CAN-2409/Vancyclovir Leads to Positive Tolerability, Immune Response in NSCLC

The combination of the adenovirus CAN-2409 and valacyclovir with continued immune checkpoint inhibitor (ICI) therapy demonstrated favorable tolerability and induced an immune response leading to a median overall survival (mOS) of 22.0 months after a median follow-up of 20.6 months. Included patients had non-resectable, stage III/IV non–small cell lung cancer (NSCLC) and were refractory or resistant to anti–PD-(L)1 therapy, according to findings from an open-label phase 2 trial (NCT04495153) presented in a poster during the 2024 ASCO Annual Meeting.

The objective of the trial was to evaluate if CAN-2409, a replication-defective adenovirus that is encoded for the HSV-thymidine kinase gene, could improve mOS in patients after 2 injections. Patients were assessed for safety, immunologic biomarkers, and OS, investigators noted. The study schematic and biomarker analysis sought to enroll 80 patients divided equally into 2 cohorts stratified by stable disease and progressive disease 18 weeks after ICI treatment.

A total of 76 patients were enrolled and 3 patients dropped out prior to treatment, resulting in a safety population of 73 patients who received at least 1 injection (7 patients in cohort 1 and 66 patients in cohort 2). Patients who received 2 courses of CAN-2409 and valacyclovir and completed 12 weeks of treatment were evaluated.

Both cohorts received 2 courses of CAN-2409 and valacyclovir with continued standard of care (anti–PDF-1/PD-L1 with or without chemotherapy). Doses were given 5 to 7 weeks apart and delivered via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis.

The primary end points were response by RECIST criteria and disease control rate (DCR). The secondary end points were progression-free survival, OS, and quality of life.

In cohort 1, the objective response rate (ORR) was 40% with a DCR of 100%. The duration of response (DOR) for partial response (PR) was 11.6 months (range, 10.4-12.8); for stable disease (SD), it was 6.2 months (range, 2.8-16.7). For cohort 2, the ORR was 8% with a DCR of 70%. This cohort had a DOR for PR of 6.1 months (range, 2.8-16.3) and a DOR of SD of 3.8 months (range, 0-14.5).

Charu Aggarwal, MD, MPH

Lead author, Charu Aggarwal, MD, MPH, and colleagues wrote that CAN-2409 improved survival in patients who were progressing under ICI treatment, with an mOS of 20.6 months with a median follow-up of 20.6 months (cohort 2). They also noted that improved survival was independent of PD-L1 status.

Regarding systemic antitumor activity, investigators wrote that systemic response or abscopal response was measured on all evaluable patients with at least 1 non-injected lesion (n = 35). An abscopal response was observed in 66% of patients and when using a threshold of greater than 10% decrease, more than half of the patients showed a response, noting that abscopal response was associated with improved survival.

Immune activity was measured after CAN-2409 treatment and showed that the adenovirus induced significant increase in circulating T-helper and cytotoxic T cells. Significant increase in circulating inflammatory mediators including granzyme A, B, and H, were also observed.

After the second CAN-2409 injection, immune activity suggested prolonged survival with investigators reporting significant T helper and central memory T helper cells in long survivors whose OS was greater than 24 months. Flow cytometry analysis also showed a significant increase in activated cytotoxic T cells, T helper cells, and memory T cells in patients who were long survivors.

In both cohorts, the median age was 67 years (range, 43-88) and the majority were male (56%). Forty-eight percent of patients had PD-L1 expression of less than 1%, 21% had an expression from 1% to 49%, and 26% had an expression over 50%, and 5% had unknown status. Histologically, the majority (78%) had nonsquamous disease, and at enrollment, 68% had undergone ICI monotherapy whereas 32% had received ICI plus pemetrexed (Alimta).

The adenovirus demonstrated a favorable safety and tolerability profile with most patients experiencing grade 1 or 2 treatment-related adverse events (TRAEs) and only 3 patients who experienced a grade 3 TRAE of pyrexia (n = 1) and pneumonitis (n = 2).

Grade 1 TRAEs were categorized as gastrointestinal disorders (n = 20), general disorders and administration site conditions (n = 39), elevated liver enzyme or creatinine (n = 4 each), metabolism and nutrition (n = 2), nervous system disorders (n = 3), or respiratory, thoracic, and mediastinal disorders (n =2).

The investigators concluded that the observed mOS of 20.6 months exceeded the mOS reported in this population who were treated with standard chemotherapy. Although 90% of patients had stage IV disease, an abscopal effect was observed in more than 70% of patients presenting with at least 1 uninjected lesion, suggesting that only 1 or 2 tumors need to be injected to teach the immune cells how to recognize the patient’s tumor and induce systemic and durable antitumor activity.

REFERENCE:

Aggarwal C, Sterman D, Alesi ER, et al. Overall survival after treatment with CAN-2409 plus valacyclovir in combination with continued ICI in patients with stage III/IV NSCLC with an inadequate response to ICI. J Clin Oncol. 2024;42(suppl 16):8634-8634. doi: 10.1200/JCO.2024.42.16_suppl.8634