This article is more than 5 years old. Information may no longer be current.
Copanlisib confers rapid, durable responses for advanced lymphoma
Click Here to Manage Email Alerts
Copanlisib, a phosphatidylinositol 3-kinase inhibitor, induced objective responses among pretreated patients with relapsed or refractory indolent lymphoma, according to a phase 2 study published in Journal of Clinical Oncology.
“The biggest takeaway from these findings was the positive results that demonstrated copanlisib’s [Aliqopa, Bayer] favorable efficacy and safety profile and the clear safety advantage of intermittent dosing with IV administration,” Martin Dreyling, MD, PhD, professor of medicine at Ludwig Maximilians University of Munich in Germany, told HemOnc Today.
In 2016, approximately 72,000 new cases and 20,000 deaths were attributed to lymphoproliferative malignancies in the United States. Since 2006, first-line therapy for indolent B-cell lymphoma has consisted of rituximab (Rituxan; Genentech, Biogen) either alone or in combination with chemotherapy, such as the alkylating agent bendamustine.
However, despite initial response to first-line therapy, indolent lymphomas are rarely cured and often lead to the development of refractory disease, which has limited treatment options.
Targeted inhibition of phosphatidylinositol 3-kinase (PI3K) has been evaluated as a therapeutic strategy for patients with relapsed or refractory indolent B-cell lymphoma. Approved by the FDA in May, copanlisib targets both the PI3K alpha and PI3K delta isoforms.
“PI3K inhibition is an established principle treatment of indolent B-cell lymphoma in double refractory lymphoma, according to current international guidelines on both sides of the Atlantic,” Dreyling said, referring to National Comprehensive Cancer Network and European Society for Medical Oncology guidelines. “When we initiated the study, a key goal was to further examine the role of PI3K inhibitors — how these compounds work — and also to focus on their immunogenically driven side effects, especially colitis and pneumonitis. This study was the starting point to explore copanlisib, targeting both alpha and delta isoforms of PI3K, and to understand its specific benefits.”
In the CHRONOS-1 study, Dreyling and colleagues assigned 142 patients (median age, 63 years; 50% women) with relapsed or refractory indolent lymphoma following two or more lines of therapy to 60 mg of IV copanlisib on days 1, 8 and 15 of a 28-day cycle.
ORR served as the primary endpoint. Researchers also evaluated safety and gene expression.
Fifty-nine percent of patients achieved an objective response. Responses appeared rapid and durable, with a median time to response of 53 days and a median duration of response of 22.6 months.
Researchers observed objective responses among 59% of patients with follicular lymphoma (14% complete response) and 70% of patients with marginal zone lymphoma (9% complete response).
Median PFS was 11.2 months, with 46 patients still receiving treatment at the time of the database closure.
The most frequent treatment-emergent adverse events included transient hyperglycemia — which occurred in 49% of all patients (41% grade 3 or 4) — and transient hypertension, which occurred in 30% of all patients (24% grade 3). Other grade 3 or worse adverse events included decreased neutrophil count (24%) and lung infection (15%). One patient (0.7%) developed colitis and two patients (1.4%) had pneumonitis.
“We observed typical side effects of alpha isoforms, including hyperglycemia and hypertension, but these were not a significant cause for treatment discontinuation,” Dreyling said. “Overall, we determined that combined PI3K inhibitors like copanlisib are a very effective and well-tolerated type of treatment for indolent lymphomas. Based on these encouraging results, we are interested in exploring copanlisib in earlier lines of treatment.”
The most significant limitation of the study was its sole focus on indolent lymphomas, specifically follicular lymphomas at the end of their cycles, Dreyling said, adding there are ongoing phase 2 trials analyzing copanlisib in combination with other treatments.
“I am excited to see the results of these combined approaches and the investment in such a combination in the first-line setting,” Dreyling said. – by Chuck Gormley
For more information:
Martin Dreyling, MD, PhD, can be reached at martin.dreyling@med.uni-muenchen.de.
Disclosures: Bayer funded this study. Dreyling reports honoraria from and consultant roles with Bayer and Gilead Sciences. Please see the full study for a list of all other authors’ relevant financial disclosures.
Perspective
Back to Top
Nilanjan Ghosh
Follicular lymphoma is considered to have a good prognosis with median survival of 18 years. However, about 20% of patients will progress within 2 years of standard chemoimmunotherapy. This high-risk group has a median survival of 5 years and, therefore, a big unmet need.
In September, the FDA granted accelerated approval — based on the results of the CHRONOS-1 study — to copanlisib, a PI3K delta and alpha inhibitor, for the treatment of adults with relapsed follicular lymphoma who have received at least two prior systemic therapies.
In 2014, idelalisib (Zydelig, Gilead) — a PI3K delta inhibitor — represented the first-in-class tyrosine kinase inhibitor to receive accelerated approval by the FDA for patients with relapsed follicular lymphoma who have received at least two prior therapies. FDA based this approval on the drug’s efficacy among double refractory patients, or those refractory to rituximab and an alkylating agent. The ORR in the follicular lymphoma group was 54% and PFS was 11 months. In an update looking at the high-risk group of patients with follicular lymphoma who had progressed within 2 years after initial chemoimmunotherapy, idelalisib conferred an ORR of 57% and PFS of 11 months.
Although the efficacy appears to be similar, there are some important differences between these two studies. Both studies included patients who had previously received rituximab and alkylators. However, unlike the idelalisib study, the CHRONOS-1 study was not restricted to patients refractory to rituximab and alkylators.
The safety profile for copanlisib appears to be different from idelalisib. Hypertension and hyperglycemia appear to be unique to copanlisib, likely due to PI3K alpha inhibition. Although both drugs are PI3K delta inhibitors, hepatic transaminitis and inflammatory colitis did not occur with copanlisib and are known complications of idelalisib. These differences may be due to intermittent — once weekly — administration of copanlisib as compared with continuous oral administration of idelalisib. Efficacy data for copanlisib in high-risk follicular lymphoma — progressed within 2 years of standard chemoimmunotherapy — is lacking.
The treatment options for patients with follicular lymphoma are expanding. PI3K delta and gamma inhibitor duvelisib (Verastem) has been reported to have efficacy in relapsed/refractory follicular lymphoma, including patients with double refractory disease. The orally administered PI3K delta inhibitor TGR-1202 (TG Therapeutics) has good clinical activity in indolent lymphomas — including follicular lymphoma — and is well tolerated with low incidence of hepatotoxicity and colitis. Hypertension and hyperglycemia are not seen with this compound due to absence of PI3K alpha inhibition.
Lenalidomide (Revlimid, Celgene) also has significant activity in relapsed/refractory follicular lymphoma. Andorsky and colleagues reported results from the MAGNIFY trial in relapsed/refractory follicular lymphoma at this year’s ASCO Annual Meeting and showed high response rates and durable responses with lenalidomide and rituximab. Leonard and colleagues had previously reported the superiority of lenalidomide and rituximab over rituximab alone in relapsed/refractory follicular lymphoma.
The increasing number of choices are welcome for patients with relapsed/refractory follicular lymphoma but pose a challenge to providers treating patients with this disease. How do you pick the best treatment for your patient? In the absence of randomized data between these agents, we often choose an agent based on patient comorbidities, prior treatment history and the toxicity profile of the drugs. Randomized trials should be conducted to compare the efficacy and toxicity of these drugs. SWOG is conducting a randomized trial to compare three options in high-risk relapsed/refractory follicular lymphoma in combination with obinutuzumab (Gazyva, Genentech) — salvage chemotherapy, lenalidomide and TGR-1202.
References:
Andorsky DJ, et al. Abstract 7502. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Leonard JP, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.59.9258.
Click Here to Manage Email Alerts