Blogs

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• Durvalumab with or without tremelimumab vs. platinum-based chemotherapy did not meet primary endpoints of OS and PFS in metastatic NSCLC patients with PD-L1 TC ≥ 25% population: MYSTIC (LBA6)
• Ligand-inducible, autologous T cells engineered to target PSCA on tumor cells in advanced solid tumors: preliminary results from the dose escalation study BP-012 (68O)
• Similar rates of fast progression in patients treated with a checkpoint inhibitor vs. chemotherapy in OAK, a Phase III trial of atezolizumab vs. docetaxel in previously treated patients with locally advanced or metastatic NSCLC (LBA1)
• Long-term pembrolizumab treatment provides durable response and long-term disease control in patients with previously treated, PD-L1-expressing advanced NSCLC KEYNOTE-010 (LBA4)

Durvalumab with or without tremelimumab vs. platinum-based chemotherapy did not meet primary endpoints of OS and PFS in metastatic NSCLC patients with PD-L1 TC ≥ 25% population: MYSTIC (LBA6)

Naiyer A. Rizvi, MD (Columbia University Medical Center, New York, NY, USA) presented results from the Phase III, global, randomized, open-label, multicenter MYSTIC study (NCT02453282), evaluating the safety and efficacy of durvalumab (anti-PD-L1) + tremelimumab (anti-CTLA-4) combination therapy and durvalumab monotherapy vs. platinum-based chemotherapy as first-line treatment in patients with epidermal growth factor receptor, ALK wild-type stage IV NSCLC, enrolled independently of PD-L1 status. A total of 1118 patients were randomized 1:1:1 to receive durvalumab (20 mg/kg, Q4W), durvalumab (20 mg/kg, Q4W) + tremelimumab (1 mg/kg Q4W), or platinum-based chemotherapy (up to 6 cycles). Primary endpoints were progression free survival (PFS) for durvalumab plus tremelimumab vs chemotherapy and overall survival (OS) for durvalumab plus tremelimumab vs. chemotherapy and for durvalumab vs. chemotherapy in patients with PD-L1 tumor cell (TC) expression ≥ 25%.
As for the primary endpoints, PFS and OS were similar in patients treated with durvalumab plus tremelimumab or chemotherapy (one year PFS: 25,8% vs 14.3%, respectively; HR 1.05 [(99.5% CI: 0.72-1.53], p = 0.70; two-years OS: 35.4% vs 22.7%, respectively; HR 0.85, [98.77% CI: 0.61-1.17], p = 0.20). The OS was increased in patients receiving durvalumab alone vs. chemotherapy without reaching the significance level, which, for this endpoint, was set at 3% (two-years OS: 38.3% vs. 22.7%, respectively; HR 0.76, 97.54% CI = 0.56-1.02, p = 0.036). In the exploratory analysis, a high tumor mutational burden (TMB) measured in the blood (≥ 16 mutations/Mb) was associated with better OS for durvalumab plus tremelimumab vs. chemotherapy: two-years OS was 39% vs. 18%, respectively; HR 0.62 [95% CI: 0.45-0.85]). Two-years OS in patients treated with durvalumab was 30%. Two-years OS in patients with low mutational load was 19%, 29%, and 24 % for the durvalumab plus tremelimumab, durvalumab, and chemotherapy, respectively. Grade 3-5 treatment-related AE occurred in 15.1%, 23.7%, and 34.7% of patients treated with durvalumab, durvalumab plus tremelimumab, and chemotherapy, respectively, consistent with data from previous trials. Although this study did not meet primary endpoints of OS and PFS in PD-L1 positive patients, durvalumab conferred a clinically meaningful improvement in overall survival.
An association of high TMB with improved OS in patients treated with durvalumab plus tremelimumab was identified; this correlation might be tested prospectively in future trials.

Ligand-inducible, autologous T cells engineered to target PSCA on tumor cells in advanced solid tumors: preliminary results from the dose escalation study BP-012 (68O)

Carlos R. Becerra, MD (Baylor University Medical Center, Dallas, TX, USA) described data from the Phase I, dose escalation study (BP-012, NCT02744287) designed to assess the safety, tolerability, and maximum tolerated dose of PSCA-specific CAR-T cells, BPX-601, in patients with previously treated, PSCA-positive advanced solid tumors. BPX601 is an autologous, T cells engineered to contain a PSCA-CD3ξ CAR for antigen-specific T cell activation, proliferation and persistence, plus the rimiducid-inducible MyD88/CD40 domain for costimulation, potentially enhancing clinical activity in solid tumors by additional stimulation. PSCA, a GPI-anchored cell-surface protein, is overexpressed in prostate, bladder, gastric, and other solid tumors, correlating with disease stage. In the ongoing study, 3 + 3 cell dose escalation (1.25 × 106 cells/kg without rimiducid [cohort 0], 1.25 × 106 cells/kg plus rimiducid [cohort 3], 2.5 × 106 cells/kg plus rimiducid [cohort 4], and 5.0 × 106 cells/kg plus rimiducid [cohort 5]) was tested to identify the recommended BPX601 cell dose (Day 0) given in combination with a fixed, single dose of rimiducid (0.4 mg/kg; Day 7) in patients with PSCA-positive advanced pancreatic cancer. Three days before BPX601 infusion, patients were treated with cyclophosphamide (1 g/m2 i.v.) . Twelve patients were enrolled. Administration of BPX-601 with single-dose rimiducid was well tolerated. No dose-limiting toxicity, cytokine release syndrome, or neurotoxicity of any grade was observed. The only treatment-related adverse event reported by more than one patient (n=2) was pyrexia (grade 1-2) on Day 0 following BPX601 infusion . Rapid BPX-601 expansion was observed by day 4 but did not persist without rimiducid. The combination of BPX-601 with rimiducid displayed enhanced expansion and prolonged persistence of T cells: cell expansion of 3- to 20-wold within 7 days was observed in 5 patients, and cell persistence of more than 3 weeks in 3 patients. There was limited evidence of lymphodepletion following cyclophosphamide. Within the 9 patients analyzed for response (cohort 0. 3, and 4), five patients achieved SD (one in cohort 0, 2 in cohort 3, and 2 in cohort 4) and 5 experienced progression; two patients with SD had tumor shrinkage > 20%. Evidence of biological activity and stable disease have been observed in pre-treated patients (2-4 therapies), in which increased cell dose was associated with increased cytokine and chemokine levels. Phase II study will include more intense lymphodepletion with cyclophosphamide/fludarabine, a repeat-dose rimiducid infusion schedule, and gastric and prostate cancer patients.

Similar rates of fast progression in patients treated with a checkpoint inhibitor vs. chemotherapy in OAK, a Phase III trial of atezolizumab vs. docetaxel in previously treated patients with locally advanced or metastatic NSCLC (LBA1)

David R. Gandara, MD (University of California Davis Cancer Center, Sacramento, CA, USA) presented results from the Phase III, global, open-label, randomized, controlled OAK trial (NCT02008227), investigating the efficacy and safety of atezolizumab compared to docetaxel in patients with locally advanced or metastatic NSCLC (any PD-1 status) after failure with platinum-containing chemotherapy. Patients were randomized 1:1 to receive atezolizumab (1200 mg IV Q3W) or docetaxel and analyzed for fast progression (FP). FP is a composite measure that incorporates rapid early disease progression or early death due to progressive disease as a surrogate for the hyperprogressive disease phenomenon. Efficacy analysis was performed on the first 850 of 1225 enrolled patients (Rittmeyer et al. Lancet 2017). Median OS was 13.8 months (95% CI: 11.8-15.7) in the atezolizumab cohort and 9.6 months (95% CI: 8.6-11.2) in the docetaxel group (HR 0.73 [95% CI: 0.62-0.87, p = 0.0003]). In the first 850 enrolled patients similar rates (10%) of FP occurred in the atezolizumab and docetaxel arms. Characteristics and outcomes of patients with FP were similar between the two arms. FP in the atezolizumab arm was associated with ≥ 3 metastatic sites (p = 0.024) and ECOG PS (p = 0.021), compared to non-FP patients, but not with other baseline factors such as age, gender, smoking status, PD-L1 + status, tumor mutational burden, baseline LDH status, and early prior treatment failure. No significant associations between FP and clinicopathologic characteristics were observed in the docetaxel arm. OS benefit of atezolizumab vs. docetaxel was observed regardless of baseline prognostic factors, such as the number of metastatic sites, LDH, sum of long diameters, the timing of prior treatment failure. These results indicate that although FP rates are similar between atezolizumab and docetaxel cohorts, atezolizumab treatment clinically improves OS in patients with locally advanced or metastatic NSCLC who have failed platinum-based therapy regardless of baseline factors.

Long-term pembrolizumab treatment provides durable response and long-term disease control in patients with previously treated, PD-L1-expressing advanced NSCLC KEYNOTE-010 (LBA4)

Roy Herbst, MD, PhD (Yale Cancer Center, New Haven, CT, USA) presented the extended follow-up data (43 months) from the global, open-label, randomized Phase II/III KEYNOTE-010 study (NCT01905657), assessing the two doses of pembrolizumab vs. docetaxel in patients with PD-L1 tumor proportional score (TPS) ≥ 1%, advanced NSCLC who had experienced disease progression after platinum-containing systemic therapy. A total of 1,033 eligible patients were randomized 1:1:1 to receive pembrolizumab 10 mg/kg or 2 mg/kg (IV, Q3W for 35 cycles, 2 years), or docetaxel. In the primary analysis, no differences in OS were observed between these pembrolizumab dose groups: therefore, pembrolizumab doses were pooled for this analysis. In PD-L1 TPS ≥ 50% population, updated median OS was 16.9 months (95% CI: 12.3-21.4, n = 199) and 8.2 months (95% CI: 6.4-9.8, n = 127) in pembrolizumab and docetaxel cohorts, respectively (HR 0.53 [95% CI: 0.42-0.66, p = 0.00001]). In PD-L1 TPS ≥ 1% population, median OS was 11.8 months (95% CI: 10.4-13.1, n = 548) and 8.4 months (95% CI: 7.6-9.5, n = 295) in pembrolizumab and docetaxel cohorts, respectively (HR 0.69 [95% CI: 0.60-0.80, p = 0.00001]). In 79 patients who completed 2 years of pembrolizumab (35 cycles), (9%), 36-month OS rate was 98.7% (95% CI: 91.2-99.8), and median OS was not reached as of March 16, 2018; the number of PFS events was 26 (32.9%), 36-month OS rate was 70.3% (95% CI: 58.1-79.5), and median OS was not reached. In this subpopulation, 64% of patients had ongoing response and 91% of patients remained alive at median follow-up of 43 months. The number of patients who experienced the grade 3/4 of treatment-related AEs in this cohort was 18%, similar to the ratio (16%) in the total population. These data support that pembrolizumab continues to prolong OS vs docetaxel in patients with previously treated, PD-L1 expressing advanced 2 NSCLC. 2 years of pembrolizumab treatment provides durable response and long-term disease control in these patients.