Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial.

BACKGROUND: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. METHODS: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. FINDINGS: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. INTERPRETATION: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. FUNDING: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.

Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.

BACKGROUND: First-line therapy for advanced non-small-cell lung cancer (NSCLC) that lacks targetable mutations is platinum-based chemotherapy. Among patients with a tumor proportion score for programmed death ligand 1 (PD-L1) of 50% or greater, pembrolizumab has replaced cytotoxic chemotherapy as the first-line treatment of choice. The addition of pembrolizumab to chemotherapy resulted in significantly higher rates of response and longer progression-free survival than chemotherapy alone in a phase 2 trial. METHODS: In this double-blind, phase 3 trial, we randomly assigned (in a 2:1 ratio) 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease to receive pemetrexed and a platinum-based drug plus either 200 mg of pembrolizumab or placebo every 3 weeks for 4 cycles, followed by pembrolizumab or placebo for up to a total of 35 cycles plus pemetrexed maintenance therapy. Crossover to pembrolizumab monotherapy was permitted among the patients in the placebo-combination group who had verified disease progression. The primary end points were overall survival and progression-free survival, as assessed by blinded, independent central radiologic review. RESULTS: After a median follow-up of 10.5 months, the estimated rate of overall survival at 12 months was 69.2% (95% confidence interval [CI], 64.1 to 73.8) in the pembrolizumab-combination group versus 49.4% (95% CI, 42.1 to 56.2) in the placebo-combination group (hazard ratio for death, 0.49; 95% CI, 0.38 to 0.64; P<0.001). Improvement in overall survival was seen across all PD-L1 categories that were evaluated. Median progression-free survival was 8.8 months (95% CI, 7.6 to 9.2) in the pembrolizumab-combination group and 4.9 months (95% CI, 4.7 to 5.5) in the placebo-combination group (hazard ratio for disease progression or death, 0.52; 95% CI, 0.43 to 0.64; P<0.001). Adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group. CONCLUSIONS: In patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck; KEYNOTE-189 ClinicalTrials.gov number, NCT02578680 .).

Multi-disciplinary proactive follow-up algorithm for patients with advanced NSCLC receiving afatinib.

PURPOSE: Afatinib is a standard first-line therapy for advanced EGFR-positive NSCLC. We implemented a pharmacist-led proactive follow-up algorithm to identify and manage early afatinib-related adverse events (AEs). METHODS: We conducted a retrospective chart review of all patients treated with afatinib after implementation of the algorithm at the Sunnybrook Odette Cancer Centre (Toronto, ON, Canada) from April 1, 2015 to July 31, 2016. Our in-house algorithm involved consultations in person and proactive pharmacist-led callbacks on days 5, 10, and 17. All AEs were graded and documented in real time and management based on toxicity grade was standardized. This study evaluated the impact of our algorithm on real-world AEs. RESULTS AND DISCUSSION: Thirty-three patients were identified and reviewed. Median follow-up was 248 days. All patients experienced at least one drug-related AE; 18.2% were grade 3/4. The most common AEs were diarrhea 87.9%, rash 81.8%, stomatitis 57.6%, and paronychia 45.5%. Median dose of afatinib was 40 mg daily; 51.5% of patients had ≥ 1 dose reduction and 6.3% discontinued afatinib due to AEs. Proactive calls by the pharmacist identified 36.5% of all drug-related AEs, 33.3% of grade 3/4 AEs, 58.1% of first drug-related AEs and identified two patients that were non-compliant. Only 3.2% of AEs were identified by an emergency room/urgent clinic visit. CONCLUSIONS: This proactive multi-disciplinary AE management algorithm resulted in a low rate of urgent assessments and discontinuation due to toxicity while maintaining afatinib at ideal dose, thus providing a useful tool for centers prescribing afatinib.

Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of AGS15E Monotherapy in Patients with Metastatic Urothelial Carcinoma.

PURPOSE: Effective treatment of locally advanced or metastatic urothelial carcinoma (mUC) remains an unmet need. Antibody-drug conjugates (ADC) providing targeted drug delivery have shown antitumor activity in this setting. AGS15E is an investigational ADC that delivers the cytotoxic drug monomethyl auristatin E to cells expressing SLITRK6, a UC-associated antigen. PATIENTS AND METHODS: This was a multicenter, single-arm, phase I dose-escalation and expansion trial of AGS15E in patients with mUC (NCT01963052). During dose escalation, AGS15E was administered intravenously at six levels (0.10, 0.25, 0.50, 0.75, 1.00, 1.25 mg/kg), employing a continual reassessment method to determine dose-limiting toxicities (DLT) and the recommended phase II dose (RP2D) for the dose-expansion cohort. The primary objective was to evaluate the safety and pharmacokinetics of AGS15E in patients with and without prior chemotherapy and with prior checkpoint inhibitor (CPI) therapy. Best overall response was also examined. RESULTS: Ninety-three patients were recruited, including 33 patients previously treated with CPI. The most common treatment-emergent adverse events were fatigue (54.8%), nausea (37.6%), and decreased appetite (35.5%). Peripheral neuropathy and ocular toxicities occurred at doses of ≥0.75 mg/kg. AGS15E increased in a dose-proportional manner after single- and multiple-dose administration; accumulation was low. Five DLT occurred from 0.50 to 1.25 mg/kg. The RP2D was assessed at 1.00 mg/kg; the objective response rate (ORR) was 35.7% at this dose level. The ORR in the total population and CPI-exposed subgroup were 18.3% and 27.3%, respectively. CONCLUSIONS: DLT with AGS15E were observed at 0.75, 1.00, and 1.25 mg/kg, with an RP2D of 1.00 mg/kg being determined.

Safety Related to the Timing of Radiotherapy and Immune Checkpoint Inhibitors in Patients with Advanced Non-Small Cell Lung Cancer: A Single Institutional Experience.

BACKGROUND: The safety impact of radiotherapy (RT) timing relative to immune checkpoint inhibitors (ICIs) for advanced non-small-cell lung cancer (NSCLC) is unclear. We investigated if RT within 14 days (Interval 1) and 90 days (Interval 2) of ICI use is associated with toxicities compared to RT outside these intervals. METHODS: Advanced NSCLC patients treated with both RT and ICIs were reviewed. Toxicities were graded as per CTCAE v4.0 and attributed to either ICIs or RT by clinicians. Associations between RT timing and Grade ≥2 toxicities were analyzed using logistic regression models adjusted for patient, disease, and treatment factors (α = 0.05). RESULTS: Sixty-four patients were identified. Twenty received RT within Interval 1 and 40 within Interval 2. There were 20 Grade ≥2 toxicities in 18 (28%) patients; pneumonitis (6) and nausea (2) were most prevalent. One treatment-related death (immune encephalitis) was observed. Rates of patients with Grade ≥2 toxicities were 35%/25% in the group with/without RT within Interval 1 and 30%/25% in the group with/without RT within Interval 2. No significant association between RT timing relative to ICI use period and Grade ≥2 toxicities was observed. CONCLUSION: Albeit limited by the small sample size, the result suggested that pausing ICIs around RT use may not be necessary.

Impact of Reflex EGFR/ ALK Testing on Time to Treatment of Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer.

PURPOSE: Optimal first-line systemic therapy for patients with advanced nonsquamous (nonsq) non-small-cell lung cancer (NSCLC) requires confirmation of EGFR/ ALK status, which can delay treatment. We evaluated the impact of reflex testing, defined as pathologists initiating EGFR/ ALK testing at the time of diagnosis of nonsq NSCLC, on time to treatment (TTT). METHODS: We conducted a retrospective review of patients with nonsq NSCLC with medical oncology consultation at Sunnybrook Odette Cancer Centre between March 18, 2010 and April 30, 2014. Data were compared during routine and reflex testing. TTT was defined as the interval between the first medical oncology visit with advanced NSCLC and the initiation of systemic therapy. RESULTS: A total of 306 patients were included (n = 232 for routine testing, n = 74 for reflex testing). There was a trend to improvement in median TTT with reflex testing (36 days [interquartile range {IQR}, 16 to 71 days v 26 days [IQR, 8 to 41 days], P = .071). Omitting patients with intentional delays in systemic therapy for low-volume disease, poor performance status, comorbidity management, and/or radiation therapy, median TTT improved (34 days [IQR, 15 to 67 days] v 22 days [IQR, 8 to 42 days], P = .049). Time to optimal first-line systemic therapy according to published guidelines improved (median, 36 days [IQR, 16 to 91 days] v 24 days [IQR, 8 to 43 days], P = .036). There was no impact on receipt of any first-line systemic therapy (55% v 59%, P = .66). The quality of biomarker testing improved, with fewer unsuccessful tests ( EGFR, 14% v 4%, P = .039; and ALK, 17% v 3%, P = .037). CONCLUSION: Reflex testing of EGFR/ ALK improved the time to optimal systemic therapy and the quality of biomarker testing for patients with advanced nonsq NSCLC.