Mark Leiser , 2025-05-05 18:00:00
Key takeaways:
- CAN-2409 plus valacyclovir nearly doubled survival compared with docetaxel for patients who had inadequate response to immune checkpoint inhibitors.
- Patients with nonsquamous histology derived greater benefit.
An investigational viral immunotherapy extended survival compared with standard care for patients with advanced non-small cell lung cancer who had inadequate response to immune checkpoint inhibitor therapy, phase 2 trial results showed.
The benefit observed with CAN-2409 (Candel Therapeutics) plus valacyclovir is “striking” given the trial included pretreated patients with multiple negative prognostic factors, according to principal investigator Charu Aggarwal, MD, MPH, Leslye M. Heisler Professor for Lung Cancer Excellence at University of Pennsylvania’s Perelman School of Medicine.
Data derived from Candel Therapeutics press release.
Charu Aggarwal
“We are seeing encouraging durability of activity and a long survival tail,” Aggarwal, a Healio | HemOnc Today associate medical editor, said in an interview. “Even better, we were able to avoid the introduction of cytotoxic chemotherapy.”
‘A real issue’
Prior research has shown about 25% to 30% of patients with advanced or metastatic NSCLC who do not have EGFR or ALK mutations will respond to immunotherapy.
For patients with high PD-L1 expression, response rates can reach 45% with immunotherapy or up to 65% with chemoimmunotherapy, Aggarwal said.
“What’s particularly challenging — and a real issue in clinical practice — is that even when we observe an initial response, there’s no certainty the patient will ultimately achieve a complete response or make it to the 2-year mark of immunotherapy completion without disease progression,” Aggarwal said. “Unfortunately, most patients will eventually experience recurrence. We urgently need new therapies that can reduce or eliminate the need for cytotoxic chemotherapy and its associated toxicities.”
Patients with unresectable NSCLC whose disease progresses on immune checkpoint inhibitor typically face a poor prognosis. Data from multiple published studies show median survival with docetaxel ranges from 9.8 months to 11.8 months.
CAN-2409 — an off-the-shelf, replication-defective adenovirus — is designed to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene to the tumor and induce an immune response. HSV-tk converts oral valacyclovir into a toxic nucleotide analogue that kills cancer cells, according to a Candel Therapeutics press release.
The regimen has been evaluated in trials for a variety of solid tumors, including lung cancer, prostate cancer and pancreatic cancer. The FDA granted the regimen fast track designation for patients with advanced NSCLC who are resistant to first-line therapy with PD-1/PD-L1 inhibitors who do not have activating molecular driver mutations or who progressed on targeted molecular therapy.
Trial participants
Aggarwal and colleagues conducted an open-label, phase 2A trial to evaluate CAN-2409 plus valacyclovir for patients with unresectable advanced NSCLC who had inadequate response to immune checkpoint inhibitors.
Researchers enrolled 73 patients (median age, 67 years; range, 43-88; 56% men) with stage III (10%) or stage IV (90%) disease. Most had failed multiple lines of chemotherapy, more than 90% were former or current smokers, and a majority had low or undetectable PD-L1 expression.
Trial participants received two doses of CAN-2409 — administered 5 weeks to 7 weeks apart via percutaneous or bronchoscopic injection into the lung tumor, positive lymph node or peripheral metastasis — followed by oral valacyclovir.
The per-protocol population included the 46 patients who completed treatment. Forty-one had progressive disease at enrollment and five had stable disease.
Key outcomes included OS, safety and immunologic biomarkers.
Potential ‘precision’ approach
Median follow-up was 32.4 months.
Final survival data showed median OS of 24.5 months in the per-protocol population.
Median OS reached 21.5 months for patients who had progressive disease at enrollment, with more than one-third (37%) remaining alive 2 years after CAN-2409 administration.
Biomarker analyses showed patients with nonsquamous NSCLC derived particular benefit, exhibiting greater changes in B cells, T cells and dendritic cells than those with squamous histology. Fourteen of 15 patients who survived longer than 24 months and all nine patients who survived longer than 30 months had nonsquamous NSCLC.
Researchers reported median OS of 25.4 months among those with nonsquamous histology who had progressive disease at enrollment.
The trial had not been designed for an intent-to-treat analysis; however, researchers performed an exploratory intent-to-treat analysis (n = 53) that showed median OS of 16.7 months among patients with nonsquamous NSCLC who had progressive disease at enrollment. Prior trials showed median survival of 9.9 months to 12.3 months with docetaxel in this setting.
“We know squamous and nonsquamous histologies behave very differently, so homing in on the molecular level will be very important,” Aggarwal said, noting prior studies of pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol Myers Squibb) showed differences in response rates and PFS between these groups. “We have some biomarker data that we are evaluating to discern the differences in the immune profiles, and there will be more to come on that.”
In the overall per-protocol population, researchers observed evidence of a systemic immune response, as 24 (69%) of 35 patients with multiple lesions exhibited reduction in size of uninjected tumors.
Earlier results from the trial — presented at last year’s ASCO Annual Meeting and based on median follow-up of about 18.2 months — showed no dose-limiting toxicities, as well as no grade 4 or higher treatment-related adverse events.
The regimen continued to exhibit a generally favorable safety profile throughout the additional follow-up, Aggarwal said. Researchers observed no new safety signals.
“These patients have had minimal long-term adverse events, apart from the acute intervention of having to go through bronchoscopy,” Aggarwal said. “It’s been fascinating to see no increase in immune-related adverse events. We haven’t seen higher rates of pneumonitis or other immunotherapy adverse events such as endocrinopathies. It’s great that patients have been able to remain on that backbone of immunotherapy.”
Candel Therapeutics will prepare for a potentially registrational phase 3 clinical trial to assess the regimen for patients with nonsquamous NSCLC.
“It’s important to emphasize the survival benefit we observed is in the context of a nonrandomized trial,” Aggarwal said. “The data are very encouraging and they call for a phase 3 trial. We have to see how this stacks up in a randomized prospective fashion.”
References:
For more information:
Charu Aggarwal, MD, MPH, can be reached at charu.aggarwal@uphs.upenn.edu.
Sources/Disclosures
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Disclosures:
Candel Therapeutics funded the study. Aggarwal reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.