Patients with relapsed/refractory follicular lymphoma often have limited options beyond the available standard therapies once their disease progresses.
Recognizing the treatment challenges faced by this patient population, the phase II CHRONOS-1 trial (NCT01660451) was initiated to evaluate treatment with copanlisib, an intravenously administered pan-class I phosphatidylinositol 3-kinase (PI3K) inhibitor, for indolent B-cell lymphomas. The data demonstrated that copanlisib has a durable tumor response and manageable safety profile (J Clin Oncol 2017; doi:10.1200/JCO.2017.35.15_suppl.7535).
“Based on NCCN guidelines, inhibition of the PI3K pathway has been shown to be a promising therapeutic pathway in treating indolent lymphomas, like follicular lymphoma,” said study author Martin Dreyling, MD, Professor of Medicine at the University of Munich Hospital in Grosshadern, Germany.
The study included 104 follicular lymphoma patients (grade 1-3a) who had relapsed or were refractory to two or more prior lines of therapy and had been previously treated with rituximab and an alkylating agent.
Copanlisib (60 mg IV infusion) was intermittently administered on days 1, 8, and 15 of a 28-day cycle. Objective response rate (ORR) per independent radiologic review was the primary endpoint of the study.
Among the enrolled follicular lymphoma patients, 62 percent were refractory. Participants had received a median of three prior lines of therapy (range 2-8). Additionally, the median time from progression was 8 weeks (range 1-73 weeks), according to researchers.
Of the patients included in the study, 52 percent were male, 83 percent were white, the median age was 62 years, and 62 percent had an ECOG score of 0. The ORR was 58.7 percent at the time of initial analysis; among those patients, 15 (14.4%) had a complete response and 46 (44.2%) had a partial response, investigators reported.
Additionally, 35 (33.7%) patients had stable disease while progression of disease as best response was observed in two patients. Data showed a median duration of response of 370 days (range 0-687), with 43 responders censored at cutoff, according to study authors. The median duration of treatment was 22 weeks and 33 (32%) patients remained on treatment.
In terms of safety, the most common any-grade treatment-related adverse events (AEs) occurring in more than 25 percent of patients, included diarrhea (34%), reduced neutrophil count (30%), fatigue (30%), and fever (25%) as well as hyperglycemia (50%) and hypertension (30%), both of which were transient.
Rates of AEs, grade 3 or higher, included diarrhea (5%), reduced neutrophil count (24%), fatigue (2%), fever (4%), hyperglycemia (41%), and hypertension (24%).
Additionally, researchers reported a low incidence of the following AEs (all grade/grade 3+): pneumonitis (8%/1.4%), hepatic enzymopathy (AST 28%/1.4%; ALT 23%/1.4%), opportunistic infection (1.4%), and colitis (0.7%). Six deaths occurred, three of which were deemed related to copanlisib and attributed to lung infection, respiratory failure, and a thromboembolic event.
“Copanlisib was highly active as a single agent in heavily pretreated relapsed/refractory follicular lymphoma patients and resulted in durable responses in the majority of patients,” researchers concluded. “Toxicities were manageable, with a low incidence of severe AEs associated with other PI3K inhibitors, especially hepatic enzymopathy, opportunistic infections, and colitis.”
“Our research shows that copanlisib is better tolerated than other PI3K inhibitors,” noted Dreyling. “And, in my opinion, there are two reasons for that. One, this compound does not have GI absorption, so colitis, which can be very life-threatening is not observed.
“Secondly, the intermittent dosing schedule, which was based on IV formulation, was better tolerated,” he continued. “While some patients experienced hypertension and hyperglycemia, it was temporary, only occurring shortly after treatment, so this was not considered a major problem.”
Dreyling acknowledged there are potential limitations to the IV application. “When it comes to real-life scenarios, this IV application can be a disadvantage for the patient compared to any oral formulation; however, the intermittent dosing was proven to be beneficial,” he explained. “Therefore, if we are considering a combination with another agent, such as rituximab or an IV chemotherapy, this does not have a serious impact. However, when it comes to maintenance approaches, one has to restructure the schedule and think about some intelligent maintenance strategies, which is already being testing in current trials.”
Based on the findings of CHRONOS-1, specifically the overall response rate, the FDA recently granted copanlisib Accelerated Approval for the treatment of adults with relapsed follicular lymphoma who have received at least two prior therapies.
“For patients with relapsed follicular lymphoma, the cancer often comes back even after multiple treatments,” Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research, said in a statement. “Options are limited for these patients and [FDA] approval provides an additional choice for treatment, filling an unmet need for them.”
Previously, the FDA granted Priority Review designation to copanlisib for this patient population in May 2017. Additionally, copanlisib was granted Orphan Drug Designation by the FDA Office of Orphan Products Development in February 2015 for the treatment of follicular lymphoma and in February 2017 for the treatment of splenic, nodal, and extranodal subtypes of marginal zone lymphoma.
Given the high efficacy and the favorable toxicity profile, copanlisib offers a clear advantage over comparable therapies, noted Dreyling. “This treatment is a viable option for patients with follicular lymphoma who have relapsed or were refractory to prior lines of therapy.”
“When treating patients with relapsed follicular lymphoma, two factors for physicians involve lessening tumor burden and reducing adverse events patients may experience from treatments. Therapies need to be both effective and tolerable,” commented Anas Younes, MD, Medical Oncologist and Chief of Lymphoma Service at Memorial Sloan Kettering Cancer Center, New York, N.Y. “The PI3K pathway is activated in many tumor types, including lymphoma, and targeting PI3K therapeutically is a very important strategy in this area of disease. Copanlisib has a safety and efficacy profile that is a welcome advance for both doctors and patients in third-line follicular lymphoma.”
The CHRONOS-1 study has also laid the groundwork for continued research. Investigators are building on these positive results to further understand the potential of this therapy among follicular lymphoma patients.
“This study was performed exclusively among patients who previously received standard treatment,” said Dreyling. “Currently, there are two phase III studies underway that will test this compound in combination with rituximab and R-CHOP or rituximab plus bendamustine. When they achieve confirmation of the significant improvement in outcome, they will pave the way for the earlier application of copanlisib.”
One such trial, the phase III CHRONOS-3 study (NCT02367040), is conducting an analysis of copanlisib in combination with rituximab for patients with B-cell non-Hodgkin lymphoma. Researchers intend to enroll approximately 567 patients randomized to rituximab plus placebo or copanlisib. Progression-free survival is the primary endpoint; the safety and tolerability of copanlisib will also be investigated.
CHRONOS-4, another phase III study, is analyzing copanlisib in combination with standard immunochemotherapy in relapsed indolent non-Hodgkin lymphoma, including follicular lymphoma (NCT02626455). This trial will evaluate the progression-free survival of this combination therapy. Additionally, researchers will assess the occurrence of dose-limiting toxicities and adverse events to determine a recommended dose of copanlisib in combination with immunochemotherapy.
Secondary endpoints will include objective tumor response rate, duration of tumor response, complete tumor response rate, time to tumor progression, overall survival, quality of life, safety, and tolerability.
Additionally, Dreyling noted, the German Lymphoma Alliance is currently discussing a phase II study of copanlisib in first-line treatment.
“Copanlisib has proven to be powerful treatment option for relapsed/refractory disease,” he concluded. “And, looking forward, current and future clinical trials will continue to uncover the impact this treatment can have on the various settings of follicular lymphoma.”
Catlin Nalley is associate editor.