Anti-CD22 Immunoconjugate Inotuzumab Ozogamicin (CMC-544) + Rituximab: Clinical Activity Including Survival in Patients with Recurrent/Refractory Follicular or ‘Aggressive' Lymphoma.

CMC-544 is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose (MTD) for single agent CMC-544 was previously determined to be 1.8 mg/m²administered IV every 28 days, and clinical activity was shown in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Preliminary safety and efficacy data without long-term follow-up on patients with FL and non-refractory DLBCL treated with CMC-544 given in combination with rituximab was previously reported.

To assess clinical activity of CMC-544 in combination with rituximab in refractory ‘aggressive' NHL and to present long-term follow-up, including progression free survival (PFS) and overall survival (OS) of pts with relapsed FL and DLBCL.

Patients were eligible if they had CD20+/CD22+ B cell NHL, which had not responded to or progressed after 1 or 2 therapies of probable clinical benefit, including at least 1 regimen containing rituximab. In patients with FL and DLBCL, subjects could have had no more than 2 prior therapies and could not be refractory to rituximab or a rituximab-containing therapy. Patients in the latter part of the study could have DLBCL, mantle cell lymphoma, transformed FL with no limit on number of prior therapies and must have had no response to, or relapse within 6 months of, the first dose of the previous rituximab-containing therapy (refractory ‘aggressive' lymphoma). After a limited dose-escalation to determine the MTD of CMC-544 in combination with rituximab, an expanded cohort at the MTD was conducted. Patients received 375 mg/m² of rituximab IV on day 1 followed by CMC-544 on day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression.

The MTD of CMC-544 given with rituximab was confirmed as the single agent dose of 1.8 mg/m². Enrollment is complete at 119 patients, with 110 treated with CMC-544 at the MTD of 1.8 mg/m². Based on 112 patients, median age was 66 y (range: 20-85), 60% were male; 36% had 1 prior chemo/immunotherapy regimen, 46% had 2, and 13% had ≥3; 71% had stage III/IV disease, 38% elevated LDH, and 17% bulky disease (>7.5 cm). Patients with recurrent DLBCL were generally older, with a median age of 72 y and were thus deemed inappropriate for high-dose therapy. The most common treatment-emergent adverse events (AEs), all grades, were nausea (48%), thrombocytopenia (46%), fatigue (44%), and increased aspartate aminotransferase (AST) (34%). AEs resulting in discontinuation from treatment were most commonly hematologic AEs or elevation of ≥1 liver function test. Median follow-up is approximately 14.5 months, 10.3 months, and 2.5 months for patients with FL, recurrent DLBCL, and refractory ‘aggressive' lymphoma, respectively. The 1-year OS rate was 97% for FL and 77% for patients with recurrent DLBCL. Patients with FL (n=38) had an objective response rate (ORR) of 87%, with a median PFS of 23.6 months. Patients with relapsed DLBCL (n=40) had an ORR of 80%, with a median PFS of 15.1 months while in the rituximab-refractory pt arm (n=25) the response rate was much lower at 20%, with a median PFS of only 2 months. One year PFS was 84% for FL and 53% for recurrent DLBCL. The lower response rates and PFS in the refractory subgroup are consistent with the poor prognosis of patients with refractory 'aggressive' lymphoma. PFS in DLBCL (either de novo or from transformed follicular) with 1-2 prior therapies based on time-to-tumor progression was also analyzed. DLBCL patients with a prior time to tumor progression of less than 1 year (n=19) had an ORR of 47% (21% CR/CRu), with a median PFS of 4.3 months while DLBCL patients with a prior time to tumor progression of greater than 1 year (n=28) had an ORR of 79% (50% CR/CRu) and a median PFS of 15.1 months.

The combination of inotuzumab ozogamicin (CMC-544) plus rituximab has a safety profile similar to that previously reported for CMC-544 alone, with hematologic, gastrointestinal, and hepatic AEs being the main toxicities. The response rates and PFS results indicate promising efficacy in patients with recurrent/refractory FL and DLBCL, These results, particularly in patients with follicular lymphoma and recurrent DLBCL, support continued clinical development of this regimen.

Dang:Wyeth Research: Consultancy; Genentech: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Speakers Bureau. Smith:Millennium: Research Funding; Genentech: Research Funding; Wyeth Research: Consultancy, Research Funding. Johnson:Wyeth Research: Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Coiffier:Wyeth Research: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Wyeth Research: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Foran:Wyeth Research: Research Funding. Hua:Wyeth Research: Employment. Vandendries:Wyeth Research: Employment, Equity Ownership. Fayad:Wyeth Research: Consultancy, Research Funding.