Real-world Experience With Sunitinib Treatment in Patients With Metastatic Renal Cell Carcinoma: Clinical Outcome According to Risk Score

BackgroundADONIS is an ongoing observational study in 9 European countries, designed to evaluate treatment patterns/outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with first-line sunitinib and/or second-line axitinib post sunitinib. We present an evaluation of sunitinib efficacy by risk group, in the real-world setting examined in ADONIS.Patients and MethodsPatients were enrolled at the start of first-line sunitinib treatment or second-line axitinib post sunitinib treatment. Evaluation of sunitinib efficacy was assessed by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center risk criteria.ResultsFor all patients in this analysis (N = 467), the median progression-free survival was 23.8 months (95% confidence interval [CI], 16.5-28.5 months), 11.8 months (95% CI, 8.1-17.4 months), and 4.6 months (95% CI, 2.5-7.7 months) for IMDC favorable-, intermediate-, and poor-risk groups, respectively. The median overall survival was 97.1 months (95% CI, 46.3 months-not evaluable [NE]), 33.5 months (95% CI, 20.5-46.6 months), and 10.0 months (95% CI, 4.5-19.8 months) for the respective risk groups. Data on individual risk factors were available for a subgroup of patients, allowing analysis by intermediate risk by 1 versus 2 risk factors. When including this subgroup (n = 120), the median overall survival for IMDC favorable-, intermediate-1, and intermediate-2 risk factors was 21.6 months (95% CI, 16.3 months-NE), 20.5 months (15.5 months-NE), and 15.1 months (4.1 months-NE), respectively.ConclusionsFor patients overall and by risk-group stratification, survival estimates were aligned with previously published data. In patients with intermediate-1 risk, overall survival was very similar to patients with favorable risk. However, further exploration of outcome data from different sources is needed to confirm these observations.     

The European Medicines Agency Approval of Axitinib (Inlyta) for the Treatment of Advanced Renal Cell Carcinoma After Failure of Prior Treatment With Sunitinib or a Cytokine: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

Axitinib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR‐1), VEGFR‐2, and VEGFR‐3. Based on the positive opinion from the European Medicines Agency (EMA), a marketing authorization valid throughout the European Union (EU) was issued for the treatment of advanced renal cell carcinoma (RCC) after failure of prior treatment with sunitinib or a cytokine. The demonstration of clinical benefit for axitinib was based on a phase III, randomized, open‐label, multicenter study of axitinib compared with sorafenib in patients with advanced RCC after failure of a prior systemic first‐line regimen containing one or more of the following agents: sunitinib, bevacizumab plus interferon‐α, temsirolimus, or cytokines. In the primary analysis, a 2‐month increase in median progression‐free survival (PFS) was observed for axitinib compared with sorafenib (hazard ratio [HR]: 0.665; 95% confidence interval [CI]: 0.544–0.812; p < .0001). In the subgroup of patients with a prior cytokine‐containing regimen, the increase in median PFS associated with axitinib was 5.4 months (updated analysis, HR: 0.519; 95% CI: 0.375–0.720; p < .0001). In the subgroup of patients with prior sunitinib treatment, the increase in median PFS was 1.4 months (updated analysis, HR: 0.736; 95% CI: 0.578–0.937; p = .0063). The analysis of overall survival showed no statistically significant survival benefit of axitinib over sorafenib in patients previously treated with cytokine‐containing regimens (HR: 0.813; 95% CI: 0.556–1.191) or sunitinib (HR: 0.997; 95% CI: 0.782–1.270). The most common treatment‐related adverse events associated with axitinib included diarrhea, hypertension, fatigue, nausea, decreased appetite, dysphonia, and palmar‐plantar erythrodysesthesia. Most of these events were mild or moderate in severity. This paper summarizes the scientific review of the application leading to approval in the EU. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the EMA website ( http://www.ema.europa.eu ).     

Overall survival of first‐line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression‐free survival of 27.6 months in treatment‐naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and safety in 44 Japanese patients and compared the results with 169 non‐Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first‐line metastatic RCC were explored in all patients using a Cox proportional hazard model. With median follow‐up of 33 months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months–not estimable), whereas 107 of 169 (63%) non‐Japanese patients had died and median OS was 33.9 months (95% CI, 28.9–42.7). Estimated 1‐year, 2‐year and 3‐year survival probability (95% CI) was 86.4% (76.2–96.5), 75.0% (62.2–87.8) and 68.2% (54.4–81.9), respectively, in Japanese patients, and was higher than that in non‐Japanese patients (75.1% [68.4–81.8], 62.1% [54.5–69.7] and 47.2% [39.3–55.1], respectively). The updated safety analysis did not reveal any new adverse events of concern among Japanese or non‐Japanese patients. The multivariate analysis identified that lower baseline Eastern Cooperative Oncology Group performance status, lower baseline tumor burden, and longer time from histopathological diagnosis to treatment were significant positive predictors of OS. The current analysis confirmed the clinical activity of axitinib in treatment‐naïve Japanese patients with metastatic RCC, with an acceptable toxicity profile.     

Axitinib or Bevacizumab Plus FOLFIRI or Modified FOLFOX-6 After Failure of First-Line Therapy for Metastatic Colorectal Cancer: A Randomized Phase II Study

ObjectiveAxitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, shows activity in multiple tumor types, including those refractory to previous antiangiogenic therapy. This randomized, multicenter, parallel-group, open-label phase II trial compared axitinib with bevacizumab each in combination with 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) or 5-fluorouracil/leucovorin/irinotecan (FOLFIRI) for second-line treatment of metastatic colorectal cancer.MethodsPatients were randomized 1:1 to axitinib 5 mg twice daily or bevacizumab 5 mg/kg every 2 weeks plus modified FOLFOX-6 (if previously treated with irinotecan) or FOLFIRI (if previously treated with oxaliplatin) and were stratified by performance status and prior bevacizumab therapy. Primary endpoint was progression-free survival.ResultsIn 171 patients, progression-free survival was 7.6 months with axitinib/FOLFOX vs. 6.4 months with bevacizumab/FOLFOX (hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.55-1.96; 1-sided P = .55) and 5.7 months with axitinib/FOLFIRI vs. 6.9 months with bevacizumab/FOLFIRI (HR, 1.27; 95% CI, 0.77-2.11; 1-sided P = .83). Overall survival was 17.1 vs. 14.1 months with axitinib/FOLFOX and bevacizumab/FOLFOX (HR, 0.69; 95% CI, 0.37-1.27; 1-sided P = .12) and 12.9 vs. 15.7 months with axitinib/FOLFIRI and bevacizumab/FOLFIRI (HR, 1.36; 95% CI, 0.82-2.24; 1-sided P = .88). More grade ≥ 3 adverse events (eg, diarrhea, fatigue, decreased appetite) and treatment discontinuations due to adverse events occurred with axitinib.ConclusionsCompared with bevacizumab, axitinib did not improve outcomes when added to second-line chemotherapy for metastatic colorectal cancer. With current dosing regimens, axitinib plus FOLFOX or FOLFIRI seems to be less well tolerated than bevacizumab-based regimens.     

Avelumab first-line maintenance plus best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma: JAVELIN Bladder 100 Japanese subgroup analysis

Background

The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab as first-line (1L) maintenance therapy + best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-containing chemotherapy. Efficacy and safety were assessed in patients enrolled in Japan.

Methods

Patients with locally advanced or metastatic UC that had not progressed with 4–6 cycles of 1L platinum-containing chemotherapy were randomized to avelumab (10 mg/kg intravenously every 2 weeks) + BSC or BSC alone. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and safety.

Results

In Japanese patients (n = 73) randomized to avelumab + BSC (n = 36) or BSC alone (n = 37), median OS was 24.7 months (95% CI, 18.2-not estimable) vs 18.7 months (95% CI, 12.8–33.0), respectively (HR, 0.81 [95% CI, 0.41–1.58]), and median PFS was 5.6 months (95% CI, 1.9–9.4) vs 1.9 months (95% CI, 1.9–3.8), respectively (HR, 0.63 [95% CI, 0.36–1.11]). In the avelumab + BSC and BSC-alone arms, grade ≥ 3 treatment-emergent adverse events (AEs) occurred in 50.0% vs 8.1%, including grade ≥ 3 treatment-related AEs in 13.9% vs 0%, respectively. Efficacy and safety results in Japanese patients were generally consistent with findings in the overall trial population.

Conclusion

Avelumab 1L maintenance treatment showed a favorable benefit-risk balance in Japanese patients, supporting avelumab 1L maintenance as a new standard of care in Japanese patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy.

Trial registration

Clinicaltrials.gov NCT02603432.

     

Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine‐refractory metastatic renal cell carcinoma

In an open‐label, multicenter phase II study of Japanese patients with cytokine‐refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty‐four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6–49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7–64.2); the median duration of response, 11.1 months (95% CI, 8.2–13.7); and the median progression‐free survival was 11.0 months (95% CI, 9.2–12.0), assessed by the independent review committee. Common treatment‐related all‐grade adverse events were hypertension (88%), hand‐foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and dysphonia (53%). In an exploratory analysis, median overall survival was found to be significantly longer in patients who had greater decreases in plasma levels of soluble vascular endothelial growth factor receptor‐2 during the first cycle of treatment. In conclusion, the present study showed axitinib to be effective, and toxicities with long‐term treatment were generally controllable with axitinib dose modification and/or standard medications in these Japanese patients. Some frequently reported adverse events warrant close monitoring and management. Changes in the plasma levels of soluble vascular endothelial growth factor receptor‐2 may be used as a prognostic factor for overall survival in metastatic renal cell carcinoma following axitinib treatment. This study is registered at ClinicalTrial.gov (identifier NCT00569946).     

KEYNOTE‐025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1–positive advanced non–small‐cell lung cancer

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has been shown to improve overall survival (OS) in patients with previously treated advanced non–small‐cell lung cancer (NSCLC) with programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE‐025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD‐L1 TPS ≥1% and had received ≥1 platinum‐doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD‐L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD‐L1 TPS ≥50%. Thirty‐eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41‐78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3‐5 treatment‐related adverse events (AE); 9 patients (24%) experienced immune‐mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD‐L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6‐61). Among evaluable patients with PD‐L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10‐38). Median (95% CI) progression‐free survival and OS were 3.9 (2.0‐6.2) months and 19.2 (8.0‐26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD‐L1–expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE‐010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.)     

Real-world Effectiveness and Safety of Pazopanib in Patients With Intermediate Prognostic Risk Advanced Renal Cell Carcinoma

IntroductionThe objective of this study was to determine the effectiveness and safety of pazopanib in patients with intermediate-risk advanced/metastatic renal cell carcinoma in the PRINCIPAL study (NCT01649778).Patients and MethodsPatients had clear-cell advanced/metastatic renal cell carcinoma and met intermediate-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) and Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Assessments included progression-free survival, overall survival, objective response rate, and safety. We also evaluated effectiveness based on number of risk factors, age, and performance status (PS), as well as safety in older and younger patients.ResultsThree hundred sixty three and 343 intermediate-risk MSKCC and IMDC patients were included, respectively. The median progression-free survival was 13.8 months (95% confidence interval [CI], 10.7-18.1 months) and 7.4 months (95% CI, 6.2-10.3 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 13.1 months (95% CI, 10.7-18.1 months) and 8.1 months (95% CI, 6.4-10.7 months) for patients with 1 and 2 IMDC risk factors, respectively. The median overall survival was not reached and was 15.2 months (95% CI, 12.3-26.5 months) for patients with 1 and 2 MSKCC risk factors, respectively, and 33.9 months (95% CI, 33.9 months to not estimable) and 19.4 months (95% CI, 14.3 months to not estimable) with 1 and 2 IMDC risk factors, respectively. A lower overall response rate was observed with Eastern Cooperative Oncology Group PS ≥ 2 (vs. PS < 2). All-grade treatment-related adverse events occurred in approximately 63% of patients, and the safety profile among older and younger patients was similar.ConclusionsOutcomes with pazopanib in intermediate-risk patients suggest that patients can be further stratified by number of risk factors (1 vs. 2) and Eastern Cooperative Oncology Group PS (< 2 vs. ≥ 2) to more accurately predict outcomes.     

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.

     

Progression-free Survival Outcome Is Independent of Objective Response in Patients With Estrogen Receptor-positive,Human Epidermal Growth Factor Receptor 2-negative Advanced Breast Cancer Treated With Palbociclib Plus Letrozole Compared With Letrozole: Analysis From PALOMA-2

BackgroundIn PALOMA-2, palbociclib + letrozole significantly prolonged progression-free survival (PFS) versus placebo + letrozole in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER⁺/HER2⁻) advanced breast cancer (ABC). We investigated clinical outcomes of patients who achieved or did not achieve a confirmed objective response (OR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (data cutoff: May 31, 2017).Patients and MethodsPostmenopausal patients untreated for ER⁺/HER2⁻ ABC were randomized 2:1 to palbociclib + letrozole or placebo + letrozole. Median PFS, median duration of OR, baseline characteristics, and palbociclib exposure were compared in patients with or without OR by treatment arm.ResultsIn the intent-to-treat population, OR was achieved by 194 (44%) of 444 and 77 (35%) of 222 patients in the palbociclib and placebo arms, respectively (odds ratio, 1.5; 95% confidence interval [CI], 1.0-2.1; P = .0156). Regardless of treatment, more OR than non-OR patients had de novo metastatic disease (47%-50% and 28%-31%, respectively) and no prior endocrine therapy (55% and 35%-37%, respectively). Rates of palbociclib dose reduction owing to adverse events were similar regardless of OR (41% and 38%, respectively). Among the patients with OR during the study, approximately 50% achieved OR within the first 3 months regardless of treatment. The median PFS was significantly prolonged with palbociclib + letrozole versus placebo + letrozole in patients with measurable disease in both OR (37.2 months; 95% CI, 28.1 months to not estimable vs. 27.4 months; 95% CI, 22.2-31.1 months; hazard ratio, 0.66; 95% CI, 0.47-0.94; P = .009) and non-OR groups (10.9 months; 95% CI, 8.2-11.2 months vs. 5.6 months; 95% CI, 5.3-8.3 months; hazard ratio, 0.72; 95% CI, 0.54-0.97; P = .016).ConclusionsPalbociclib + letrozole provided significant clinical benefit versus placebo + letrozole to patients with ER⁺/HER2⁻ ABC regardless of achieving RECIST-defined OR.Pfizer; ClinicalTrials.gov: NCT01740427     

First-line Treatment of Metastatic Renal Cell Carcinoma in the Immuno-oncology Era: Systematic Review and Network Meta-analysis

Combination treatments with immuno-oncology (IO) agents and IO agents plus a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) have been approved for first-line treatment of patients with metastatic renal cell carcinoma (mRCC). No direct comparisons have been performed among these treatment options. We performed a systematic review and network meta-analysis to compare and rank the available regimens for first-line treatment in terms of survival benefit and efficacy. In accordance with the Preferred Reporting Items for Systematic Review statement, a systematic search of reported studies was performed in MEDLINE, the Cochrane Central Register of Controlled Trials, and EMBASE up to May 31, 2019. Network meta-analysis models were adjusted using the Bayesian method. Four randomized clinical trials, with a total of 3758 patients, met the inclusion criteria. Considering systemic therapy, 1880 patients had received sunitinib and 550, 432, 442, and 454 patients had received ipilimumab plus nivolumab (ipi + nivo), pembrolizumab plus axitinib (pembro + axi), avelumab plus axitinib (avelu + axi), and atezolizumab plus bevacizumab (atezo + bev). No difference was found in overall survival between ipi + nivo and pembro + axi for the intention to treat population (hazard ratio [HR], 1.34; 95% credible interval [CrI], 0.92-1.97). No difference was found in progression-free survival among the treatments. The overall response rate (ORR) was superior with pembro + axi and avelu + axi compared with the ORR with the other treatments (atezo + bev vs. pembro + axi: HR, 0.66; 95% CrI, 0.52-0.84; ipi + nivo vs. pembro + axi: HR, 0.73; 95% CrI, 0.59-0.90; atezo + bev vs. avelu + axi: HR, 0.55; 95% CrI, 0.43-0.71; avelu + axi vs. ipi + nivo: HR, 1.66; 95% CrI, 1.31-2.12), with no differences across them (HR, 1.21; 95% CrI, 0.95-1.53). In the present indirect comparison, for an intention to treat population, we found no survival differences between pembro + axi and ipi + nivo. All treatments showed better progression-free survival compared with sunitinib that was similar among them. The combination of an IO agent (pembrolizumab or avelumab) and axitinib seemed to be the most effective therapy for the ORR.     

Impact of tumor microenvironment on the efficacy of epidermal growth factor receptor‐tyrosine kinase inhibitors in patients with EGFR‐mutant non‐small cell lung cancer

We retrospectively investigated the impact of the tumor microenvironment (TME) on the efficacy of epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) as first‐line treatment in 70 patients with advanced EGFR‐mutant non‐small cell lung cancer and who were seen at Osaka City University Hospital (Osaka, Japan) between August 2013 and December 2017. Using immunohistochemical staining with 28‐8 and D7U8C Abs, the tumor proportion score was assessed for programmed cell death‐1 ligand‐1 (PD‐L1), as high (50% or more) or low (less than 50%), and ligand‐2 (PD‐L2) expression, respectively. The extent of CD8⁺ tumor‐infiltrating lymphocytes was evaluated on a scale of 0‐3, with 0‐1 as low and 2‐3 as high. The TME of the 52 evaluable pretreatment specimens was categorized into 4 subtypes, according to the respective PD‐L1 tumor proportion and CD8⁺ scores, as follows: (a) high/high (13.5%, n = 7); (b) low/low (42.3%, n = 22); (c) high/low (17.3%, n = 9); and (d) low/high (26.9%, n = 14). Expression of PD‐L2 was significantly the highest in type 1 (57.1% vs 4.5% vs 11.1% vs 7.1%, respectively; P = .0090). Response rate was significantly the lowest in type 1 (14.3% vs 81.8% vs 66.7% vs 78.6%, respectively; P = .0085). Progression‐free survival was the shortest in type 1 and the longest in type 4 (median, 2.4 vs 11.3 vs 8.4 vs 17.5 months, respectively; P = .00000077). The efficacy of EGFR‐TKIs differed according to the TME, and the phenotype with high PD‐L1 and CD8⁺ expression might be the subset that would poorly benefit from such treatment.     

Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4)

BackgroundRECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting.MethodsPatients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis.ResultsEnrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7–11.0]; in the cohorts, it was 5.7 months (95% CI 3.7–11.3) with previous sunitinib, 7.8 months (95% CI 5.7–11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6–not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0–NE) and, in the cohorts, it was 23.8 months (95% CI 13.7–NE) with previous sunitinib, 17.2 months (95% CI 11.9–NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9–NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug).ConclusionsThese results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience.Clinical trial name and identifierEverolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.     

Clinical Outcomes of First-line Sunitinib Followed by Immuno-oncology Checkpoint Inhibitors in Patients With Metastatic Renal Cell Carcinoma

BackgroundThe present retrospective, longitudinal cohort study assessed the association between the first-line sunitinib treatment duration and clinical outcomes with second-line immuno-oncology (IO) therapy among patients with metastatic renal cell carcinoma (mRCC).Patients and MethodsA total of 161 patients with mRCC who had been treated with first-line sunitinib and subsequent IO therapy from select International mRCC Database Consortium centers were included. The overall survival, time to next therapy, time to treatment discontinuation, and real-world physician-assessed best response measured from IO therapy initiation were analyzed and compared between patients treated with first-line sunitinib for ≥ 6 months and those treated for < 6 months.ResultsThe 116 patients treated with sunitinib for ≥ 6 months tended to be older and to have a better International mRCC Database Consortium risk than the 45 patients treated for < 6 months (favorable, 36% vs. 8%, P = .001; intermediate, 59% vs. 70%, P = .21; poor, 5% vs. 22%, P = .007). The receipt of sunitinib for ≥ 6 months versus < 6 months was associated with longer survival (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.21-0.87; P = .02). No significant association was observed between the first-line sunitinib duration and second-line IO outcomes, including the time to next therapy (HR, 0.89; 95% CI, 0.52-1.51; P = .66), time to treatment discontinuation (HR, 0.85; 95% CI, 0.54-1.34; P = .49), and tumor response (odds ratio, 0.73; 95% CI, 0.22-2.49; P = .62).ConclusionsWe found no statistically significant association between the first-line sunitinib duration and clinical outcomes with second-line IO therapy. Patients receiving first-line sunitinib for ≥ 6 months compared with < 6 months was associated with better overall survival, although potential unadjusted confounders could have been present. These findings support the paradigm that previous therapy will not dictate the effectiveness of subsequent immunotherapy.     

Long‐term efficacy and predictive correlates of response to nivolumab in Japanese patients with esophageal cancer

The long‐term efficacy of nivolumab in esophageal squamous cell carcinoma and its association with disease biomarkers are currently not well known. Therefore, we investigated the association in Japanese patients with treatment‐refractory advanced esophageal cancer who participated in an open‐label, single‐arm, multicenter phase II study. Patients received nivolumab 3 mg/kg i.v. every 2 weeks until disease progression or unacceptable toxicity, and were followed up for 2 years after the initial dosing of the last patient. Archival tissue samples were collected before treatment and analyzed for programmed death ligand‐1 (PD‐L1) and CD8⁺ status of tumors and tumor‐infiltrating lymphocytes (TILs) and human leukocyte antigen class 1. Efficacy end‐points included objective response rate (ORR), overall survival (OS), progression‐free survival (PFS), time to response, and duration of response. Of 65 enrolled patients (83% male), 64 were evaluable for efficacy and 41 (63%) for biomarkers. The ORR, median OS, and survival rate were 17.2%, 10.78 months, and 17.2%, respectively. Time to response was 1.45 months and duration of response was 11.17 months. The PD‐L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut‐off 1%) and OS (11.33 vs 6.24 months, cut‐off 1%). Median OS was prolonged in patients with a median number of TILs greater than 63.75% vs 63.75% or less (11.33 vs 7.85 months). Nivolumab showed continued long‐term efficacy, as seen by the stability of PFS and OS, in Japanese patients with esophageal squamous cell carcinoma. Further investigation of PD‐L1 tumor expression and TILs as potential biomarkers for predicting patients likely to benefit from nivolumab therapy is warranted.     

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE‐100

Interim results from the two‐cohort, phase 2 KEYNOTE‐100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4‐11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE‐100. Patients with epithelial ROC had received either 1‐3 prior chemotherapy lines and had platinum‐free interval or treatment‐free interval (PFI; TFI) of 3‐12 months (cohort A) or 4‐6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand‐1 (PD‐L1) tumor expression. The relationship between PD‐L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty‐one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37‐78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III‐IV disease. ORR was 19.0% (95% CI, 5.4‐41.9) and seemed to increase with increasing PD‐L1 expression. A total of 13 (61.9%) patients had treatment‐related adverse events (TRAE), and 5 (23.8%) had grade 3‐4 TRAE. There were no treatment‐related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD‐L1 expression among some patients with higher ORR.     

Prognostic value of programmed death‐ligand 1 expression in patients with stage III colorectal cancer

The programmed death‐1/programmed death‐ligand 1 (PD‐L1) pathway is a negative feedback pathway that suppresses the activity of T cells. Previous studies reported that high PD‐L1 expression on tumor cells (TC) was associated with poor survival in patients with colorectal cancer; however, the prognostic evaluation of these studies was limited because they included patients at various disease stages. The purpose of the present study was to evaluate the relationship between PD‐L1 status in the immune microenvironment and the clinicopathological features of stage III colorectal cancer. Two hundred and thirty‐five patients were included in the analysis. PD‐L1 expression on TC and tumor‐infiltrating mononuclear cells (TIMC) was evaluated by immunohistochemistry. The median follow‐up of thisi study was 52.9 months. A total of 8.1% of stage III colorectal cancer showed high PD‐L1 expression on TC and 15.3% showed high PD‐L1 expression on TIMC. Patients with high PD‐L1 expression on TC had significantly shorter disease‐free survival (DFS) than patients with low expression (hazard ratio [HR] 2.36; 95% confidence interval [CI], 1.21–4.62; P = 0.012). In addition, patients with high PD‐L1 expression on TIMC were associated with longer DFS than patients with low expression (HR 0.40; 95% CI, 0.16–0.98; P = 0.046). These findings suggest that PD‐L1 expression status may be a new predictor of recurrence for stage III colorectal cancer patients and highlight the necessity of evaluating PD‐L1 expression on TC and TIMC separately in the tumor microenvironment.     

PD‐L1 expression associated with worse survival outcome in malignant pleural mesothelioma

1 Aim

There is currently a need to identify prognostic biomarkers to assist in a risk adopted approach in treatment of malignant pleural mesothelioma (MPM). Expression of programmed death ligand 1 (PD‐L1) has been studied as a prognostic biomarker in a number of tumors given its central role in antitumoral immune response evasion. Four previously published analyses found PD‐L1 positivity to be an adverse survival prognostic factor in MPM. This study aims to further investigate the relationship between PD‐L1 expression in mesothelioma tissues and survival outcome.

2 Methods

Clinical data of MPM patients from a single institution between 2006 and 2016 were reviewed. Patient's archived tissues were stained with PD‐L1 (Clone Ventana SP263). PD‐L1 positivity was defined as > 1% membranous staining regardless of intensity.

3 Results

Data from fifty eight patients were analyzed. Median age was 73, majority was male (49, 84%) and had ECOG between 0 and 2 (46, 79%). Most common histopathological subtype was epithelioid (42, 72%), 9 (16%) biphasic subtype and 7 (12%) sarcomatoid. Thirty one patients (53%) received best supportive care and twenty seven patients (47%) received chemotherapy or combination treatment. Forty‐two patients had positive PD‐L1 expression (72.4%). The median survival time for PD‐L1 negative group is 15.5 months and 6 months for the positive group. Positive PD‐L1 expression is independently correlated with worse prognosis (HR = 2.02; 95% CI, 1.005–4.057; P‐value = 0.0484).

4 Conclusions

Our analysis found a higher percentage of MPM patients with positive PD‐L1 (> 1%) compared to other studies. Highly positive PD‐L1 expression was associated with statistically significantly lower median survival time.     

Five-Year Survival in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma Treated With Axitinib

BackgroundIn a phase II study of axitinib for cytokine-refractory metastatic renal cell carcinoma, median overall survival (OS) was 29.9 months (95% CI, 20.3 to not estimable months).Patients and MethodsLong-term survival data were collected retrospectively from 52 patients with cytokine-refractory metastatic renal cell carcinoma who received axitinib in a completed phase II study (protocol 1), 11 of whom enrolled in a continuing access protocol (protocol 2), for the current observational study (protocol 3). In a post hoc analysis, the patients were grouped into quartiles based on cycle 1 day 1, 1- to 2-hour post-dose axitinib plasma levels to explore the impact of drug exposure on efficacy.ResultsThe 5-year survival rate was 20.6% (95% CI, 10.9%-32.4%), with a median follow-up of 5.9 years. Frequent all-grade adverse events were fatigue (n = 38; 73.1%), diarrhea (n = 34; 65.4%), hypertension (n = 33; 63.5%), and nausea (n = 33; 63.5%). Quartile 3 patients (axitinib level, 45.2-56.4 ng/mL; n = 12) had the best clinical outcome: objective response rate 82%, median progression-free survival (PFS) 28.3 months, and median OS that was not reached after 5 years.ConclusionsAxitinib was well tolerated and provided an estimated 5-year survival rate of 20.6% for cytokine-refractory metastatic renal cell carcinoma. Exploratory analyses showed numerically higher objective response rate and longer OS and PFS in patients who achieved post–first-dose axitinib plasma concentrations within a specific range.     

Pembrolizumab in advanced renal cell carcinoma: a meta-analysis providing level 1a evidence

The recent introduction of immunotherapy in the first line setting of advanced renal cell carcinoma (aRCC) has dramatically improved patients’ prognosis. The aim of the current meta-analysis was to provide level 1a evidence supporting the use of pembrolizumab plus tyrosine kinase inhibitors (TKI) as first-line treatment for advanced RCC. All published randomized prospective trials including patients with advanced RCC treated with pembrolizumab in combination with TKIs vs Sunitinib were included in this meta-analysis. An algorithm was used to reconstruct survival data from the published Kaplan-Meier curves of overall survival (OS), progression free survival (PFS) and duration of response (DoR) from the included trials. Restricted mean survival time (RMST) with 95% confidence interval (CI) for comparison among the different regimens was calculated. Main outcomes were differences in RMST for OS, PFS and DoR for pembrolizumab plus TKIs vs sunitinib arm. Reconstructed survival data from 1,573 patients were retrieved from 2 trials (KEYNOTE-581 and KEYNOTE-426) comparing pembrolizumab plus TKI (lenvatinib or axitinib, respectively) to sunitinib. Patients who received pembrolizumab-lenvatinib or pembrolizumab-axinitinib had better OS (24-month ΔRMST of 1.79 months [95% CI: 0.12-2.50; P < 0.001]), PFS (24-month ΔRMST of 3.83 months [95% CI: 2.93-4.74; P < 0.001]) and DoR (24-month ΔRMST of 2.32 months [95% CI: 0.97-3.67; P < 0.001]) relative to sunitinib. Pembrolizumab-lenvatinib combination gave a marginal benefit in terms of OS, PFS and DoR relative to pembrolizumab-axitinib group. By relying on individual survival data, we provided a level-1a evidence supporting the use of pembrolizumab plus TKI for first-line aRCC treatment.