Pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous non-small-cell lung cancer in KEYNOTE-407

The global phase III KEYNOTE-407 (NCT02775435) trial showed that pembrolizumab plus chemotherapy prolonged overall and progression-free survival (OS/PFS) versus placebo plus chemotherapy in patients with metastatic squamous non-small-cell lung cancer (NSCLC). We present outcomes of patients from Japan enrolled in KEYNOTE-407. Patients were randomized 1:1 to receive pembrolizumab 200 mg or placebo with paclitaxel 200 mg/m² every 3 weeks (Q3W) or nab-paclitaxel 100 mg/m² (weekly) plus carboplatin area under the concentration-time curve of 6 mg/mL/min Q3W for four cycles, followed by pembrolizumab or placebo Q3W for a total of 35 cycles. Primary end-points were OS and PFS per RECIST version 1.1 by blinded independent central review. Fifty patients were randomized at Japanese sites (pembrolizumab plus chemotherapy, n = 22; placebo plus chemotherapy, n = 28). Median follow-up time at data cut-off (May 9, 2019) was 15.1 (range, 0.5–24.0) months. Median OS (95% confidence interval [CI]) was 17.3 (12.5–not reached) versus 11.0 (8.6–19.5) months in the pembrolizumab plus chemotherapy versus placebo plus chemotherapy group (hazard ratio [HR] 0.56; 95% CI, 0.27–1.15). Median PFS (95% CI) was 8.3 (6.1–13.0) versus 7.2 (3.9–8.8) months (HR 0.65; 95% CI, 0.35–1.23). Grade 3–5 adverse events (AEs) occurred in 86% and 75% of patients, respectively. There were three fatal AEs, two of which were treatment-related (one from each treatment group, pneumonitis and pulmonary hemorrhage). Efficacy and safety outcomes were consistent with the global study and support the use of pembrolizumab plus chemotherapy in Japanese patients with metastatic squamous NSCLC.     

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized,phase III,open-label KEYNOTE-426 study

Background

In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan.

Methods

Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints.

Results

The Japanese subgroup comprised 94 patients (pembrolizumab–axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6–37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab–axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab–axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab–axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab–axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred.

Conclusions

Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.

     

Prognosis and chemosensitivity of deficient MMR phenotype in patients with metastatic colorectal cancer: An AGEO retrospective multicenter study

Mismatch repair-deficient (dMMR) and/or microsatellite instability-high (MSI) colorectal cancers (CRC) represent about 5% of metastatic CRC (mCRC). Prognosis and chemosensitivity of dMMR/MSI mCRC remain unclear. This multicenter study included consecutive patients with dMMR/MSI mCRC from 2007 to 2017. The primary endpoint was the progression-free survival (PFS) in a population receiving first-line chemotherapy. Associations between chemotherapy regimen and survival were evaluated using a Cox regression model and inverse of probability of treatment weighting (IPTW) methodology in order to limit potential biases. Overall, 342 patients with dMMR/MSI mCRC were included. Median PFS and overall survival (OS) on first-line chemotherapy were 6.0 and 26.3 months, respectively. For second-line chemotherapy, median PFS and OS were 4.4 and 21.6 months. Longer PFS (8.1 vs. 5.4 months, p = 0.0405) and OS (35.1 vs. 24.4 months, p = 0.0747) were observed for irinotecan-based chemotherapy compared to oxaliplatin-based chemotherapy. The association was no longer statistically significant using IPTW methodology. In multivariable analysis, anti-VEGF as compared to anti-EGFR was associated with a trend to longer OS (HR = 1.78, 95% CI 1.00–3.19, p = 0.0518), whatever the backbone chemotherapy used. Our study shows that dMMR/MSI mCRC patients experienced short PFS with first-line chemotherapy with or without targeted therapy. OS was not different according to the chemotherapy regimen used, but a trend to better OS was observed with anti-VEGF. Our study provides some historical results concerning chemotherapy in dMMR/MSI mCRC in light of the recent nonrandomized trials with immune checkpoint inhibitors.     

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048

Background

Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab–chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Methods

Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67).

Results

At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09–0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25–1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31–1.41]). Pembrolizumab–chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23–2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55–2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55–2.22]). Median PFS was similar for pembrolizumab and pembrolizumab–chemotherapy versus EXTREME in all subgroups. Grades 3–5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab–chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab–chemotherapy died because of treatment-related pneumonitis.

Conclusion

These results support the use of first-line pembrolizumab and pembrolizumab–chemotherapy for Japanese patients with R/M HNSCC.

Clinical trial registry ClinicalTrials.gov, NCT02358031.

     

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001

BackgroundPembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.Patients and methodsPatients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan–Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017).ResultsKEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2–30.4) and 38.6 months (95% CI, 27.2–not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8–11.1) and 16.9 months (95% CI, 9.3–35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE.ConclusionsThis 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma.Clinical Trial RegistryClinicalTrials.gov, NCT01295827.     

China special issue on gastrointestinal tumors-Cetuximab retreatment plus camrelizumab and liposomal irinotecan in patients with RAS wild-type metastatic colorectal cancer: Cohort B of the phase II CRACK study

Patients with metastatic colorectal cancer (mCRC) have poor long-term survival. Rechallenge with anti-epidermal growth factor receptor (anti-EGFR) based therapy has shown certain activity as late-line therapy. To further improve clinical outcomes, we evaluated the antitumor efficacy and safety of cetuximab in combination with camrelizumab and liposomal irinotecan in patients with RASwt mCRC pretreated with anti-EGFR-based therapy. Patients with RASwt mCRC who had received at least two prior systemic therapies, including anti-EGFR-based treatment in the metastatic or unresectable disease setting, were enrolled in cohort B. Patients were treated with cetuximab (500 mg/m²) and camrelizumab (200 mg) plus liposomal irinotecan (HR070803, 60 mg/m²) intravenously once every 2 weeks. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. At the data cutoff (23 November 2022), 19 patients were enrolled in the two stages, and 16 were evaluable for efficacy analyses. The ORR was 25% (95% confidence interval [CI]: 10.2%-49.5%), and DCR was 75% (95% CI: 50.5%-89.8%). The median PFS and OS were 6.9 (95% CI: 2.6-11.2) and 15.1 (95% CI: 6.1-24.0) months, respectively. Grade 3 treatment-related adverse events (TRAEs) occurred in 15.8% (3/19) of patients. No grade ≥4 TRAEs were found in the safety population. Our study suggests that anti-EGFR retreatment therapy with cetuximab plus camrelizumab and liposomal irinotecan (HR070803) is a promising late-line treatment option with good antitumor activity and well-tolerated toxicity in RASwt mCRC patients.     

Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel,docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator’s choice of paclitaxel (175 mg/m² Q3W), docetaxel (75 mg/m² Q3W), or vinflunine (320 mg/m² Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years’ follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436.     

A Randomized,Placebo-Controlled Trial of Pembrolizumab Plus Chemotherapy in Patients With Metastatic Squamous NSCLC: Protocol-Specified Final Analysis of KEYNOTE-407

IntroductionIn the randomized KEYNOTE-407 study (ClinicalTrials.gov, NCT02775435), pembrolizumab plus carboplatin and paclitaxel/nab-paclitaxel (chemotherapy) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus chemotherapy in patients with previously untreated metastatic squamous NSCLC. We report updated efficacy outcomes from the protocol-specified final analysis and, for the first time, progression on next line of treatment.MethodsEligible patients were randomized to chemotherapy plus either pembrolizumab (n = 278) or placebo (n = 281). After positive results from the second interim analysis, patients still receiving placebo could cross over to pembrolizumab monotherapy at the time of confirmed progressive disease. The primary end points were OS and PFS. PFS-2 (time from randomization to progression on next-line treatment/death, whichever occurred first) was an exploratory end point.ResultsAfter median (range) follow-up of 14.3 (0.1–31.3) months, pembrolizumab plus chemotherapy continued to exhibit a clinically meaningful improvement over placebo plus chemotherapy in OS (median, 17.1 mo [95% confidence interval (CI): 14.4‒19.9] versus 11.6 mo [95% CI: 10.1‒13.7]; hazard ratio [HR], 0.71 [95% CI: 0.58‒0.88]) and PFS (median, 8.0 mo [95% CI: 6.3‒8.4] versus 5.1 mo [95% CI: 4.3‒6.0]; HR, 0.57 [95% CI: 0.47‒0.69]). PFS-2 was longer for patients randomized to first-line pembrolizumab plus chemotherapy (HR, 0.59 [95% CI: 0.49‒0.72]). Grade 3 to 5 adverse events occurred in 74.1% and 69.6% of patients receiving pembrolizumab plus chemotherapy and placebo plus chemotherapy, respectively.ConclusionsPembrolizumab plus chemotherapy continued to exhibit substantially improved OS and PFS in patients with metastatic squamous NSCLC. The PFS-2 outcomes support pembrolizumab plus chemotherapy as a standard first-line treatment in patients with metastatic squamous NSCLC.     

Outcomes With Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With NSCLC and Stable Brain Metastases: Pooled Analysis of KEYNOTE-021, -189, and -407

IntroductionThis exploratory analysis retrospectively evaluated outcomes in patients with advanced NSCLC to determine whether baseline brain metastases influenced the efficacy of first-line pembrolizumab plus chemotherapy versus chemotherapy alone.MethodsWe pooled data for patients with advanced NSCLC in KEYNOTE-021 cohort G (nonsquamous), KEYNOTE-189 (nonsquamous), and KEYNOTE-407 (squamous). Patients were assigned to platinum-doublet chemotherapy with or without the addition of 35 cycles of pembrolizumab 200 mg every 3 weeks. All studies permitted enrollment of patients with previously treated or untreated (KEYNOTE-189 and KEYNOTE-407 only) stable brain metastases. Patients with previously treated brain metastases were clinically stable for 2 or more weeks (≥4 wk in KEYNOTE-021 cohort G), had no evidence of new or enlarging brain metastases, and had no steroid use at least 3 days before dosing. Patients with known untreated asymptomatic brain metastases required regular imaging of the brain.ResultsA total of 1298 patients were included, 171 with and 1127 without baseline brain metastases. Median (range) durations of follow-up at data cutoff were 10.9 (0.1‒35.1) and 11.0 (0.1‒34.9) months, respectively. Hazard ratios (pembrolizumab + chemotherapy/chemotherapy) were similar for patients with and without brain metastases for overall survival (0.48 [95% confidence interval (CI): 0.32‒0.70] and 0.63 [95% CI: 0.53‒0.75], respectively) and progression-free survival (0.44 [95% CI: 0.31‒0.62] and 0.55 [95% CI: 0.48‒0.63], respectively). In patients with brain metastases, median overall survival was 18.8 months with pembrolizumab plus chemotherapy and 7.6 months with chemotherapy, and median progression-free survival was 6.9 months and 4.1 months, respectively. Objective response rates were higher and duration of response longer with pembrolizumab plus chemotherapy versus chemotherapy regardless of brain metastasis status. Incidences of treatment-related adverse events with pembrolizumab plus chemotherapy versus chemotherapy were 88.2% versus 82.8% among patients with brain metastases and 94.5% versus 90.6% in those without.ConclusionsWith or without brain metastasis, pembrolizumab plus platinum-based histology-specific chemotherapy improved clinical outcomes versus chemotherapy alone across all programmed death ligand 1 subgroups, including patients with programmed death ligand 1 tumor proportion score less than 1% and had a manageable safety profile in patients with advanced NSCLC. This regimen is a standard-of-care treatment option for treatment-naive patients with advanced NSCLC, including patients with stable brain metastases.     

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial

BackgroundPembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy.Patients and methodsIn the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS).ResultsBetween 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%–49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18–37) and median overall survival was 22.1 months (95% CI 17.1–27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%–71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%–36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths.ConclusionsPembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%.Clinical trial name and numberKEYNOTE-001 (ClinicalTrials.gov, NCT01295827).     

Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study

BackgroundPatients with castration-resistant prostate cancer derive only modest clinical benefit from available therapies. Blockade of the inhibitory programmed death 1 (PD-1) receptor by monoclonal antibodies has been effective in several malignancies. Results from the prostate adenocarcinoma cohort of the nonrandomized phase Ib KEYNOTE-028 trial of pembrolizumab in advanced solid tumors are presented.Materials and methodsKey eligibility criteria included advanced prostate adenocarcinoma, unsuccessful standard therapy, measurable disease per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1), and PD-1 ligand (PD-L1) expression in ≥1% of tumor or stromal cells. Patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression or intolerable toxicity for up to 24 months. Primary end point was objective response rate (ORR) per RECIST v1.1 by investigator review.ResultsMedian patient age in this cohort (n = 23) was 65 years; 73.9% of patients received at least two prior therapies for metastatic disease. There were four confirmed partial responses, for an ORR of 17.4% [95% confidence interval (CI) 5.0%–38.8%]; 8 of 23 (34.8%) patients had stable disease. Median duration of response was 13.5 months. Median progression-free survival (PFS) and overall survival (OS) were 3.5 and 7.9 months, respectively; 6-month PFS and OS rates were 34.8% and 73.4%, respectively. One patient remained on treatment at data cutoff. After a median follow-up of 7.9 months, 14 (60.9%) patients experienced treatment-related adverse events (TRAEs), most commonly nausea (n = 3, 13.0%). Four (17.3%) experienced grade 3/4 TRAEs: grade 3 peripheral neuropathy, grade 3 asthenia, grade 3 fatigue, and grade 4 lipase increase. No pembrolizumab-related deaths or discontinuations occurred.ConclusionPembrolizumab resulted in durable objective response in a subset of patients with heavily pretreated, advanced PD-L1–positive prostate cancer, and its side effect profile was favorable.ClinicalTrials.gov IdentifierNCT02054806     

Pembrolizumab plus pemetrexed-platinum for metastatic nonsquamous non–small-cell lung cancer: KEYNOTE-189 Japan Study

Pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) with manageable safety compared with placebo plus pemetrexed-platinum in patients with previously untreated metastatic nonsquamous non–small-cell lung cancer (NSCLC) without EGFR/ALK alterations in the global, randomized, double-blind, phase 3 KEYNOTE-189 study. We present results of Japanese patients enrolled in the KEYNOTE-189 global and Japan extension studies. Patients were randomized 2:1 to intravenous pembrolizumab 200 mg or placebo every 3 weeks (Q3W) for up to 35 cycles. All patients received pemetrexed 500 mg/m² plus the investigator’s choice of cisplatin or carboplatin Q3W for four cycles, followed by maintenance pemetrexed 500 mg/m² Q3W (all intravenous). Co–primary endpoints were OS and PFS. Forty Japanese patients enrolled (pembrolizumab, n = 25; placebo, n = 15). At data cutoff (20 May 2019; median time from randomization to data cutoff, 18.5 [range, 14.7‒38.2] months), the median OS was not reached in the pembrolizumab plus pemetrexed-platinum arm; the median OS was 25.9 (95% confidence interval [CI], 11.9‒29.0) months in the placebo plus pemetrexed-platinum arm (hazard ratio [HR] .29; 95% CI, .07‒1.15). The median (95% CI) PFS was 16.5 (8.8‒21.1) compared with 7.1 (4.7‒21.4) months (HR, .62; 95% CI, .27‒1.42), respectively. There were no grade 5 adverse events (AE). Grade 3/4 AE occurred in 72% vs 60% of patients in the pembrolizumab vs placebo arms; 40% vs 20% had immune-mediated AE, and 4% vs 0% had infusion reactions. Efficacy and safety outcomes were similar to those from the global study and support first-line therapy with pembrolizumab plus pemetrexed-platinum in Japanese patients with nonsquamous NSCLC without EGFR/ALK alterations.     

Use of archival versus newly collected tumor samples for assessing PD-L1 expression and overall survival: an updated analysis of KEYNOTE-010 trial

BackgroundIn KEYNOTE-010, pembrolizumab versus docetaxel improved overall survival (OS) in patients with programmed death-1 protein (PD)-L1-positive advanced non-small-cell lung cancer (NSCLC). A prespecified exploratory analysis compared outcomes in patients based on PD-L1 expression in archival versus newly collected tumor samples using recently updated survival data.Patients and methodsPD-L1 was assessed centrally by immunohistochemistry (22C3 antibody) in archival or newly collected tumor samples. Patients received pembrolizumab 2 or 10 mg/kg Q3W or docetaxel 75 mg/m² Q3W for 24 months or until progression/intolerable toxicity/other reason. Response was assessed by RECIST v1.1 every 9 weeks, survival every 2 months. Primary end points were OS and progression-free survival (PFS) in tumor proportion score (TPS) ≥50% and ≥1%; pembrolizumab doses were pooled in this analysis.ResultsAt date cut-off of 24 March 2017, median follow-up was 31 months (range 23–41) representing 18 additional months of follow-up from the primary analysis. Pembrolizumab versus docetaxel continued to improve OS in patients with previously treated, PD-L1-expressing advanced NSCLC; hazard ratio (HR) was 0.66 [95% confidence interval (CI): 0.57, 0.77]. Of 1033 patients analyzed, 455(44%) were enrolled based on archival samples and 578 (56%) on newly collected tumor samples. Approximately 40% of archival samples and 45% of newly collected tumor samples were PD-L1 TPS ≥50%. For TPS ≥50%, the OS HRs were 0.64 (95% CI: 0.45, 0.91) and 0.40 (95% CI: 0.28, 0.56) for archival and newly collected samples, respectively. In patients with TPS ≥1%, OS HRs were 0.74 (95% CI: 0.59, 0.93) and 0.59 (95% CI: 0.48, 0.73) for archival and newly collected samples, respectively. In TPS ≥50%, PFS HRs were similar across archival [0.63 (95% CI: 0.45, 0.89)] and newly collected samples [0.53 (95% CI: 0.38, 0.72)]. In patients with TPS ≥1%, PFS HRs were similar across archival [0.82 (95% CI: 0.66, 1.02)] and newly collected samples [0.83 (95% CI: 0.68, 1.02)].ConclusionPembrolizumab continued to improve OS over docetaxel in intention to treat population and in subsets of patients with newly collected and archival samples.Trial registrationClinicalTrials.gov: NCT01905657.     

Randomized Phase 2 Studies of Checkpoint Inhibitors Alone or in Combination With Pegilodecakin in Patients With Metastatic NSCLC (CYPRESS 1 and CYPRESS 2)

IntroductionCheckpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2.MethodsCYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers.ResultsMedian follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5–2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54–1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708–3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3–5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519–1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772–4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms.ConclusionsDespite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs.     

Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial

BackgroundWe report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT).Patients and methodsmCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups.ResultsBetween November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2–10.3] and 8.4 (95% CI 7.2–9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70–1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia.ConclusionsThe addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population.Clinical trial numberNCT01878422.     

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non–Small Cell Lung Cancer

Introduction

Cohort G of KEYNOTE-021 (NCT02039674) evaluated the efficacy and safety of pembrolizumab plus pemetrexed-carboplatin (PC) versus PC alone as first-line therapy for advanced nonsquamous NSCLC. At the primary analysis (median follow-up time 10.6 months), pembrolizumab significantly improved objective response rate (ORR) and progression-free survival (PFS); the hazard ratio (HR) for overall survival (OS) was 0.90 (95% confidence interval [CI]: 0.42?1.91). Herein, we present an updated analysis.

Atezolizumab Treatment Beyond Progression in Advanced NSCLC: Results From the Randomized,Phase III OAK Study

Introduction

Cancer immunotherapy may alter tumor biology such that treatment effects can extend beyond radiographic progression. In the randomized, phase III OAK study of atezolizumab (anti–programmed death-ligand 1) versus docetaxel in advanced NSCLC, overall survival (OS) benefit with atezolizumab was observed in the overall patient population, without improvement in objective response rate (ORR) or progression-free survival (PFS). We examine the benefit-risk of atezolizumab treatment beyond progression (TBP).

Influence of mRNA expression of epiregulin and amphiregulin on outcome of patients with metastatic colorectal cancer treated with 5‐FU/LV plus irinotecan or irinotecan plus oxaliplatin as first‐line treatment (FIRE 1‐trial)

Our aim was to investigate the impact of EREG and AREG mRNA expression (by RT‐qPCR) in patients with metastatic colorectal cancer (mCRC). In addition, epidermal growth factor receptor (EGFR) expression (by immunohistochemistry) as well as RAS‐and PIK3CA‐mutations (by pyrosequencing) were assessed. Tumors of 208 mCRC patients receiving 5‐fluorouracil/leucovorin plus irinotecan (FUFIRI) or irinotecan plus oxaliplatin (mIROX) within the FIRE‐1 trial were analyzed for mutations. Molecular characteristics were correlated with response, progression‐free survival (PFS), overall survival (OS). mRNA expression was evaluated using ROC‐analysis in 192 tumors (AREG high n = 31 vs. low n = 161; EREG high n = 89 vs. low n = 103). High versus low AREG expression was associated with PFS of 10.0 versus 8.0 months (HR = 0.62, 95% CI: 0.402–0.940, p = 0.03) and OS of 24.6 versus 18.7 months (HR = 0.72, 95% CI: 0.476–1.078, p = 0.11). High versus low EREG expression correlated with prolonged PFS (9.4 vs. 6.8 months, HR = 0.62, 95% CI: 0.460–0.846, p = 0.002) and OS (25.8 vs. 15.5 months, HR = 0.48, 95% CI: 0.351–0.657, p < 0.001). The positive prognostic effect of high EREG expression was confirmed in a multivariate analysis and was neither affected by EGFR expression nor by mutations of RAS‐ and PIK3CA‐genes. EREG expression appears as an independent prognostic marker in patients with mCRC receiving first‐line irinotecan‐based chemotherapy.     

Final analysis of a randomised trial comparing pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory advanced melanoma

AimTo evaluate the protocol-specified final analysis of overall survival (OS) in the KEYNOTE-002 study (NCT01704287) of pembrolizumab versus chemotherapy in patients with ipilimumab-refractory, advanced melanoma.MethodsIn this randomised, phase II study, eligible patients had advanced melanoma with documented progression after two or more ipilimumab doses, previous BRAF or MEK inhibitor or both, if BRAF^V600 mutant-positive. Patients were randomised to pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy. Crossover to pembrolizumab was allowed following progression on chemotherapy. The protocol-specified final OS was performed in the intent-to-treat population. Survival was positive if p < 0.01 in one pembrolizumab arm.ResultsA total of 180 patients were randomised to pembrolizumab 2 mg/kg, 181 to pembrolizumab 10 mg/kg and 179 to chemotherapy. At a median follow-up of 28 months (range 24.1–35.5), 368 patients died and 98 (55%) crossed over to pembrolizumab. Pembrolizumab 2 mg/kg (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.67–1.10, p = 0.117) and 10 mg/kg (0.74, 0.57–0.96, p = 0.011) resulted in a non-statistically significant improvement in OS versus chemotherapy; median OS was 13.4 (95% CI 11.0–16.4) and 14.7 (95% CI 11.3–19.5), respectively, versus 11.0 months (95% CI 8.9–13.8), with limited improvement after censoring for crossover. Two-year survival rates were 36% and 38%, versus 30%. Progression-free survival, objective response rate and duration of response improved with pembrolizumab versus chemotherapy, regardless of dose. Grade III–V treatment-related adverse events occurred in 24 (13.5%), 30 (16.8%) and 45 (26.3%) patients, respectively.ConclusionImprovement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.