Canakinumab Plus Pembrolizumab and Chemotherapy Appears Safe in Advanced NSCLC

Dose-limiting toxicities (DLTs) were minimal with the combination of canakinumab plus pembrolizumab (Keytruda), and platinum-based doublet chemotherapy in patients with advanced or metastatic non–small cell lung cancer who were treated in the phase II CANOPY-1 study (NCT03631199), demonstrating that the combination could be well-tolerated in these patients.¹

Results from the safety run-in portion of the study were presented at the 2020 American Association for Cancer Research (AACR) Virtual Annual Meeting. The purpose for part 1 of the CANOPY-1 study was to determine a safe dose of canakinumab for the second portion of the study.

Overall, 30 patients with previously untreated stage IIIB or IIIC or stage IV NSCLC were enrolled to the safety run-in portion of CANOPY-1. For induction therapy, patients in cohort A (n = 10) received canakinumab in combination with pembrolizumab, carboplatin and pemetrexed; cohort B (n = 11) received canakinumab plus pembrolizumab, cisplatin, and pemetrexed; and cohort C (n = 9) received canakinumab plus pembrolizumab, carboplatin, and paclitaxel. All cohorts received maintenance treatment of canakinumab, pembrolizumab, and pemetrexed.

The median age of patients was 63 years (range, 28-77), and the majority of patients were men (73.3%). Patients had an ECOG performance status of 0 (30.0%) or 1 (70.0%) and were either white (60.0%) or Asian (40.0%). Most patients were former smokers (63.3%) while some were never smokers (23.3%) and current smokers (13.3%).

Treatment was discontinued in 6 of the 30 patients (20.0%) and remained ongoing in the remaining 24 patients (80.0%). The reason for treatment discontinuation was progressive disease in 5 patients and death in 1 patient.

No serious adverse events (AEs) were fatal or considered related to canakinumab. AEs led to discontinuation of 1 of the study drugs in 3 patients (10%), all of which were included in cohort C. Hepatitis led to discontinuation of pembrolizumab, and both polyneuropathy and peripheral neuropathy led to discontinuation of chemotherapy.

A dose-limiting toxicity was observed in 1 patient within the first 42 days of therapy, which was grade 3 hepatitis and was deemed related to pembrolizumab in cohort C. The most common grade 3 AEs included pulmonary embolism in 3 patients (2 from cohort A and 1 from cohort C; 10%) and decreased neutrophil count in 2 patients (1 from each cohort; 10%).

Only 1 patient experienced a grade 4 AE, which was cardiac tamponade in cohort B, and 1 patient in cohort B died due to NSCLC.

Based on these findings, the 200-mg dose of canakinumab administered subcutaneously every 3 weeks in combination with the standard dose of pembrolizumab and a platinum-based chemotherapy doublet will be used in the next phase of the CANOPY-1 study, which will be a randomized double-blind, placebo-controlled phase III part to evaluate the safety and efficacy of the triplet regimen. Enrollment for this portion of the study was completed in January 2020 with 643 patients enrolled.

The primary end point of the study was DLTs in the first 42 days of treatment in order to determine the recommended phase III doses of canakinumab in combination with pembrolizumab and a platinum-based doublet chemotherapy. Secondary end points included objective response rate, duration of response, disease control rate, safety, and PK and immunogenicity.

A phase III clinical trial, CANOPY-A (NCT03447769), is underway to evaluate the efficacy and safety adjuvant canakinumab (ACZ885) in patients with non–small cell lung cancer (NSCLC) after complete surgical resection versus placebo, according to a presentation at the 2020 American Association for Cancer Research (AACR) Annual Meeting.²

The trial is designed to assess 1500 adult patients with completely resected NSCLC. The rationale for evaluating canakinumab, a monoclonal antibody against pro-inflammatory cytokine IL-1ß in this patient population is based on previous findings from the phase III CANTOS study, which evaluated the role of this agent in preventing cardiovascular events among patients with myocardial infarction who had an elevated C-reactive protein (CRP) level.

“The clinical development of canakinumab as an antineoplastic agent is somewhat atypical as a particularly compelling piece of evidence supporting the potential clinical efficacy of canakinumab in NSCLC comes from a clinical study of an unrelated disease,” said Edward B. Garon, MD, MS, director, Thoracic Oncology Program, David Geffen School of Medicine, University of California, Los Angeles, during his presentation at the 2020 AACR Annual Meeting.

Results from the CANTOS study, which were published in the New England Journal of Medicine in 2017, prompted interest in the agent’s potential as therapy in lung cancer. The trial demonstrated a highly significant reduction in lung cancer incidence, as well as mortality, in the group of patients that received canakinumab compared with placebo.³

“As part of that cardiovascular study, which evaluated over 10,000 patients, the incidence and mortality from lung cancer was reduced among patients receiving canakinumab,” Garon said.² “Intriguingly, this effect was dose-dependent with the greatest reduction occurring among patients treated at the highest dose level evaluated.”

IL-1ß is an inflammatory cytokine released by various cell types to promote tumor growth, progression, and metastasis. It upregulates tumor-association inflammation, which is known to suppress antitumor immune responses. Canakinumab targets tumor-promoting inflammation to reduce immunosuppression by binding to human IL-1ß and neutralizing the activity by blocking its interaction with IL-1 receptors.²

The multicenter randomized double-blind, placebo-controlled CANOPY-A study is enrolling patients with stage IIA-IIIA and IIIB NSCLC and an ECOG performance status of 0 or 1. Patients can have any histology and must have recovered from all toxicities related to prior systemic therapy to grade ≤ 1, although patients with any grade alopecia and grade 2 or less neuropathy are allowed to enter the study as well.

If patients have unresectable or metastatic disease, they are ineligible to participate. They will also be unable to enter the study if they received neoadjuvant chemotherapy or neoadjuvant radiotherapy. If there is a presence or a history of a malignant disease besides the resected NSCLC that has been diagnosed or required therapy within the past 3 years, they could not enter the study. Patients with a history of current diagnosis of cardiac disease or uncontrolled diabetes are also ineligible.

Patients enrolled to the CANOPY-A study will undergo appropriate adjuvant therapy, which is primarily inclusive of cisplatin-based chemotherapy and in some cases radiotherapy if indicated by local guidelines or practices. Patients are randomized 1:1 to receive 18 cycles of either Canakinumab at 200 mg or placebo subcutaneously every 3 weeks.

The primary end point of the trial is disease-free survival. Secondary end points include overall survival, lung cancer-specific survival, adverse events, and EKG and laboratory abnormalities. Additional secondary end points also include PK evaluation, anticanakinumab antibodies, and health-related quality of life.

A biomarker substudy will also be conducted under CANOPY-A to determine the impact of surgical resection on biomarkers, such as CRP and cytokines. Eligibility criteria for this substudy mirror the criteria for the randomized study post-resection. Patients will undergo blood sample collection both pre- and post-surgery.

Canakinumab has already been approved by the FDA for the treatment of a spectrum of autoinflammatory conditions, such as rheumatologic disorders.³

_References

1. _{Johnson BE, Kim TM, Hiltermann JN, et al. CANOPY-1: Safety run-in results from phase (ph) 3 study of canakinumab (CAN) or placebo (PBO) in combination (comb) with pembrolizumab (PEM) plus platinum-based doublet chemotherapy (Ctx) as 1st line therapy in patients (pts) with advanced or metastatic NSCLC. Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I: Virtual; April 27-28, 2020. Abstract CT214. https://bit.ly/3bbUHGj.}
2. _{Garon EB, Ardizzoni A, Barlesi F, et al. CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non–small cell lung cancer (NSCLC). Presented at: 2020 American Association for Cancer Research Virtual Annual Meeting I: Virtual; April 27-28,2020. Abstract CT287. https://bit.ly/35FlkCk.}
3. _{PM, Everett BM, Thuren T, et al; CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377(12):1119-1131. doi: 10.1056/NEJMoa1707914.}