Brentuximab Vedotin Monotherapy in DLBCL Patients with Undetectable CD30: Preliminary Results from a Phase 2 Study

Background

Patients (pts) with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) have a poor outcome. In pts who progress <1 year after frontline treatment with rituximab-containing combination chemotherapy, response rates to salvage therapy and autologous stem cell transplant (SCT) are 46–51% with a 3-year event-free survival of ~20% (Gisselbrecht 2010). For pts ineligible for transplant, no standard of care exists and median overall survival for pts not responding to second-line therapy is only 4 months (Elstrom 2010). Novel therapeutic options are needed for these pts.

A phase 2, open-label study was initiated to assess antitumor activity of brentuximab vedotin (ADCETRIS®), an anti-CD30 antibody-drug conjugate, in relapsed/refractory CD30+ non-Hodgkin lymphoma, including DLBCL. Significant antitumor activity was observed in DLBCL over a wide range of CD30 expression, including very low levels (<1–10%) as assessed by pathology at participating sites. As previously reported, 41% of DLBCL pts achieved an objective response (16% CR), regardless of CD30 expression (Bartlett, ASH 2013, Abstract 848). Subsequently, the trial was amended to investigate the antitumor activity of brentuximab vedotin in ~50 DLBCL pts with undetectable CD30 expression using standard immunohistochemistry (IHC) (NCT01421667). Preliminary results for this planned subset analysis of those pts are now available.

Methods

Eligible pts must have DLBCL with undetectable CD30 expression on tumor cells by visual assessment using routine IHC (anti-CD30 BerH2 antibody) per local lab. Pts must also have had 1–3 prior therapies and an ECOG performance status ≤2. Brentuximab vedotin 1.8 mg/kg is administered every 3 weeks until disease progression or unacceptable toxicity for pts who achieve stable disease or better. The primary endpoint is objective response rate per Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Key secondary endpoints include safety and duration of response.

Results

Thus far, 27 DLBCL pts with undetectable CD30 expression per local lab have been enrolled and treated. All patients had elevated soluble CD30 at baseline with a median of 166 ng/mL and range of 55–1,696 ng/mL (normal, ≤29 ng/mL). Most pts had advanced stage disease at baseline (78%); median age was 65 years (range, 42–91); and 81% had an ECOG performance status of 1–2. The median number of prior therapies was 2, and 8 pts had 3 prior therapies. Six (22%) pts had received prior autologous SCT. Of 14 pts (52%) with refractory disease at study entry, 11 were also refractory to their frontline treatment. To date, pts have received a median of 2 cycles of brentuximab vedotin (range, 1–10), and 12 (44%) pts remain on treatment. Thirteen pts discontinued treatment due to progressive disease, 1 withdrew consent, and 1 pt died due to an unrelated serious adverse event (SAE) of cardiac arrest.

At the time of this analysis, 6 (27%) of 22 pts who have had restaging assessments achieved an objective response, including 1 CR and 5 PRs. The CR began at Cycle 6 and is ongoing after 9 weeks. It is too early to assess median response duration. For the 6 pts who achieved an objective response, undetectable CD30 was confirmed by central review.

Peripheral sensory neuropathy and nausea were the most frequently occurring adverse events (AEs; 22% each). AEs ≥ Grade 3 occurring in more than 1 pt included hypokalemia, neutropenia (11% each), dehydration, diarrhea, nausea, and vomiting (7% each). All were Grade 3 in severity with the exception of 1 Grade 4 neutropenia. Four deaths occurred within 30 days of last dose; all were disease related except one due to cardiac arrest unrelated to study drug in a pt with prior cardiovascular disease and co-existing risk factors.

Conclusions

In this interim analysis of DLBCL pts with undetectable CD30, objective responses have been observed in 6 of 22 pts (27%) who have undergone restaging assessments. Safety data are consistent with historic results and pts continue to enroll on study. Activity of brentuximab vedotin in pts with undetectable CD30 by IHC may be explained wholly or in part by one of several factors, including tumor heterogeneity, levels of CD30 on tumor below the level of IHC sensitivity, uptake by cells in the tumor microenvironment that can release the cytotoxic payload, or deletion of repressive cells within the tumor microenvironment. Correlative work to better understand this activity is ongoing.