advanced or metastatic disease within 1 month of study enrollment, having received prior gene therapy or any radiotherapy to the skull, spine, thorax, or pelvis in that period, among others.

The study will be done in 2 phases, a dose-escalation phase (phase 1) and an expansion phase (phase 2). The first phase of the trial will involve a 3+3 dose-escalation schema in which patients will receive the gene therapy up to 0.12 mg/kg in combination with a fixed dose of pembrolizumab at 200 mg given once during each 21-day treatment cycle. The following 3 dose levels of the gene therapy will be examined: 0.06 mg/kg, 0.09 mg/kg, and 0.12 mg/kg.

The randomized portion of the trial will evaluate the gene therapy in combination with pembrolizumab vs docetaxel with or without ramucirumab (Cyramza). In this second phase, 126 patients will be randomized 2:1 to the combination vs active comparator treatment arms. A total of 84 patients will receive the gene therapy at the recommended phase 2 dose (RP2D) identified in phase 1, plus 200 mg of pembrolizumab during each 21-day cycle until progressive disease or intolerable toxicity.

Forty-two patients randomized to the active comparator arm will be given docetaxel at the approved dose of 75 mg/m² every 21 days until disease progression or intolerable toxicity per investigator determination.

The primary outcome measures of the trial included identifying the maximum tolerated dose of the gene therapy and progression-free survival in the phase 2 portion of the research.

References

1. Genprex receives US FDA fast track designation for REQORSA immunogene therapy in combination with Keytruda for the treatment of non-small cell lung cancer. News release. Genprex, Inc.; January 3, 2022. Accessed January 3, 2022. https://bit.ly/3JEpuxV
2. REQORSA immunogene therapy: the first systemically delivered gene therapy used for cancer in humans. Genprex, Inc. website. Accessed January 3, 2022. https://bit.ly/32DZMcs
3. TUSC2-nanoparticles (GXP-001) in combination with pembrolizumab in previously treated non-small lung cancer (Acclaim-2). ClinicalTrials.gov. Updated September 30, 2021. Accessed January 3, 2022. https://clinicaltrials.gov/ct2/show/NCT05062980