Citations

Key Points A total of 38% of patients who achieved CR (13 of 34) on brentuximab vedotin have remained in remission for >5 years and may be cured. Nine of the 13 patients (9% of all enrolled patients) have remained in long-term remission without a consolidative allogeneic transplant.

Abstract The addition of trastuzumab to chemotherapy extends survival among patients with HER2+ breast cancer. Prior work showed that trastuzumab and chemotherapy augments HER2 extracellular domain (ECD)-specific antibodies. The current study investigated whether combination therapy induced immune responses beyond HER2-ECD and, importantly, whether those immune responses were associated with survival. Pretreatment and posttreatment sera were obtained from 48 women with metastatic HER2+ breast cancer on NCCTG (now Alliance for Clinical Trials in Oncology) studies, N0337 and N983252. IgG to HER2 intracellular domain (ICD), HER2-ECD, p53, IGFBP2, CEA, and tetanus toxoid were examined. Sera from 25 age-matched controls and 26 surgically resected HER2+ patients were also examined. Prior to therapy, some patients with metastatic disease had elevated antibodies to IGFBP2, p53, HER2-ICD, HER2-ECD, and CEA, but not to tetanus toxin, relative to controls and surgically resected patients. Treatment augmented antibody responses to HER2-ICD in 69% of metastatic patients, which was highly associated with improved progression-free survival (PFS; HR = 0.5, P = 0.0042) and overall survival (OS; HR = 0.7, P = 0.038). Augmented antibody responses to HER2-ICD also correlated (P = 0.03) with increased antibody responses to CEA, IGFBP2, and p53, indicating that treatment induces epitope spreading. Paradoxically, patients who already had high preexisting immunity to HER2-ICD did not respond to therapy with increased antibodies to HER2-ICD and demonstrated poorer PFS (HR = 1.6, P < 0.0001) and OS (HR = 1.4, P = 0.0006). Overall, the findings further demonstrate the importance of the adaptive immune system in the efficacy of trastuzumab-containing regimens. Cancer Res; 76(13); 3702–10. ©2016 AACR.

Purpose To develop a genomic signature that predicts benefit from trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. Patients and Methods DASL technology was used to quantify mRNA in samples from 1,282 patients enrolled onto the Combination Chemotherapy With or Without Trastuzumab in Treating Women With Breast Cancer (North Central Cancer Treatment Group N9831 [NCCTG-N9831]) adjuvant trastuzumab trial. Cox proportional hazard ratios (HRs), adjusted for significant clinicopathologic risk factors, were used to determine the association of each gene with relapse-free survival (RFS) for 433 patients who received chemotherapy alone (arm A) and 849 patients who received chemotherapy plus trastuzumab (arms B and C). Network and pathway analyses were used to identify key biologic processes linked to RFS. The signature was built by using a voting scheme. Results Network and functional ontology analyses suggested that increased RFS was linked to a subset of immune function genes. A voting scheme model was used to define immune gene enrichment based on the expression of any nine or more of 14 immune function genes at or above the 0.40 quantile for the population. This model was used to identify immune gene–enriched tumors in arm A and arms B and C. Immune gene enrichment was linked to increased RFS in arms B and C (HR, 0.35; 95% CI, 0.22 to 0.55; P < .001), whereas arm B and C patients who did not exhibit immune gene enrichment did not benefit from trastuzumab (HR, 0.89; 95% CI, 0.62 to 1.28; P = .53). Enriched immune function gene expression as defined by our predictive signature was not associated with increased RFS in arm A (HR, 0.90; 95% CI, 0.60 to 1.37; P = .64). Conclusion Increased expression of a subset of immune function genes may provide a means of predicting benefit from adjuvant trastuzumab.

Key PointsA total of 47% of patients who achieved CR on brentuximab vedotin remain progression-free after being followed a median of 53 months. Younger age, less functional impairment, and lower disease burden at baseline were associated with CR and prognostic for longer survival.

Purpose Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. Patients and Methods In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. Results The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Conclusion The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Objective. Anaphylaxis after immunization, although rare, is serious and potentially life-threatening. Understanding risk factors for this reaction is therefore important. Gelatin is added to many vaccines as a heat stabilizer. Japanese researchers have demonstrated a strong association between immediate hypersensitivity reactions to measles, mumps, rubella, varicella, and Japanese encephalitis immunizations and subsequent detection of anti-gelatin immunoglobulin E (IgE) antibodies. They suggested that previous receipt by these patients of diphtheria-tetanus-acellular pertussis vaccines with trace amounts of gelatin was responsible for the sensitization. We aimed to assess whether a similar association exists for vaccinees in the United States who reported anaphylaxis after receipt of measles-mumps-rubella (MMR) or measles vaccines and to review recent trends in reporting of hypersensitivity reactions. Methods. We conducted a retrospective case-control study. Cases of anaphylaxis that met a predefined case definition were identified from the US Vaccine Adverse Event Reporting System (VAERS). Mayo Clinic patients who received MMR vaccine uneventfully served as controls. The study subjects were interviewed to obtain the history of allergies. Sera from study subjects and their matched controls were tested for IgE antibodies to gelatin, whole egg, and vaccine viral antigens using solid-phase radioimmunoassay. Data from the Biologics Surveillance System on annual numbers of doses of MMR and varicella vaccines distributed in the United States were used to evaluate possible changes in reporting of selected allergic adverse events. Results. Fifty-seven study subjects were recruited into the study and interviewed. Of these, 22 provided serum samples for IgE testing. Twenty-seven subjects served as a comparison group and provided a sample for IgE testing; 21 of these completed an allergy history questionnaire. Self-reported history of food allergies was present more frequently in the interviewed study subjects than in the controls, whereas the proportions of people with other characteristics were similar in both groups. None of the interviewed people had a history of food allergy to gelatin. The level of anti-gelatin IgE antibodies was significantly higher among study subjects than among controls, whereas the levels of IgE antibodies against egg and all 3 viral antigens did not differ significantly. Of 22 study subjects, 6 (27%) tested positive for anti-gelatin IgE, whereas none of the 27 controls did. The rate of anaphylactic reactions reported to VAERS after measles virus-containing immunization in the United States between 1991 and 1997 is 1.8 per 1 million doses distributed. No substantial increase in the number of reported allergic events after frequently used gelatin containing MMR and varicella vaccines could be observed during the first 4 years (1997–2000) since the introduction of diphtheria-tetanus-acellular pertussis vaccines for use in infancy. Conclusion. Anaphylactic reactions to MMR in the United States are rare. The reporting rate has the same order of magnitude as estimates from other countries. Almost one fourth of patients with reported anaphylaxis after MMR seem to have hypersensitivity to gelatin in the vaccine. They may be at higher risk of developing anaphylaxis to subsequent doses of other gelatin-containing vaccines. These people should seek an allergy evaluation before such immunization.