Novartis' IL-1β Antibody Canakinumab Fails Phase III CANOPY-2 Trial in NSCLC

Today, Novartis announced that its IL-1β antibody canakinumab, in combination with docetaxel, failed to meet the primary endpoint of overall survival (OS) in the Phase III CANOPY-2 trial. The trial enrolled 237 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who were currently receiving or had previously received platinum-based chemotherapy and PD-1 inhibitors. The results showed that the combination of canakinumab and docetaxel did not extend OS compared with docetaxel alone. Canakinumab is also being evaluated in two other Phase III trials for first-line treatment of NSCLC and as post-surgical maintenance therapy, as well as in a Phase II trial investigating its use in combination with pembrolizumab (Keytruda) in the neoadjuvant setting.

Drug Source Analysis

IL-1β is a critical cytokine and one of the ultimate inflammatory signals released upon activation of the currently prominent NLRP3 inflammasome. Dysregulated IL-1β levels are observed in many diseases; besides rare conditions such as Cryopyrin-Associated Periodic Syndromes (CAPS) caused by NLRP3 activation mutations, elevated IL-1β levels are also associated with gout, cardiovascular diseases, and severe cases of COVID-19. Similar to current small-molecule NLRP3 inhibitors, canakinumab’s primary approved indication is CAPS, which has a relatively clear pathogenesis, and it has already been marketed. Due to its ability to lower high-sensitivity C-reactive protein (hs-CRP) levels, canakinumab was hypothesized to reduce cardiovascular events. The landmark CANTOS trial, involving thousands of participants, demonstrated that canakinumab indeed reduces the risk of cardiovascular events as a secondary prevention agent; however, it did not receive this labeling due to safety concerns. Nevertheless, retrospective analyses of canakinumab revealed a 77% reduction in lung cancer incidence, which spurred the initiation of the CANOPY series of clinical trials. Another significant finding from the CANTOS trial was that canakinumab reduced the risk of gout flares by 50–60% in patients with hyperuricemia.

Careful clinical observation is a significant avenue for the discovery of new drugs. Dimethyl fumarate from Biogen and Viagra from Pfizer were both serendipitous findings during clinical use, representing one of the primary discovery paradigms for central nervous system (CNS) drugs. However, this approach has its limitations, mainly due to incomplete or unreliable chains of evidence. Since the target is not predefined, hitting the bullseye with a casual shot makes it difficult to determine whether this result stems from exceptional marksmanship or simply from the fact that the bullet had to land somewhere. Therefore, such observations typically serve only as clues rather than as conclusive evidence.The relationship between inflammation and cancer is intricate. Prior to the advent of immunotherapy, inflammation, particularly chronic inflammation, was more commonly associated with tumorigenesis and progression. Although certain types of inflammation can inhibit tumors—such as the Coley's toxins and acute infections facilitating tumor regression mentioned earlier—there is also substantial literature supporting the anticancer potential of inhibiting the inflammatory cytokine IL-1β. In fact, in this era of information explosion, it is not difficult to find a chain of supporting evidence for any hypothesis. Thus, it is prudent to assume that every target acts as a "double agent"; otherwise, one risks falling into the trap of mistaking coincidence for causality, akin to waiting by a tree stump for another hare after having planted the forest oneself.

Another critical issue is that even if the 77% reduction in lung cancer incidence reported by Cantos is genuine, it does not guarantee that cana will have any efficacy in second-line treatment for advanced non-small cell lung cancer (NSCLC). One should not mistake Hangzhou for Bianzhou; in other words, do not conflate distinct contexts. Although carcinogenesis is a complex and protracted process, preventing tumor onset is relatively easier. Once a tumor has formed, especially upon reaching the metastatic stage, it has undergone years of rigorous evolution, enabling it to counteract various innate defense mechanisms within the body, particularly immune tolerance. First-line therapies further eliminate tumor clones with poorer fitness, leaving behind only the most aggressive and resilient survivors. This is precisely why Novartis is continuing to develop preoperative neoadjuvant maintenance therapy and postoperative adjuvant maintenance therapy, as these patient populations are more relevant to the findings reported by Cantos. Of course, the core reason for the high failure rate of new drugs remains the scarcity of truly safe and effective agents. Whether starting from high-throughput screening (HTS) or conducting subgroup analyses in large-scale clinical trials involving tens of thousands of patients, the probability of identifying a novel drug capable of changing the standard of care is very low. The apparent prevalence of false positives is primarily due to the extreme rarity of true positives.