Phase III CANOPY Studies to Investigate Canakinumab in NSCLC

Three phase III studies are set to investigate the value of canakinumab, a monoclonal antibody, in the treatment of non-small-cell lung cancer (NSCLC), according to abstracts presented at the International Association for the Study of Lung Cancer (IASLC) 2019 North America Conference on Lung Cancer.

Canakinumab has a high affinity and specificity for interleukin-1 beta. In the CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) trials, the investigators noted a significant reduction in the incidence of lung cancer, with both fatal and non-fatal cases included.

Now, the three-part prospective, multicenter, randomized, double-blind, placebo controlledphase III CANOPY study will determine how effective canakinumab can be in the treatment of NSCLC.

CANOPY-A

The CANOPY-A investigation will determine the efficacy and safety of adjuvant canakinumab, compared to placebo. The 1,500 patients will all be adults with completely resected AJCC/UICC v.8 stages II to IIIA and IIIB NSCLC, all of whom have completed standard-of-care adjuvant treatments (including, potentially, cisplatin-based chemotherapy and mediastinal radiational therapy).¹

The group will be randomized in a 1:1 ratio to receive 200 mg canakinumab once every 3 weeks, or placebo at the same interval. That regimen is expected to repeat for 18 cycles or until extenuating circumstances, including: disease recurrence, unacceptable toxicity, treatment discontinuation due to patient or doctor intervention, death, or loss to follow-up.

The primary objective will be disease-free survival; the secondary metrics will be overall survival (OS), lung cancer-specific survival, safety, pharmacokinetics and immunogenicity of canakinumab, and patient reported outcomes.

“Pre-clinical data has shown that IL-1B inhibition stably reduces tumor growth, by limiting inflammation and inducing the maturation of MDSCs (myeloid-derived suppressor cells) into M1 macrophages,” the researchers wrote in their abstract. 

CANOPY-1

CANOPY-1 is a phase III trial seeking to determine the efficacy and safety of canakinumab with pembrolizumab (Keytruda) and platinum-based chemotherapy among patients with untreated stage IIIB/IIIC to IV squamous and non-squamous NSCLC.²

The study is split into 2 parts. The primary objectives are first, to confirm the recommended phase III regimen, and then to compare progression-free survival (PFS) and OS between the treatment arms. 

The first part is an open-label safety test, involving 3 cohorts of 9 patients each to confirm the recommended phase III canakinumab regimen. The patients will receive 200 mg of canakinumab administered subcutaneously plus 200 mg of pembrolizumab intravenously every 3 weeks, along with a platinum-based chemotherapy. For the first cohort of non-squamous patients that means carboplatin and pemetrexed. The second cohort (non-squamous) will receive cisplatin and pemetrexed. The third (squamous or non-squamous) will receive carboplatin and paclitaxel.

The second part will involve roughly 600 patients and will evaluate the efficacy and safety of the combination. The patients will be randomized to receive either canakinumab or a placebo, in addition to pembrolizumab and a chemotherapy: for the non-squamous group, carboplatin or cisplatin and paclitaxel; for the squamous group, carboplatin and paclitaxel or nab-paclitaxel. 

The secondary objectives throughout are overall response rate, disease control rate, safety, pharmacokinetics,and duration of response.

“Inhibition of IL-1B-driven inflammation may lead to a tumor microenvironment more susceptible to anti-PD-(L)1 therapies,” the researchers wrote. “Recent studies have shown that low levels of C-reactive protein (CRP) at baseline or decreased levels over time correlated with improved responses to anti-PD-(L)1 agents, providing rationale for combination of canakinumab and pembrolizumab.”

CANOPY-2

CANOPY-2 will evaluate the safety and efficacy of canakinumab in combination with docetaxel for patients with squamous/non-squamous stage IIIB to IV NSCLC.

The first part of the study is open label to confirm the recommended phase III regimen by documenting the dose-limiting toxicities. The second part of the study, double-blind, and placebo controlled, intends to look at OS. 

The first part will enroll roughly 9 patients to ensure evaluation of at least 6 evaluable patients. The second part will randomize 225 patients to docetaxel and canakinumab.

“Currently, there is no data to guide treatment following progression on sequential/concomitant use of platinum-based chemotherapy and PD-1 inhibitors,” the researchers wrote. “Activation of inflammation and elevated baseline C-reactive protein (CRP levels are associated with lower response/resistance to immunotherapies).”

Enrollment for all three CANOPY studies is ongoing. The CANOPY program was also laid out in the Journal of Clinical Oncology in May. 

References:

1. Spigel D, E Garon, A Ardizzoni, et al. CANOPY-A: A phase 3 study of canakinumab as adjuvant therapy in patients with surgically resected NSCLC. Presented at: IASLC 2019 North America Conference on Lung Cancer; October 11, 2019; Chicago, Ill. Abstract PD01.04.
2. Johnson B, G Castro, Greystroke A, et al. CANOPY-1: Phase 3 study of canakinumab/placebo+pembrolizumab+platinum-chemotherapy in untreated stage IIIB-IV NSCLC patients. Presented at: IASLC 2019 North America Conference on Lung Cancer; October 11, 2019; Chicago, Ill. Abstract PD01.05
3. Papadimitrakopoulou, V, Goto Y, Lim D, et al. CANOPY-2: Phase 3 study of canakinumab plus docetaxel as second-third line therapy in locally advanced/metastatic NSCLC. Presented at: IASLC 2019 North America Conference on Lung Cancer; October 11, 2019; Chicago, Ill. Abstract PD01.06
4. Paz-Ares L, Garon E, Ardizzoni A, et al. The CANOPY program: Canakinumab in patients (pts) with non-smell-cell lung cancer (NSCLC). J Clin Oncol. 37(15). Published online May 26, 2019.