CAN-2409 Plus Valacyclovir Shows Favorable Tolerability, Induces Immune Responses in NSCLC

Key Takeaways

  • Combination therapy with CAN-2409 and valacyclovir showed a median overall survival of 22.0 months in NSCLC patients refractory to anti–PD-(L)1 therapy.
  • The trial demonstrated significant immune responses, including increased circulating T-helper and cytotoxic T cells.

Findings from a phase 2 trial (NCT04495153) showed that combination therapy with CAN-2409 and valacyclovir (Valtrex) with ongoing immune checkpoint inhibitor (ICI) therapy was tolerable and led to immune responses in patients with unresectable, stage III/IV non–small cell lung cancer (NSCLC) who were refractory or resistant to anti–PD-(L)1 therapy. A presentation of the data at the 2024 ASCO Annual Meeting showed these patients achieved a median overall survival (mOS) of 22.0 months at a median follow-up of 20.6 months.

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).

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.


  1. 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
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