AACR: Novartis aims to keep canakinumab's early lung cancer hopes alive despite metastatic failure

When Novartis failed in an attempt to repurpose Ilaris for metastatic non-small cell lung cancer (NSCLC), the Swiss pharma played up signs that it said supported continued exploration of the med in earlier stages of disease. Now, the company has unveiled those data and hopes to prove it’s not a headstrong drug developer that refuses to cut its losses.

Ilaris, or canakinumab, showed benefit “in the right direction” when added to Merck & Co.’s Keytruda and chemotherapy in previously untreated metastatic NSCLC, Jeff Legos, Ph.D., Novartis’ global head of oncology and hematology development, said in an interview with Fierce Pharma.

In newly diagnosed metastatic NSCLC patients, the addition of canakinumab cut the risk of death by 13% and the risk of disease progression or death by 17%. Neither of those improvements was statistically significant. The data, from the phase 3 CANOPY-1 trial, were presented at the American Association for Cancer Research annual meeting.

CANOPY-1 marked the second flop for canakinumab, an FDA-approved inflammatory disease drug, in NSCLC. The interleukin-1 beta inhibitor had previously also failed to tackle previously treated NSCLC in the CANOPY-2 trial.

Still, Legos pointed to several encouraging signs, suggesting canakinumab monotherapy might eventually triumph as an adjuvant treatment that’s given after surgery and chemo in early-stage NSCLC. In that setting, the drug is being tested in the ongoing CANOPY-A study.

The most important insight that gives Novartis hope came from a predefined subgroup analysis based on a marker of inflammation called high-sensitivity C-reactive protein (hsCRP). The marker is a well-established negative prognostic factor for most cancers, including NSCLC, Legos explained.

Novartis divided patients into four groups based on their baseline hsCRP levels. In the lowest quartile, canakinumab reduced the risk of death by 55% and the risk of disease progression or death by 43%. In contrast, for patients with hsCRP levels in the highest quartile, almost no difference was observed between the canakinumab takers and those in the control group.

The results don’t bear statistical rigor because of the trial design, but Novartis is pleased to find “a relationship between outcomes and CRP that supports the biomolecular hypothesis or the mechanism of action,” Legos said.

The findings are important because patients who are getting canakinumab in the early-stage setting in CANOPY-A have low levels of hsCRP, Legos said. Plus, this patient subgroup also resembles those enrolled in the CANTOS cardiovascular outcomes trial, which originally sparked Novartis’ interest in exploring canakinumab in lung cancer.

The CANTOS trial evaluated canakinumab as a secondary prevention measure for cardiovascular events in patients who had suffered a heart attack. But Novartis found that people who got the drug enjoyed a much lower rate of lung cancer death.

In CANTOS, patients had hsCRP levels in the range of 2 mg/L to 6 mg/L, Legos said. Similarly, blinded data show early-stage NSCLC patients enrolled in the ongoing CANOPY-A study had median baseline hsCRP of 2 mg/L, compared with 16 mg/L in the failed CANOPY-1 study.

What’s more, the patient populations in CANOPY-A and CANTOS are more “synonymous” also because CANOPY-A patients would have just undergone surgical resection and chemotherapy, leaving them with either no sign of cancer or only small traces of disease, Legos said.

CANOPY-A is slated to read out in the second half of this year. Novartis has said the adjuvant NSCLC setting could represent over $1 billion in peak sales opportunity for canakinumab.

Meanwhile, the adjuvant NSCLC landscape has changed since Novartis launched CANOPY-A in 2018. In October 2021, the FDA approved Roche’s PD-L1 inhibitor Tecentriq and chemotherapy as adjuvant treatment for stages 2 to 3a NSCLC with PD-L1 expression of at least 1%.

Merck & Co. also recently showed postsurgery use of its PD-1 inhibitor Keytruda lowered the risk of disease recurrence or death by 24% in a broad patient population with stages 1b to 3a NSCLC regardless of tumor PD-L1 expression status. However, Keytruda’s benefit in patients with high PD-L1 expression of 50% and above hadn’t reached statistical significance at an interim analysis.

The CANOPY-A trial represents an opportunity for canakinumab to potentially provide a treatment for either more patients or certain subgroups that may not be fully benefiting from PD-1/L1s, Legos said. CANOPY-A enrolled patients across stages 2 to 3b and includes several subgroup analyses based on molecular alterations, PD-L1 expression and hsCRP.

The trial also includes some secondary endpoints measuring patient-reported outcomes on some common symptoms for lung cancer patients. In CANOPY-1, canakinumab significantly reduced the risk of cough, chest pain and shortness of breath by 41%, 38% and 33%, respectively.