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.     

Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non‐small cell lung cancer harboring activating EGFR mutations: Subgroup analysis of LUX‐Lung 3

In LUX‐Lung 3, afatinib significantly improved progression‐free survival (PFS) versus cisplatin/pemetrexed in EGFR mutation‐positive lung adenocarcinoma patients and overall survival (OS) in Del19 patients. Preplanned analyses in Japanese patients from LUX‐Lung 3 were performed. Patients were randomized 2:1 to afatinib or cisplatin/pemetrexed, stratified by mutation type (Del19/L858R/Other). Primary endpoint was PFS (independent review). Secondary endpoints included OS, objective response, and safety. Median PFS (data cut‐off: February 2012) for afatinib versus cisplatin/pemetrexed was 13.8 vs 6.9 months (hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20–0.70; P = 0.0014) in all Japanese patients (N = 83), with more pronounced improvements in those with common mutations (Del19/L858R; HR, 0.28; 95% CI, 0.15–0.52; P < 0.0001) and Del19 mutations (HR, 0.16; 95% CI, 0.06–0.39; P < 0.0001). PFS was also improved in L858R patients (HR, 0.50; 95% CI, 0.20–1.25; P = 0.1309). Median OS (data cut‐off: November 2013) with afatinib versus cisplatin/pemetrexed was 46.9 vs 35.8 months (HR, 0.75; 95% CI, 0.40–1.43; P = 0.3791) in all Japanese patients, with greater benefit in patients with common mutations (HR, 0.57; 95% CI, 0.29–1.12; P = 0.0966) and Del19 mutations (HR, 0.34; 95% CI, 0.13–0.87; P = 0.0181); OS was not significantly different in L858R patients (HR, 1.13; 95% CI, 0.40–3.21; P = 0.8212). Following study treatment discontinuation, most patients (93.5%) received subsequent anticancer therapy. The most common treatment‐related adverse events were diarrhea, rash/acne, nail effects and stomatitis with afatinib and nausea, decreased appetite, neutropenia, and leukopenia with cisplatin/pemetrexed. Afatinib significantly improved PFS versus cisplatin/pemetrexed in Japanese EGFR mutation‐positive lung adenocarcinoma patients and OS in Del19 but not L858R patients ( www.clinicaltrials.gov ; NCT00949650).     

Daratumumab,Bortezomib, and Dexamethasone versus Bortezomib and Dexamethasone in Chinese Patients With Relapsed or Refractory Multiple Myeloma: Updated Analysis of LEPUS

BackgroundIn the phase 3 LEPUS study, daratumumab, bortezomib, and dexamethasone (D-Vd) demonstrated significant clinical benefit versus Vd alone in Chinese patients with relapsed or refractory multiple myeloma (RRMM). Here, we report updated efficacy and safety results from LEPUS.Patients and MethodsChinese patients with ≥ 1 prior line of therapy were randomized 2:1 to bortezomib (1.3 mg/m²) and dexamethasone (20 mg) for eight cycles ± daratumumab (16 mg/kg) until disease progression. The primary endpoint was progression-free survival (PFS).ResultsIn total, 211 patients were randomized to D-Vd (n = 141) or Vd (n = 70). At a 25.1-month median follow-up, D-Vd prolonged PFS versus Vd (median, 14.8 vs. 6.3 months; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.51; P < .00001). PFS benefit of D-Vd versus Vd was maintained across prespecified subgroups, including patients with prior bortezomib (HR, 0.36; 95% CI, 0.25-0.53), patients who were refractory to last prior line of therapy (HR, 0.42; 95% CI, 0.27-0.65), and patients with high-risk cytogenetics (HR, 0.41; 95% CI, 0.23-0.71). Overall response rate (84.7% vs.66.7%; P = .00314) and rates of very good partial response or better (71.5% vs. 34.9%; P < .00001) and complete response or better (40.1% vs 14.3%; P = .00016) were higher with D-Vd versus Vd. No new safety concerns were identified.ConclusionsIn this updated analysis, D-Vd maintained significant efficacy benefits versus Vd alone and demonstrated a consistent safety profile, further supporting the use of D-Vd as a standard of care in Chinese patients with RRMM.     

Frontline treatment for transplant‐eligible multiple myeloma: A 6474 patients network meta‐analysis

Autologous transplantation continues to be the cornerstone of younger and fit multiple myeloma patients. It is known that frontline induction therapy before transplantation can influence post‐transplant results. Therefore, best frontline treatment for transplant‐eligible patients should be based on best available evidence to guide therapy. Furthermore, until now due to data scarcity, it was not possible to thoroughly compare lenalidomide to other regimens in this setting. We performed a systematic review and network (mixed treatment comparison) meta‐analysis of 21 clinical trial publications, enrolling 6474 patients and comparing 11 different treatment frontline setting regimens regarding survival, response, and safety outcomes. OS analysis showed superiority of CRD (cyclophosphamide‐lenalidomide‐dexamethasone) over TD‐based (thalidomide‐dexamethasone, HR = 0.76,0.62‐0.90), VAD‐based (HR = 0.71,0.52‐0.90), and Z‐Dex (idarubicin‐dexamethasone, HR = 0.37,0.17‐0.76) regimens. Concerning PFS, VTD (bortezomib‐thalidomide‐dexametasone) showed superior results when compared with TD‐based (HR = 0.66,0.51‐0.84), VAD‐based (HR = 0.61,0.46‐0.82), Z‐Dex (HR = 0.42,0.22‐0.78), and high dose dexamethasone (Dex, HR = 0.62,0.41‐0.90) regimens. Bortezomib/thalidomide regimens were not superior to lenalidomide, considering these outcomes. Also, concerning complete and overall response, VTD ranked first among other regimens, showing clear superiority over thalidomide‐only containing protocols. Safety outcome evaluated infectious, cardiac, gastrointestinal, neurological, thrombotic, and hematological grade 3 to 4 adverse events. Risk of thrombotic events was higher with TAD (thalidomide‐doxorubicin‐dexamethasone), neurological with PAD (bortezomib‐doxorubicin‐dexamethasone), infectious with Dex, hematological with Z‐Dex, gastrointestinal with VTD, and cardiac with PAD regimens. Our study endorses current recommendations on combined immunomodulatory drugs and proteasome inhibitors frontline regimens (in triplets) in transplant‐eligible multiple myeloma patients, but also formally demonstrates the favorable performance of lenalidomide in overall and progression‐free survival, when compared with bortezomib/thalidomide protocols.     

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.

     

Safe and prolonged survival with long-term exposure to pomalidomide in relapsed/refractory myeloma

BackgroundThe IFM2009-02 trial studied pomalidomide (4 mg daily, 21/28 versus 28/28) and dexamethasone in very advanced relapsed or refractory multiple myeloma (RRMM). We observed that 40% of patients had a prolonged progression-free survival (PFS) and subsequently overall survival (OS). We sought to analyze the characteristics of these patients and study the effect of long exposure to pomalidomide.DesignWe separated the studied population into two groups: 3 months to 1 year (<1 year) and more than 1 year (≥1 year) of treatment with pomalidomide and dexamethasone based on clinical judgment and historical control studies. We then analyzed the characteristics of patients according to duration of treatment.ResultsThe overall response rate (ORR) for the <1-year group was 43%, the median PFS 4.6 months [95% confidence interval (95% CI) 3.8–6.4] with only 6% at 12 months, and the median OS was 15 months (11.7–20.3) and 40% at 18 months. For the ≥1-year group, the response rate and survival were strikingly different, ORR at 83%, median PFS 20.7 months (14.7–35.4), median OS not reached, and 91% at 18 months.ConclusionPomalidomide and dexamethasone favored prolonged and safe exposure to treatment in 40% of heavily treated and end-stage RRMM, a paradigm shift in the natural history of RRMM characterized with a succession of shorter disease-free intervals and ultimately shorter survival. Although an optimization of pomalidomide–dexamethasone regimen is warranted in advanced RRMM, we claim that pomalidomide has proven once more to change the natural history of myeloma in this series, which should be confirmed in a larger study.     

Meta-analysis in metastatic uveal melanoma to determine progression free and overall survival benchmarks: an international rare cancers initiative (IRCI) ocular melanoma study

BackgroundDespite the completion of numerous phase II studies, a standard of care treatment has yet to be defined for metastatic uveal melanoma (mUM). To determine benchmarks of progression free survival (PFS) and overall survival (OS), we carried out a meta-analysis using individual patient level trial data.MethodsIndividual patient variables and survival outcomes were requested from 29 trials published from 2000 to 2016. Univariable and multivariable analysis were carried out for prognostic factors. The variability between trial arms and between therapeutic agents on PFS and OS was investigated.ResultsOS data were available for 912 patients. The median PFS was 3.3 months (95% CI 2.9–3.6) and 6-month PFS rate was 27% (95% CI 24–30). Univariable analysis showed male sex, elevated (i.e. > versus ≤ upper limit of normal) lactate dehydrogenase (LDH), elevated alkaline phosphatase (ALP) and diameter of the largest liver metastasis (≥3 cm versus <3 cm) to be substantially associated with shorter PFS. Multivariable analysis showed male sex, elevated LDH and elevated ALP were substantially associated with shorter PFS. The most substantial factors associated with 6-month PFS rate, on both univariable and multivariable analysis were elevated LDH and ALP. The median OS was 10.2 months (95% CI 9.5–11.0) and 1 year OS was 43% (95% CI 40–47). The most substantial prognostic factors for shorter OS by univariable and multivariable analysis were elevated LDH and elevated ALP. Patients treated with liver directed treatments had statistically significant longer PFS and OS.ConclusionBenchmarks of 6-month PFS and 1-year OS rates were determined accounting for prognostic factors. These may be used to facilitate future trial design and stratification in mUM.     

Targeting complete response with upfront bortezomib consolidation versus observation after the achievement of complete response following autologous transplantation for multiple myeloma (TUBA study)

Complete response (CR) after treatment for multiple myeloma is associated with superior progression‐free survival (PFS). Multiple myeloma patients were prospectively recruited for induction treatment with bortezomib and dexamethasone (BD) followed by autologous hematopoietic cell transplantation (auto‐HCT) between 2010 and 2012. If patients did not achieve CR after auto‐HCT, BD consolidation therapy was added to target CR. After the BD induction phase (n = 46), greater than or equal to CR was achieved in 4 patients (8%). After auto‐HCT (n = 34), greater than or equal to CR was achieved in 9 patients (20%) and very good partial response (VGPR) was achieved in 11 (24%). Of the 24 patients who received auto‐HCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses. Finally, the maximum response with or without BD consolidation was greater than or equal to CR in 19 (41%), VGPR in 7 (15%), and PR in 6 (13%). Through BD consolidation, CR was achieved in 8 of 11 patients with post‐HCT VGPR and in 2 of 12 patients with post‐HCT PR. In total, 4 year PFS and overall survival were 43 and 80%, respectively. After adjusting for clinical factors, there was no difference in PFS between CR patients after auto‐HCT and BD consolidation, while patients with less than or equal to VGPR after consolidation had a significantly lower PFS. Patients with post‐HCT CR showed good PFS, and targeting CR through BD consolidation could improve the CR rate. It would be worthwhile to prospectively compare the efficacy of consolidation only for patients who failed to achieve CR to a universal consolidation strategy.     

First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric,gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis

First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.     

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.     

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.     

Four-Year Survival With Durvalumab After Chemoradiotherapy in Stage III NSCLC—an Update From the PACIFIC Trial

IntroductionIn the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53–0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42–65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized.MethodsPatients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan–Meier method.ResultsOverall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2–64.9), updated OS (HR = 0.71; 95% CI: 0.57–0.88) and PFS (HR = 0.55; 95% CI: 0.44–0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively.ConclusionThese updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%).     

Carfilzomib in relapsed or refractory multiple myeloma patients with early or late relapse following prior therapy: A subgroup analysis of the randomized phase 3 ASPIRE and ENDEAVOR trials

We performed analyses of the randomized phase 3 ASPIRE and ENDEAVOR trials to investigate the efficacy of carfilzomib among subgroups of relapsed or refractory multiple myeloma patients who had early or late disease relapse following initiation of the immediately prior therapy. In ASPIRE and ENDEAVOR, patients had received 1 to 3 prior lines of therapy. Patients in ASPIRE received carfilzomib, lenalidomide, and dexamethasone (KRd) or lenalidomide and dexamethasone (Rd), and patients in ENDEAVOR received carfilzomib and dexamethasone (Kd) or bortezomib and dexamethasone (Vd). Patients with relapse ≤1 year after initiating the most recent prior line of therapy were categorized as early relapsers, and patients with relapse after >1 year were categorized as late relapsers. The median progression‐free survival (PFS) in ASPIRE for early relapsers was 21.4 months for KRd vs 10.7 months for Rd (hazard ratio [HR]: 0.714; 95% confidence interval [CI]: 0.508–1.004; P = 0.0257), and for late relapsers was 29.7 months for KRd vs 18.2 months for Rd (HR: 0.675; 95% CI: 0.533–0.854; P = 0.0005). The overall response rate (ORR) for early relapsers was 83.2% for KRd vs 54.8% for Rd, and for late relapsers was 89.0% for KRd vs 69.7% for Rd. The median PFS in ENDEAVOR (Kd vs Vd) for early relapsers was 13.9 months vs 5.7 months (HR: 0.598; 95% CI: 0.423–0.846; P = 0.0017), and for late relapsers was 22.2 months vs 10.2 months (HR: 0.486; 95% CI: 0.382–0.620; P < 0.0001). The ORR (Kd vs Vd) for early relapsers was 63.4% vs 49.1% and for late relapsers was 81.8% vs 66.8%. In conclusion, patients with relapsed or refractory multiple myeloma who received carfilzomib‐containing regimens had improved PFS and ORR compared with control groups, regardless of whether they had an early or late relapse following the most recent prior therapy.     

Gemcitabine–erlotinib versus gemcitabine–erlotinib–capecitabine in the first-line treatment of patients with metastatic pancreatic cancer: Efficacy and safety results of a phase IIb randomised study from the Spanish TTD Collaborative Group

BackgroundGemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC.Patients and methodsPreviously untreated mPC patients were randomised to receive G (1000 mg/m², days 1, 8, 15) + E (100 mg/day, days 1–28) + C (1660 mg/m², days 1–21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety.Results120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine–erlotinib–capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58–1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72–1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26–0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33–0.77; p = 0.0014).ConclusionPFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy.The study was registered with ClinicalTrials.gov: NCT01303029.     

First-line nab-paclitaxel plus carboplatin for patients with advanced non-small cell lung cancer: Final results of the NEPTUN study

Real-world data on the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) are still limited. The NEPTUN study evaluated effectiveness and safety of first-line nab-paclitaxel (Abraxane) plus carboplatin (nab-P/C) in patients with advanced NSCLC in routine clinical practice in Germany. Patients included in our study were aged ≥18 years, diagnosed with locally advanced or metastatic NSCLC and with decision for first-line nab-P/C in routine clinical practice. Primary objective was 6-month progression-free survival rate (PFS6), secondary objectives included overall survival (OS), overall response rate (ORR) and safety. From 2016 to 2019, 408 patients from 75 sites were enrolled. PFS6 was 39.5% (95% CI: 34.2-44.8), median PFS was 5.1 months (95% CI: 4.6-5.6), ORR was 42.9% (95% CI: 37.7-48.2). Median OS was 10.5 months (95% CI: 9.2-11.6). In subgroup analyses, median OS for squamous vs non-squamous histology was 11.5 months (95% CI: 9.2-13.8) vs 9.8 months (95% CI: 8.1-11.3) and for patients aged ≥70 vs <70 years median OS was 12.4 months (95% CI: 9.8-15.1) vs 9.6 months (95% CI: 7.7-11.1). Adverse events (AEs) related to nab-paclitaxel were reported in 247 (66.4%) patients, while carboplatin-related AEs were documented in 224 (60.2%) patients. Most frequently related AEs were leukopenia (22.3%) for nab-paclitaxel and anemia (20.2%) for carboplatin. Nab-P/C-related deaths were reported in 2 (0.5%) patients (sepsis and neutropenic sepsis). No new or unexpected safety signals emerged. These results support the effectiveness and safety of first-line nab-P/C in patients with advanced NSCLC reported in the pivotal trial and highlight the clinical value of this regimen in the real-world setting.     

CODEL: phase III study of RT,RT + TMZ,or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design

BackgroundWe report the analysis involving patients treated on the initial CODEL design.MethodsAdults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm.ResultsThirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months.ConclusionsTMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.     

Randomized study of FOLFIRI plus either panitumumab or bevacizumab for wild‐type KRAS colorectal cancer‐WJOG 6210G

This randomized phase II trial compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with bevacizumab plus FOLFIRI as second‐line chemotherapy for wild‐type (WT) KRAS exon 2 metastatic colorectal cancer (mCRC) and to explore the values of oncogenes in circulating tumor DNA (ctDNA) and serum proteins as predictive biomarkers. Patients with WT KRAS exon 2 mCRC refractory to first‐line chemotherapy containing oxaliplatin and bevacizumab were randomly assigned to panitumumab plus FOLFIRI or bevacizumab plus FOLFIRI. Of 121 randomly assigned patients, 117 were eligible. Median overall survival (OS) for panitumumab plus FOLFIRI and bevacizumab plus FOLFIRI were 16.2 and 13.4 months [hazard ratio (HR), 1.16; 95% CI, 0.76–1.77], respectively. Progression‐free survival (PFS) was also similar (HR, 1.14; 95% CI, 0.78–1.66). KRAS, NRAS, and BRAF status using ctDNA was successfully examined in 109 patients, and mutations were identified in 19 patients (17.4%). Panitumumab plus FOLFIRI showed favorable survival compared with bevacizumab plus FOLFIRI in WT patients and unfavorable survival in those with mutations (P for interaction = 0.026 in OS and 0.054 in PFS). OS with bevacizumab plus FOLFIRI was better than panitumumab plus FOLFIRI in patients with high serum vascular endothelial growth factor‐A (VEGF‐A) levels and worse in those with low levels (P for interaction = 0.016). Second‐line FOLFIRI plus panitumumab and FOLFIRI plus bevacizumab showed a similar efficacy in patients with WT KRAS exon 2 mCRC. RAS and BRAF mutation in ctDNA could be a negative predictive marker for panitumumab.     

A randomised phase II study of continuous versus stop-and-go S-1 plus oxaliplatin following disease stabilisation in first-line chemotherapy in patients with metastatic gastric cancer

ObjectivesWe compared continuous versus stop-and-go chemotherapy after disease stabilisation with induction chemotherapy in the first-line treatment of metastatic gastric cancer (MGC).MethodsMGC patients who achieved disease control after 6 cycles of S-1/oxaliplatin (SOX) were randomised to receive either continuous SOX until progression (continuous arm) or to have a chemotherapy-free interval followed by SOX reintroduction at progression (stop-and-go arm). The primary end-point was overall survival (OS).ResultsOf the 250 patients enrolled, 247 participated in the induction phase. Of these, 121 patients were randomised to the continuous arm (n = 59) or the stop-and-go arm (n = 62). Progression-free survival (PFS) was significantly longer in the continuous arm than in the stop-and-go arm (10.5 versus 7.2 months; hazard ratio [HR] 0.55, 95% CI, 0.37–0.81; P = 0.002). Duration of disease control (DDC) and OS, however, were comparable between the two arms: median DDC, 10.5 versus 11.3 months, HR 0.92 (95% CI, 0.62–1.36; P = 0.674); median OS, 22.6 versus 22.7 months, HR 0.78 (95% CI, 0.50–1.23; P = 0.284). Adverse events including grade ≥3 fatigue (28.8% versus 8.1%; P = 0.003) and sensory neuropathy (25.4% versus 9.7%; P = 0.022) occurred more frequently in the continuous arm than in the stop-and-go arm. Quality of life (QOL) including global health status, physical/role functioning and other symptom scores significantly favoured the stop-and-go arm.ConclusionCompared with the stop-and-go strategy, maintenance chemotherapy improved PFS but not DDC and OS and had a negative impact on QOL, suggesting the stop-and-go strategy may be an appropriate option in MGC patients following induction chemotherapy.     

Abituzumab combined with cetuximab plus irinotecan versus cetuximab plus irinotecan alone for patients with KRAS wild-type metastatic colorectal cancer: the randomised phase I/II POSEIDON trial

BackgroundIntegrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part).MethodsEligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed.ResultsPhase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78–1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77–1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54–1.28); arm B versus SoC, HR 0.80 (95% CI 0.52–1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A [HR 0.55 (0.30–1.00)] and B [HR 0.41 (0.21–0.81)] than in arm C.ConclusionThe primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted.ClinicalTrials.gov identifierNCT01008475     

Impact of the introduction of rituximab in first‐line follicular lymphoma: a retrospective study of 247 unselected patients referred to a single institution with a long‐term follow‐up

Rituximab was approved in France in 2004, following randomized trials that demonstrated efficacy in newly diagnosed high tumour burden follicular lymphoma (FL). This retrospective study compared the management and outcome of FL in unselected patients treated in a single institution before and after rituximab approval. Two hundred and forty‐seven adult patients were referred with first‐line FL between 1996 and 2010 and are included in this study. The 103 pre‐rituximab patients comprising cohort 1 were diagnosed between January 1996 and December 2003; cohort 2 includes the 144 patients diagnosed after the approval of rituximab between January 2004 and December 2010. Baseline clinical and biological data, type of therapy, treatment response, progression‐free survival (PFS) and overall survival (OS) rates were compared. There were no statistically significant differences between the two cohorts with respect to baseline clinical and disease characteristics, including FL International Prognostic Index score. The major difference between the two cohorts is the use of rituximab in first line. Seventy‐one per cent of patients in cohort 2 received rituximab (19% alone, 52% with chemotherapy) versus 10% in cohort 1 (2% alone, 8% with chemotherapy; p < 0.0001). The objective response rate (ORR) was significantly higher for cohort 2 (ORR 84% compared with 72% for cohort 1; p = 0.03). The PFS and OS rates were also significantly better: 3‐year PFS 72% [95% confidence interval (CI) 64–80%] versus 55% (95% CI 45–64%), p = 0.0039 and 3‐year OS 98% (95% CI 94–99%) versus 83% (95% CI 74–90%), p = 0.0007. Effect of period of study is significant when using multivariate analysis on PFS and OS and lactate dehydrogenase level (PFS and OS) and age (OS). These data from everyday practice confirm the benefit for patients with FL treated in the last decade through availability of rituximab in first line used alone or in association with various chemotherapy regimens. Copyright © 2014 John Wiley & Sons, Ltd.