A Pilot Study of Weekly Brentuximab Vedotin in Patients with CD30+ Malignancies Resistant to Every 3 Week Brentuximab Vedotin

Abstract

Background:Brentuximab vedotin (BV) is effective in treating of relapsed/refractory CD30 positive malignancies, such as classical Hodgkin lymphoma (CHL) and systemic anaplastic large cell lymphoma (ALCL). BV combines an anti-CD30 monoclonal antibody with a potent anti-microtubule agent, Monomethyl auristatin E (MMAE), disrupting the cell cycle of CD30 positive cells. Patients (pts) with relapsed/refractory CHL and systemic ALCL have shown promising overall response rates (ORR) with BV, but most patients will eventually suffer progressive disease (PD). The mechanism of resistance to BV remains unclear, however, most lymphomas with PD following BV still demonstrate CD30 expression suggesting that it may remain a viable target. Prior clinical data indicate that weekly BV dosing given on Days 1, 8 and 15 of a 28 day cycle was tolerable, had an ORR of 59% and a higher complete remission rate than was seen in a similar phase I trial of 21-day dosing of BV. We, thus, hypothesized that patients with CD30-positive lymphomas who progressed on standard BV dosing may still respond to weekly BV dosing and tested this in a prospective phase II trial. We also quantified CD30 expression to evaluate the impact of BV on CD30 expression and the impact of CD30 on response to BV, and assessed T and NK cell infiltrates for correlation with response.Methods:Eligible pts were age >18 or older with relapsed or refractory CD30 positive lymphoma who had progressed during or achieved less than a partial response following a minimum of 2 cycles of BV. Key inclusion criteria included documented expression of CD30 on tumor cells following the last dose of prior BV, as well as adequate marrow, hepatic and renal function and no major infections. Key exclusion criteria were ECOG > 2, prior transplant within 100 days, radioimmunotherapy within 12 weeks, active CNS involvement, and pre-existing neuropathy > NCI-CTCAE Grade 2 (or > Grade 1 if secondary to prior BV). Each cycle consisted of BV at 1.2 mg/kg (capped at 120mg) given over 30 minutes on Days 1, 8 and 15 every 28 days. Patients with stable disease or better could remain on therapy for up to 4 cycles. CD30 expression was quantified using multiparameter flow cytometry to identify the Hodgkin-Reed-Sternberg (HRS) cells.Results:Eight (8) pts enrolled in the study. The median age was 42 (27-68). The pts were heavily pretreated (median 6 prior lines of treatment) and 63% had undergone autologous transplant (Table 1). Histologies included CHL (7) and ALK-negative systemic ALCL (1). Pts received between 2 to 16 (median 5) prior cycles of Q3 week BV prior to enrolling in the study. All patients suffered eventual progressive disease (PD) on Q3 week BV, though 3 had a transient prior partial response (PR). Weekly BV was well tolerated with only one grade 3 event (hypokalemia). Neuropathy was seen in 5 (63%) pts: 3 Grade 1, 2 Grade 2 resulting in one treatment discontinuation. Two pts completed all 4 BV cycles on study; both had progressive disease after the 4th cycle. Of the 6 pts who terminated the study early, the majority (67%) did so due to progressive disease. One pt had a partial response to BV after 3 cycles (with a 50% decrease in size of target nodes compared to baseline). Reduction in target lesions were seen in 5/7 (71%) response-evaluable patients (Figure 1). The overall response rate (ORR) of 13% triggered the protocol-defined early stopping rule. None of the screened patients were found to have lost CD30 expression following prior BV, however expression only ranged from dim to intermediate by IHC. CD30 surface density was quantified in paired pre and post BV samples from 3 patients and did not show a significant change or correlation with response. NK and T cell infiltrates were not correlated with response.Conclusions:Pts with BV-refractory CD30 positive malignancies can safely receive weekly BV at 1.2 mg/kg dosing given on Days 1, 8 and 15 of a 28-day cycle. Even though a majority demonstrated reduction in target lesions, the response rate was low. Alterations in CD30 density on HRS cells was not observed following BV when quantified by flow cytometry. Elucidation of tumor- and immune-related mechanisms of BV resistance is needed, as BV is poised for increased use earlier in the course of therapy for HL and ALCL. [Display omitted] DisclosuresSmith:Portola Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding; Janssen: Research Funding; Acerta: Research Funding; Genentech: Research Funding; Sharp: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Dohme Corp: Research Funding; Merck: Research Funding. Gopal:Seattle Genetics: Consultancy, Research Funding.