Novartis' Canakinumab in NSCLC Phase 3 Trial Fails Again

Novartis' latest data from the CANOPY-1 Phase 3 trial presented at the American Association for Cancer Research (AACR) annual meeting show that in patients with newly diagnosed metastatic non-small cell lung cancer, canakinumab monoclonal antibody combined with Merck's Keytruda reduces the risk of death13 %, a 17% lower risk of disease progression or death. However, these improvements were not statistically significant, and the trial is the second time the inflammatory disease drug canakinumab has failed in a trial of NSCLC patients.

Nonetheless, Novartis remains optimistic that canakinumab monotherapy may eventually succeed as an adjuvant treatment option after surgery and chemotherapy in early-stage NSCLC, and the drug is currently being studied in the CANOPY-A trial. Novartis has said that if approved for the adjuvant treatment of non-small cell lung cancer, it could represent peak sales of canakinumab of more than $1 billion.

In the face of successive trial failures, Novartis remains confident in canakinumab mainly based on a predefined subgroup analysis of the high-sensitivity C-reactive protein (hsCRP) inflammatory marker. The marker is a well-recognized negative prognostic factor for most cancers, explained Jeff Legos, PhD, head of global oncology and hematology development at Novartis. Novartis divided patients into four groups based on baseline hsCRP levels, and in the lowest quartile, canakinumab was able to reduce the risk of death by 55% and disease progression or death by 43%.

In contrast, for patients with hsCRP levels in the highest quartile, little difference was observed between canakinumab and control patients. Legos also highlighted that patients who received canakinumab in the early stages of the CANOPY-A trial had lower levels of hsCRP. In addition, the CANTOS trial evaluated canakinumab as a secondary prevention measure for cardiovascular events in patients with heart attack. It was found that lung cancer mortality was much lower in patients taking the drug.

The CANOPY-A trial included patients in stages 2 to 3b and included several subgroup analyses based on molecular alterations, PD-L1 expression, and hsCRP. The trial will also include secondary endpoints that measure some of the common symptoms in lung cancer patients. In the CANOPY-1 trial, canakinumab treatment significantly reduced the risk of cough, chest pain, and shortness of breath by 41%, 38%, and 33%, respectively.

Canakinumab is a human monoclonal antibody that selectively binds to human interleukin-1β (IL-1β) with high affinity and neutralizes the activity of IL-1β by blocking its interaction with the receptor. In March last year, canakinumab monoclonal antibody combined with docetaxel was used in the phase III CANOPY-2 clinical trial for the treatment of adult NSCLC patients who had previously received PD1/PDL1 inhibitors and platinum-based chemotherapy. The trial failed to meet the primary endpoint of improving OS.

It is worth noting that since Novartis advanced the CANOPY-A trial in 2018, the market landscape of adjuvant therapy for NSCLC has changed dramatically. In October 2021, the US FDA approved the Roche PD-L1 inhibitor Tecentriq combined with chemotherapy as an adjuvant treatment for stage 2 to 3a NSCLC, and requires patients to have at least 1% PD-L1 expression. A recent study by Merck also showed that the use of the PD-1 inhibitor Keytruda after surgery can reduce the risk of disease recurrence or death by 24% in the group of patients with stage 1b to 3a NSCLC, regardless of tumor PD-L1 expression status. However, at the interim analysis, the benefit of Keytruda in patients with 50% or more high PD-L1 expression did not reach statistical significance.