Nogapendekin Alfa Inbakicept Shows Promise in Checkpoint-Refractory NSCLC

Clinical data suggest that the addition of the interleukin-15 (IL-15) superagonist nogapendekin alfa inbakicept-pmln (Anktiva; formerly N-803) to standard checkpoint inhibitor (CPI) therapy may overcome acquired resistance in patients with advanced non–small cell lung cancer (NSCLC). Data from the phase 2b QUILT-3.055 trial (NCT03228667) indicate that this combination therapy can prolong overall survival (OS) in a patient population that has traditionally exhausted immunotherapy options.¹

Efficacy in CPI-Refractory Populations

The findings from QUILT-3.055 focused on patients with metastatic NSCLC whose disease had progressed following treatment with PD-(L)1 inhibitors such as pembrolizumab (Keytruda), nivolumab (Opdivo), or atezolizumab (Tecentriq). In a cohort of 151 evaluable patients, the administration of nogapendekin alfa inbakicept in combination with the same CPI the patient had previously progressed on resulted in a median OS of 16.2 months vs 11.8 months for nonresponders (HR, 0.52; P =.0369).

Patients achieving higher immune competence (ALC ≥1.2 ×10³ cells/µL) demonstrated additional survival benefit, with median OS of 21.1 months (HR, 0.33; P =.0009), regardless of PD-L1 status, exceeding historical overall survival of 7 to 9 months with standard-of-care chemotherapy

The results suggest that nogapendekin alfa inbakicept may function as a lymphocyte-stimulating agent, effectively resensitizing the tumor microenvironment to PD-1/PD-L1 blockade.

“Today, the default standard of care for these patients remains cytotoxic chemotherapy such as docetaxel, which is associated with substantial toxicity and limited survival benefit,” said Patrick Soon-Shiong, MD, founder, executive chairman, and global chief scientific and medical officer of ImmunityBio, in a news release. “Large, randomized trials have demonstrated median [OS] of approximately 9 months with docetaxel. The results from these studies support a potential paradigm shift toward what we define as Immunotherapy 2.0, which is the coordinated activation of the innate immune system through natural killer [NK] cells and the adaptive immune system through T cells to restore immune competence and extend survival.”

Mechanism of Action: The IL-15 Superagonist

Nogapendekin alfa inbakicept is a first-in-class IL-15 receptor agonist complex. It consists of an IL-15 genetic variant (IL-15N72D) bound to an IL-15 receptor alpha-Fc fusion protein. Unlike native IL-15, this superagonist complex mimics the natural biological process of trans-presentation, which is essential for the activation and proliferation of CD8-positive killer T cells and NK cells without the undesirable stimulation of regulatory T cells.

By stimulating the expansion of these effector cells, nogapendekin alfa inbakicept aims to convert "cold" tumors—those with low lymphocyte infiltration—into "hot" tumors. In the context of NSCLC, the agent is designed to overcome the "checkpoint fatigue" or immune exhaustion that leads to disease progression during initial CPI therapy.

QUILT-3.055 Trial Design and Safety

QUILT-3.055 is a basket trial evaluating nogapendekin alfa inbakicept across multiple solid tumor types. In the NSCLC cohort, patients received the agent via subcutaneous injection every three weeks in conjunction with their previous CPI regimen.²

The safety profile reported in the trial remained consistent with previous studies of nogapendekin alfa inbakicept. Most adverse events (AEs) were grade 1 or 2, with injection site reactions being the most common. Importantly, the addition of the IL-15 superagonist did not appear to significantly increase the incidence of immune-related AEs typically associated with CPI monotherapy, a critical consideration for a heavily pretreated clinical population.

While these results are promising, a randomized phase 3 confirmatory trial (ResQ201A; NCT06745908) is ongoing comparing nogapendekin alfa inbakicept plus tislelizumab (Tevimbra) with docetaxel in second-line NSCLC.³

REFERENCES

1. ImmunityBio announces positive results demonstrating Anktiva® as a lymphocyte stimulating agent in combination with checkpoint inhibitors in non-small cell lung cancer. News release. ImmunityBio. January13, 2026. Accessed January 14, 2026. https://tinyurl.com/4cm9bzua

2. QUILT-3.055: a study of combination immunotherapies in patients who have previously received treatment with immune checkpoint inhibitors. ClinicalTrials.gov. Updated October 17, 2025. Accessed January 14, 2026. https://clinicaltrials.gov/study/NCT03228667

3. ResQ201A: clinical trial of n-803 plus tislelizumab and docetaxel versus docetaxel monotherapy in participants with advanced or metastatic non-small cell lung cancer. ClinicalTrials.gov. Updated October 21, 2025. Accessed January 14, 2026. https://www.clinicaltrials.gov/study/NCT06745908