Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.

AZD1775 is a first-in-class, potent, and selective inhibitor of WEE1 with proof of chemopotentiation in p53-deficient tumors in preclinical models. In a phase I study, the maximum tolerated dose of AZD1775 in combination with carboplatin demonstrated target engagement. We conducted a proofof-principle phase II study in patients with p53 tumor suppressor gene (TP53)-mutated ovarian cancer refractory or resistant (, 3 months) to first-line platinum-based therapy to determine overall response rate, progression-free and overall survival, pharmacokinetics, and modulation of phosphorylated cyclin-dependent kinase (CDK1) in skin biopsies. Patients and MethodsPatients were treated with carboplatin (area under the curve, 5 mg/mL$min) combined with AZD1775 225 mg orally twice daily over 2.5 days every 21-day cycle until disease progression.Results AZD1775 plus carboplatin demonstrated manageable toxicity; fatigue (87%), nausea (78%), thrombocytopenia (70%), diarrhea (70%), and vomiting (48%) were the most common adverse events. The most frequent grade 3 or 4 adverse events were thrombocytopenia (48%) and neutropenia (37%). Of 24 patients enrolled, 21 patients were evaluable for efficacy end points. The overall response rate was 43% (95% CI, 22% to 66%), including one patient (5%) with a prolonged complete response. Median progression-free and overall survival times were 5.3 months (95% CI, 2.3 to 9.0 months) and 12.6 months (95% CI, 4.9 to 19.7), respectively, with two patients with ongoing response for more than 31 and 42 months at data cutoff. ConclusionTo our knowledge, this is the first report providing clinical proof that AZD1775 enhances carboplatin efficacy in TP53-mutated tumors. The encouraging antitumor activity observed in patients with TP53-mutated ovarian cancer who were refractory or resistant (, 3 months) to first-line therapy warrants further development.

Purpose AZD1775 is a WEE1 kinase inhibitor targeting G2 checkpoint control, preferentially sensitizing TP53-deficient tumor cells to DNA damage. This phase I study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZD1775 as monotherapy or in combination with chemotherapy in patients with refractory solid tumors. Patients and Methods In part 1, patients received a single dose of AZD1775 followed by 14 days of observation. In part 2, patients received AZD1775 as a single dose (part 2A) or as five twice per day doses or two once per day doses (part 2B) in combination with one of the following chemotherapy agents: gemcitabine (1,000 mg/m), cisplatin (75 mg/m), or carboplatin (area under the curve, 5 mg/mL⋅min). Skin biopsies were collected for pharmacodynamic assessments. TP53 status was determined retrospectively in archival tumor tissue. Results Two hundred two patients were enrolled onto the study, including nine patients in part 1, 43 in part 2A (including eight rollover patients from part 1), and 158 in part 2B. AZD1775 monotherapy given as single dose was well tolerated, and the maximum-tolerated dose was not reached. In the combination regimens, the most common adverse events consisted of fatigue, nausea and vomiting, diarrhea, and hematologic toxicity. The maximum-tolerated doses and biologically effective doses were established for each combination. Target engagement, as a predefined 50% pCDK1 reduction in surrogate tissue, was observed in combination with cisplatin and carboplatin. Of 176 patients evaluable for efficacy, 94 (53%) had stable disease as best response, and 17 (10%) achieved a partial response. The response rate in TP53-mutated patients (n = 19) was 21% compared with 12% in TP53 wild-type patients (n = 33). Conclusion AZD1775 was safe and tolerable as a single agent and in combination with chemotherapy at doses associated with target engagement.

Fedratinib is an oral, selective Janus kinase 2 (JAK2) inhibitor. The phase II JAKARTA2 study assessed fedratinib in patients with intermediate‐ or high‐risk myelofibrosis (MF) who were resistant or intolerant to prior ruxolitinib per investigator assessment. Patients received fedratinib 400 mg/day in 28‐day cycles. The JAKARTA2 outcomes were initially reported using a last‐observation‐carried forward (LOCF) analysis in a “Per Protocol” population. This updated analysis of JAKARTA2 employs intention‐to‐treat analysis principles without LOCF for all treated patients (ITT Population; N = 97), and for a patient subgroup who met more stringent definitions of prior ruxolitinib failure (Stringent Criteria Cohort; n = 79). Median duration of prior ruxolitinib exposure was 10.7 months. The primary endpoint was spleen volume response rate (SVRR; ≥35% spleen volume decrease from baseline to end of cycle 6 [EOC6]). The SVRR was 31% in the ITT Population and 30% in the Stringent Criteria Cohort. Median duration of spleen volume response was not reached. Symptom response rate (≥50% reduction from baseline to EOC6 in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF]) was 27%. Grade 3‐4 anemia and thrombocytopenia rates were 38% and 22%, respectively. Patients with advanced MF substantially pretreated with ruxolitinib attained robust spleen responses and reduced symptom burden with fedratinib.