CANOPY-A Trial of Adjuvant Canakinumab Misses Primary End Point of DFS in NSCLC

Edward B. Garon, MD, MS

The phase 3 CANOPY-A study (NCT03447769) of adjuvant canakinumab (Ilaris) in patients with completely resected non-small cell lung cancer (NSCLC), failed to meet its primary end point of disease-free survival (DFS), according to data presented at the 2022 ESMO.

However, there was a numerical advantage in the canakinumab arm compared with placebo.Findings revealed the DFS for patients given canakinumab to be 30.0% vs 31.6% with placebo. The median DFS was 35.0 months with canakinumab compared with 29.7 months with placebo (HR 0.94; 95% CI 0.78-1.14; one-sided P = .258). No meaningful difference in DFS was seen in the canakinumab arm compared with the placebo arm across predefined subgroups of patients.

The phase 3, multicenter, double-blind study enrolled 1382 patients with NSCLC and randomly assigned them in a 1:1 ratio to receive either 200 mg of subcutaneous canakinumab every 3 weeks or matching placebo for up to 1 year.

Enrollment in the trial was open to patients with stage II-IIIA and IIIB NSCLC or patients with stage II-IIIA, IIIB NSCLC who are candidates for complete resection surgery. Patients were required to have mandatory cisplatin-based chemotherapy, fully recovered from all toxicities related to prior systemic therapy, and an ECOG performance score of 0 or 1.

Investigators evaluated the primary end point of DFS and the secondary end points of overall survival, DFS in PD-L1 subgroups, DFS in CD8 subgroups, lung-cancer-specific survival, and maximum observed plasma concentration of canakinumab.

In an interview with Targeted Oncology^TM, Edward B. Garon, MD, MS, professor of medicine, Geffen School of Medicine, Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, discussed the results of the phase 3 CANOPY-A study.

Targeted Oncology: Can you discuss canakinumab and its mechanism of action?

Garon: Canakinumab is a high-affinity monoclonal antibody directed against an interleukin-1beta [IL-1β].IL-1β has been considered a key mediator of inflammation. One of the unique aspects of canakinumab is that it is an approved drug in many countries, including the United States, for a variety of inflammatory disorders.

There has been a tremendous amount of preclinical data looking at IL-1β and other mediators of inflammation in lung cancer. Prior to the development of canakinumab, there was much less clinical data available looking at this pathway.

Can you provide some background on the CANOPY-A study?

The CANOPY-A study was designed as a 1500 patient study to evaluate the potential for canakinumab in patients with completely resected non–small cell lung cancer. The design was a 1:1 randomization between canakinumab every 3 weeks, continuously, vs placebo. The primary end point of the study was disease-free survival, and key secondary end point was overall survival to be tested only if disease-free survival was positive.

Unfortunately, the primary end point which was disease-free survival was not positive. Although numerically it did favor canakinumab, particularly at the median, the one-sided P value was 0.26, reflecting the similarity of the curves throughout the entirety of the curve, with a hazard ratio that was not particularly impressive. In addition, when looking for different subgroups, we were not able to find subgroups where the 95% confidence interval excluded 1. As a result, this is a study that was not able to show the value of canakinumab in the setting of completely resected non–small cell lung cancer.

Despite the negative results of study, were there any results which may lead to more trials in the future?

At the [ESMO] conference, there was some enthusiasm about IL-1β while we had the CANOPY-A readout, which is the third negative phase 3 study in the CANOPY program, evaluating canakinumab as a therapeutic for lung cancer. Charlie Swanton in his presidential discussion yesterday discussed the potential role of IL-1β as a mediator of cancer development among non-smokers. That evaluation was specifically looking at patients with EGFR mutations. While there has been this disappointing data looking at therapeutic uses of IL-1β, there was at least a glimmer of light looking in a prevention setting at this IL-1β. I think that there will be, presumably additional preclinical data, and it is certainly hoped that the biomarker data that was collected as part of both CANOPY-A as well as the other studies that were part of the CANOPY program can help guide further evaluation to elucidate the potential role of IL-1β in lung cancer tumorigenesis and potential therapeutic uses.

What do you think these data mean for the future of canakinumab?

In the end, the only sort of questions we can answer with this data are the ones that were asked. I think that this data is clear that in the setting of resected non–small cell lung cancer, this is not an attractive avenue. I don't know if that means that there are not other places where there could be therapeutic utility across cancer, but what I would say is that I would anticipate future exploration of this will rely on additional preclinical evaluation looking at the role of inflammation in lung cancer.

Thinking of the NSCLC space as a whole, what questions remain unanswered?

After many years of somewhat unimpressive advances or minimal advances in the setting of early stage, non–small cell lung cancer, there's been a tremendous amount of exciting data over the last few months to years looking at the role of immune checkpoint inhibitors in this early stage setting, as well as data looking at signal transduction inhibitors, and osimertinib [Tagrisso]. Still, we recommend cisplatin based chemotherapy for patients which is a sort of chemotherapeutic approach associated with a fairly high degree of toxicity. Overall, the efficacy is less than we would hope for.

I think that an emerging question is for what to do in patients who receive neoadjuvant chemoimmunotherapy and do not have a complete response. Very nice work as part of the Checkmate-816 study [NCT02998528] showed the importance of nivolumab [Opdivo] plus chemotherapy as a potential approach that could improve outcomes in early-stage disease. The data was impressive, particularly for patients who achieved a complete pathologic response, which was about a quarter of the patients. In the other patients, it's not clear what the value was. I think 1 of the challenges that we will have is, what to do in that group of patients after they've completed their chemoimmunotherapy?