Median First-line Progression-free Survival Research Articles

Real-World Survival Outcomes of First-Line Therapies in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis from Two Centres in Saudi Arabia.

Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3-14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4-12.4), combination ICI group (9.0 months; 95% CI: 0.0-24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6-39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9-69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0-71.7), the combination ICI group, 42.0 months (95% CI: 0.06-84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2-26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3-57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5-55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs.

Relationship between immune-inflammatory markers and clinical features and deepness of tumor response and prognosis of patients with PD-L1 ≥50% metastatic NSCLC receiving first-line immunotherapy.

e14547 Background: Patients with programmed cell death-ligand 1 (PD-L1) ≥50% metastatic non-small cell lung cancer (NSCLC) treated with first-line immunotherapy have heterogeneous clinical assessment and outcomes. In this study, we sought to identify features of patients with metastatic NSCLC who achieved high deepness of response (HDPR) to first-line immunotherapy, and how these might differ from features predictive of non-high deepness of response (NHDPR). The influence of clinical features on prognosis of patients with PD-L1 ≥50% were further clarified. Methods: This retrospective study analyzed patients with PD-L1≥50% metastatic NSCLC treated with first-line immunotherapy at Beijing Tiantan Hospital between July 2020 and December 2023. All the patients had at least one measurable lesion in lung according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. HDPR was defined as deepness of lung tumor response ≥50%, while NHDPR was defined as deepness of lung tumor response &lt;50% or tumor enlargement. Tumor PD-L1 expression, target mutation, neutrophil-to-lymphocyte ratio (NLR), lactic dehydrogenase (LDH) level, and other prognostic variables were analyzed to identify characteristics enriched in patients achieving HDPR compared to NHDPR. We also investigated the effects of these variables on first-line progression-free survival (PFS) and overall survival (OS) of the patients. Results: A total of 17 patients were included in our retrospective analysis. Seven (41.2%) patients achieved HDPR (range: -50%, -72%) and ten (58.8%) patients achieved NHDPR (range: -13%, -45%). Seven (41.2%) patients had central nervous system (CNS) metastases at the first diagnosis of lung malignancy, and their CNS target lesions shrinkages were observed after therapy (range: -32%, -100%). Lower Th/Ts ratio ( P=0.01) and drug resistance mutations (TP53/KRAS/EGFR) ( P=0.001) were found enriched for NHDPR compared to HDPR. However, no differences were found in tumor PD-L1 expression, NLR, LDH, B lymphocyte subset, NK cell subset, pathological type, T-stage, smoking index, ECOG score, immunotherapeutic schemes, or CNS metastases between the two groups ( P&gt;0.05). With a median follow-up of 26.0 months (range: 17.2-34.8 months), the median first-line PFS and OS were 9.0 months (95% CI: 5.0-13.0) and not reached (NR), respectively. The NLR was identified as an independent prognostic factor on first-line PFS. Patients with an NLR≥4 exhibited a worse median PFS (7.0 months vs. NR; P=0.033; 95%CI: 1.2-80.2) than those with an NLR&lt;4 following first-line immunotherapy. Conclusions: Among patients with PD-L1≥50% metastatic NSCLC who received first-line immunotherapy, lower Th/Ts ratio and drug resistance mutations showed a diminished tumor response and higher NLR ratio exhibited a worse median PFS.

Early onset metastatic colorectal cancer in Australia

BackgroundColorectal cancer (CRC) incidence and mortality rates have been increasing among young patients (YP), for uncertain reasons. It is unclear whether YP have a distinct tumor biology or merit a different treatment approach to older patients (OP). MethodsWe reviewed prospectively collected data from consecutive patients with metastatic CRC (MCRC) enrolled in the multi-site Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) Australian registry. Clinicopathological features, treatment and survival outcomes were compared between YP (<50 years) and OP (≥50 years). ResultsOf 3692 patients diagnosed August 2009 - March 2023, 14 % (513) were YP. YP were more likely than OP to be female (52% vs. 40 %, P < 0.0001), have ECOG performance status 0–1 (94% vs. 81 %, P < 0.0001), to have a left-sided primary (72% vs. 63 %, P = 0.0008) and to have fewer comorbidities (90% vs. 60 % Charleston score 0, P < 0.0001). There were no differences in the available molecular status, which was more complete in YP. YP were more likely to have de novo metastatic disease (71% vs. 57 %, P < 0.0001). YP were more likely to undergo curative hepatic resection (27% vs. 17 %, P < 0.0001), to receive any chemotherapy (93% vs. 78 % (P < 0.0001), and to receive 3+ lines of chemotherapy (30% vs. 24 % (P < 0.0034)). Median first-line progression free survival (10.2 versus 10.6 months) was similar for YP vs OP, but overall survival (32.1 versus 25.4 months, HR = 0.745, P < 0.0001) was longer in YP. ConclusionKnown prognostic variables mostly favored YP versus OP with newly diagnosed mCRC, who were also more heavily treated. Consistent with this, overall survival outcomes were improved. This data does not support that CRC in YP represent a distinct subset of mCRC patients, or that a modified treatment approach is warranted.

Comprehensive characterization of genomic features and clinical outcomes following targeted therapy and secondary cytoreductive surgery in OCCC: a single center experience.

Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.

Outcome of Second Line Treatment of Recurrent High- Grade Glioma by re-Irradiation or Bevacizumab-based Chemotherapy: A Cross Sectional Study.

Currently, there is no standard of treatment for the management of the recurrent high-grade glioma. Re-resection, re-irradiation, and chemotherapy are among main treatment options without any proven efficacy. To compare the outcome of second line treatment of recurrent high-grade glioma by re-irradiation or bevacizumab-based chemotherapy. Retrospectively, patients with the recurrent high-grade glioma treated by re-irradiation (ReRT group) (34 patients) or bevacizumab-based chemotherapy (Bev group) (40 patients) as the first-file after the first recurrence were compared in term of first-line progression free survival (PFS), second-line PFS, and overall survival (OS). Both groups were similar in term of gender (p=0.859), age (=0.071), type of first-line treatment (p=0.227), and performance status (p=0.150). With a median follow-up of 31 months (m), mortality rate was 41.2% and 70% in the ReRT and Bev groups, respectively. In the Bev and ReRT groups, median OS was 27 m (95% confidence interval (CI) 20-33.9 m) vs. 132 m (95% CI 52.9-211 m) (p<0.0001), median first-line PFS was 11 m (95% CI 7.14-28.7 m) vs. 37 m (95% CI 8.42-65.75 m) (p<0.0001), and median second-line PFS was 7 m (95% CI 3.9-10 m) vs. 9 m (95% CI 5.5-12.4 m) (p=0.564), respectively. The PFS is similar after the second line treatment of recurrent primary central nervous system malignancies either by re-irradiation or bevacizumab-based chemotherapy.

Association of Endocrine Therapy for HR+/ERBB2+ Metastatic Breast Cancer With Survival Outcomes

Evidence suggests that patients with human epidermal growth factor receptor 2-positive (ERBB2+ [formerly HER2+]) metastatic breast cancer (MBC) have different clinical characteristics and outcomes according to their hormone receptor (HR) status. The place of endocrine therapy (ET) for patients with HR+/ERBB2+ is still not clearly defined in this setting. To evaluate the association of HR status and first-line inclusion of ET with outcomes among patients with ERBB2+ MBC. This cohort study was an analysis of clinical data from the French clinical Epidemiological Strategy and Medical Economics (ESME) cohort, including patients with MBC who started treatment between 2008 and 2017. The last date of follow-up was June 18, 2020. Data were analyzed from May 2021 to May 2022. Patients were treated with first-line ERBB2-targeted therapy and either chemotherapy (CT) with or without ET or ET alone. For the study of the association of maintenance ET with outcomes, we included patients treated with first-line ERBB2-targeted therapy with CT and with or without maintenance ET. Median overall survival (OS) and median first-line progression-free survival (PFS) were reported using the Kaplan-Meier method. Cox proportional hazards models and a propensity score were constructed to report and adjust for prognostic factors. Multivariable analysis included age at MBC, time to MBC, number of metastatic sites, type of metastases, and Eastern Cooperative Oncology Group performance status. Among 4145 women with ERBB2+ MBC, 2696 patients had HR+ (median [IQR] age, 58.0 [47.0-67.0] years) and 1449 patients had HR- (56.0 [47.0-64.0] years) tumors. The median OS for patients with HR+ vs HR- tumors was 55.9 months (95% CI, 53.7-59.4 months) vs 42.0 months (95% CI, 38.8-45.2 months), confirmed in multivariable analysis (hazard ratio, 1.40; 95% CI, 1.26-1.56; P < .001). The median PFS for patients with HR+ vs HR- tumors was 12.2 months (95% CI, 11.5-12.9 months) vs 9.8 months (95% CI, 9.2-11.0 months; P = .01), and the HR was 1.15 (95% CI, 1.06-1.26; P < .001). In multivariable analysis, no significant difference was found in OS or PFS for 1520 patients treated with ERBB2-targeted therapy with CT and with or without ET vs 203 patients receiving ERBB2-targeted therapy with ET, regardless of type of ERBB2-targeted therapy (trastuzumab or trastuzumab with pertuzumab). This result was confirmed by matching patients using a propensity score. Using the time-dependent ET variable among patients with ERBB2-targeted therapy with CT, those with maintenance ET had significantly better PFS (hazard ratio, 0.70; 95% CI, 0.60-0.82; P < .001) and OS (hazard ratio, 0.47; 95% CI, 0.39-0.57; P < .001). These results suggest that ET-containing first-line regimens may be associated with benefits among a subgroup of patients with HR+/ERBB2+ MBC.

Outcomes of Patients with Metastatic Castration-Resistant Prostate Cancer According to Somatic Damage DNA Repair Gene Alterations.

(1) Background: In literature, approximately 20% of mCRPC present somatic DNA damage repair (DDR) gene mutations, and their relationship with response to standard therapies in mCRPC is not well understood. The objective was to evaluate outcomes of mCRPC patients treated with standard therapies according to somatic DDR status. (2) Methods: Eighty-three patients were recruited at Caen Cancer Center (France). Progression-free survival (PFS) after first-line treatment was analyzed according to somatic DDR mutation as primary endpoint. PFS according to first exposure to taxane chemotherapy and PFS2 (time to second event of disease progression) depending on therapeutic sequences were also analyzed. (3) Results: Median first-line PFS was 9.7 months in 33 mutated patients and 8.4 months in 50 non-mutated patients (p = 0.9). PFS of first exposure to taxanes was 8.1 months in mutated patients and 5.7 months in non-mutated patients (p = 0.32) and significantly longer among patients with ATM/BRCA1/BRCA2 mutations compared to the others (10.6 months vs. 5.5 months, p = 0.04). PFS2 was 16.5 months in mutated patients, whatever the sequence, and 11.7 months in non-mutated patients (p = 0.07). The mutated patients treated with chemotherapy followed by NHT had a long median PFS2 (49.8 months). (4) Conclusions: mCRPC patients with BRCA1/2 and ATM benefit from standard therapies, with a long response to taxanes.

Targeted therapy response in early versus late recurrence of renal cell carcinoma after surgical treatment: A propensity score‐matched study using the Korean Renal Cancer Study Group database

To investigate the clinicopathological features and outcomes of targeted therapy in patients with recurrence of renal cell carcinoma in <5years or ≥5years after the surgical treatment for renal cell carcinoma. Patients with metastatic renal cell carcinoma treated with targeted therapy in a multicenter database were retrospectively characterized according to time from surgery to recurrence. Early recurrence was defined as recurrence within 5years after surgery, and late recurrence was defined as occurring ≥5years after surgery. The propensity scores for recurrence status were calculated, and patients with late recurrence were matched to patients with early recurrence at a 1:3 ratio. The oncological outcomes of targeted therapy in both groups were compared. Among 716 patients, 512 (71.5%) experienced early recurrence and 204 (28.5%) experienced late recurrence. The patients with late recurrence presented with younger age at surgery, lower tumor stages and Fuhrman grade, and fewer sarcomatoid features and lymphovascular invasion (all P<0.005). All differences in clinicopathological characteristics before targeted therapy disappeared after matching. Patients with late recurrence had significantly longer median overall survival (56months vs 36months; P<0.0001) and median first-line progression-free survival (12months vs 8months; P=0.031). The early recurrence status was a significantly worse predictor for overall survival and first-line progression-free survival (hazard ratio 1.30, P=0.007; and hazard ratio 1.76, P<0.001, respectively). Late recurrence might have prognostic value in terms of oncological outcomes in metastatic renal cell carcinoma treated with targeted therapy.

Effect of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF v600-mutated metastatic colorectal cancer: a real-world study in Spain

BackgroundOutcomes are poorer in metastatic colorectal cancer (mCRC) patients with BRAF V600E mutations than those without it, but the effect of these mutations on treatment response is unclear. This real-world study assessed the effects of antiangiogenic-based treatment and systemic inflammatory factors on outcomes in patients with BRAF V600-mutated mCRC.MethodsThis real-world, multicenter, retrospective, observational study included patients with BRAF V600-mutated mCRC treated in eight hospitals in Spain. The primary endpoints were overall survival (OS) and progression-free survival (PFS); overall response rate (ORR) and disease control rate (DCR) were also assessed. The effect of first- and second-line treatment type on OS, PFS, ORR, and DCR were evaluated, plus the impact of systemic inflammatory markers on these outcomes. A systemic inflammation score (SIS) of 1–3 was assigned based on one point each for platelet-lymphocyte ratio (PLR) ≥200, neutrophil-lymphocyte ratio (NLR) ≥3, and serum albumin < 3.6 g/dL.ResultsOf 72 patients, data from 64 were analyzed. After a median of 69.1 months, median OS was 11.9 months and median first-line PFS was 4.4 months. First-line treatment was triplet chemotherapy-antiangiogenic (12.5%), doublet chemotherapy-antiangiogenic (47.2%), doublet chemotherapy-anti-EGFR (11.1%), or doublet chemotherapy (18.1%). Although first-line treatment showed no significant effect on OS, antiangiogenic-based regimens were associated with prolonged median PFS versus non-antiangiogenic regimens. Negative predictors of survival with antiangiogenic-based treatment were NLR, serum albumin, and SIS 1–3, but not PLR. Patients with SIS 1–3 showed significantly prolonged PFS with antiangiogenic-based treatment versus non-antiangiogenic-based treatment, while those with SIS=0 showed no PFS benefit.ConclusionsAntiangiogenic-based regimens, SIS, NLR, and albumin were predictors of survival in patients with mCRC, while SIS, NLR and serum albumin may predict response to antiangiogenic-based chemotherapy.Trial registrationGIT-BRAF-2017-01.

Simulating Progression-Free and Overall Survival for First-Line Doublet Chemotherapy With or Without Bevacizumab in Metastatic Colorectal Cancer Patients Based on Real-World Registry Data

Simulation models utilizing real-world data have potential to optimize treatment sequencing strategies for specific patient subpopulations, including when conducting clinical trials is not feasible. We aimed to develop a simulation model to estimate progression-free survival (PFS) and overall survival for first-line doublet chemotherapy with or without bevacizumab for specific subgroups of metastatic colorectal cancer (mCRC) patients based on registry data. Data from 867 patients were used to develop two survival models and one logistic regression model that populated a discrete event simulation (DES). Discrimination and calibration were used for internal validation of these models separately and predicted and observed medians and Kaplan-Meier plots were compared for the integrated DES. Bootstrapping was performed to correct for optimism in the internal validation and to generate correlated sets of model parameters for use in a probabilistic analysis to reflect parameter uncertainty. The survival models showed good calibration based on the regression slopes and modified Hosmer-Lemeshow statistics at 1 and 2years, but not for short-term predictions at 0.5years. Modified C-statistics indicated acceptable discrimination. The simulation estimated that median first-line PFS (95% confidence interval) of 219 (25%) patients could be improved from 175days (156-199) to 269days (246-294) if treatment would be targeted based on the highest expected PFS. Extensive internal validation showed that DES accurately estimated the outcomes of treatment combination strategies for specific subpopulations, with outcomes suggesting treatment could be optimized. Although results based on real-world data are informative, they cannot replace randomized trials.

Final results from IMPROVE: a randomized, controlled, open-label, two-arm, cross-over phase IV study to determine patients\u2019 preference for everolimus in combination with exemestane or capecitabine in combination with bevacizumab in advanced HR-positive, HER2-negative breast cancer

BackgroundThe objective of the IMPROVE study was patients’ preference for either endocrine-based therapy or combined chemo- and anti-angiogenic therapy in advanced HR-positive/HER2-negative breast cancer.MethodsIn this randomized, cross-over phase IV study, 77 patients were recruited in 26 sites in Germany. Patients were randomized 1:1 to receive either capecitabine plus bevacizumab (Cap+Bev) as first-line therapy followed by cross-over to everolimus plus exemestane (Eve+Exe) as second-line therapy (Arm A) or the reverse sequence (Arm B). The primary endpoint was patients’ preference for either regimen, assessed by the Patient Preference Questionnaire 12 weeks after cross-over. Key secondary endpoints included progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL).Results61.5% of patients preferred Cap+Bev (p = 0.1653), whereas 15.4% preferred Eve+Exe and 23.1% were indecisive. Physicians showed a similar tendency towards Cap+Bev (58.1%) as the preferred regimen versus Eve+Exe (32.3%). Median first-line PFS was longer for Cap+Bev than for Eve+Exe (11.1 months versus 3.5 months). Median second-line PFS was similar between Cap+Bev and Eve+Exe (3.6 months versus 3.7 months). Median OS was comparable between Arm A (28.8 months) and Arm B (24.7 months). 73.0% and 52.6% (first−/second-line, Cap+Bev) and 54.1% and 52.9% (first−/second-line, Eve+Exe) of patients experienced grade 3/4 TEAEs. No treatment-related deaths occurred. QoL and treatment satisfaction were not significantly different between arms or treatment lines.ConclusionsPatients tended to favor Cap+Bev over Eve+Exe, which was in line with physicians’ preference. Cap+Bev showed superior first-line PFS, while QoL was similar in both arms. No new safety signals were reported.Trial registrationEudraCT No: 2013–005329-22. Registered on 19 August 20

Assessment of the efficacy of successive endocrine therapies in hormone receptor–positive and HER2-negative metastatic breast cancer: a real-life multicentre national study

BackgroundFor luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study. MethodsThe Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation. ResultsThe ESME research programme included 9921 patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8–12.1), 5.8 (95% CI, 5.3–6.1) and 5.5 (95% CI, 4.6–6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P < 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P < 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months. ConclusionsMedian PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.

Survival of non-transplant patients with multiple myeloma in routine care differs from that in clinical trials\u2014data from the prospective German Tumour Registry Lymphatic Neoplasms

Despite increasing treatment options, multiple myeloma (MM) remains incurable for most patients. Data on improvement of outcomes are derived from selected patient populations enrolled in clinical trials and might not be conferrable to all patients. Therefore, we assessed the trial eligibility, sequential treatment, and survival of non-transplant patients with MM treated in German routine care. The prospective clinical cohort study TLN (Tumour Registry Lymphatic Neoplasms) recruited 285 non-transplant patients with symptomatic MM at start of first-line treatment in 84 centres from 2009 to 2011. Demographic and clinical data were collected until August 2016. Trial-ineligibility was determined by presence of at least one of the common exclusion criteria: heart/renal failure, liver/renal diseases, polyneuropathy, HIV positivity. All other patients were considered potentially trial-eligible. Thirty percent of the patients in our study were classified as trial-ineligible. Median first-line progression-free survival (PFS) and overall survival (OS) of trial-ineligible patients were inferior to that of potentially trial-eligible patients: PFS 16.2 months (95% CI (confidence interval) 11.1–20.4) vs. 27.3 months (95% CI 23.3–33.0); OS 34.2 months (95% CI 21.6–48.1) vs. 58.6 months (95% CI 48.6–64.4). A high percentage of non-transplant patients with MM in German routine care would be ineligible for participation in clinical trials. Despite similar treatment algorithms, their first-line PFS and OS were shorter than those of potentially trial-eligible patients; the survival data of the latter were similar to results from clinical trials. Physicians should be aware of the fact that results from clinical trials may not mirror “real world” patient outcomes when discussing outcome expectations with patients. Trial registration: Clinicaltrials.gov identifier: NCT00889798.

Prospective randomized phase II study of FOLFIRI versus FOLFOX7 in advanced gastric adenocarcinoma: a Chinese Western Cooperative Gastrointestinal Oncology Group Study.

Until now, no standard chemotherapy has been widely accepted for advanced gastric cancer (GC). The current research aimed to compare folinic acid, fluorouracil with irinotecan (mFOLFIRI) or with oxaliplatin (mFOLFOX7) as first-line treatments in patients with locally advanced GC in an open, randomized, phase II study. Previously untreated metastatic or recurrent GC patients with measurable disease received mFOLFIRI (arm A) or mFOLFOX7 (arm B) every 2 weeks. The defined second-line treatment was mFOLFOX7 for arm A and mFOLFIRI for arm B. Primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS), disease control rate (DCR) and toxicity. The evaluable population consisted of 128 patients (54 in arm A; 74 in arm B). Median PFS of arm A was 2.9 months (m) (95% confidence interval, CI, 1.9 to 4.1 m) versus 4.1 m (95% CI, 3.2 to 4.8 m) for arm B (p = 0.109). Median OS was 9.9 months (95% CI, 6.0 to 13.5 m) for arm A versus 12.0 m for arm B (95% CI, 10.3 to 13.7m; p = 0.431). DCRs for arm A and arm B were 59.3% and 66.3%, respectively (p = 0.850). In subgroup analysis of the patients who completed both treatment lines per protocol, the median first-line PFS was 2.1 m for the mFOLFIRI/mFOLFOX7arm versus 8.0 m for the mFOLFOX7/mFOLFIRI arm (p = 0.053), and the median second-line PFS values were 1.2 m versus 5.1 m (p = 0.287). Total PFS and OS were 8.1m and 11.0 m for the mFOLFIRI/mFOLFOX7 group compared with 12.2m and 20.2 m for the mFOLFOX7/mFOLFIRI group (p = 0.008, p = 0.030). Both regimens were well-tolerated with acceptable and manageable toxicities. Hence, there was no significant difference in the PFS or DCR. However, mFOLFOX7 followed by mFOLFIRI might have a better OS.

Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

BackgroundMetastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. ObjectiveTo evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participantsTargeted sequencing of 341 cancer genes at ∼540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysisAssociations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitationsPrevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. ConclusionsPBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summaryLarge-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Interferon treatment for Japanese patients with favorable-risk metastatic renal cell carcinoma in the era of targeted therapy.

PurposeSingle-agent interferon (IFN) is no longer regarded as a standard option for first-line systemic treatment of metastatic renal cell carcinoma (RCC) in Western countries. However, some patients with favorable-risk RCC may still achieve complete and long-lasting remission in response to IFN treatment. The present study compared favorable-risk Japanese patients with metastatic RCC Japanese patients who had been treated with IFN or tyrosine kinase inhibitor (TKI) therapy as a first-line systemic therapy.Materials and MethodsFrom 1995 to 2014, a total of 48 patients with favorable risk as defined by the Memorial Sloan Kettering Cancer Center criteria who did not receive adjuvant systemic therapy were retrospectively enrolled in this study. We assessed the tumor response rate, progression-free survival (PFS), and overall survival (OS).ResultsThe objective response rate for first-line therapy was 29% in the IFN group and 47% in the TKI group, but this difference did not reach the level of statistical significance. Median OS for IFN and TKI was 71 and 47 months, respectively (p=0.014). Median first-line PFS for IFN and TKI was 20 and 16 months, respectively (no significant difference). First-line IFN therapy did not prove inferior to TKI therapy in terms of OS according to metastatic sites.ConclusionsIFN is associated with a survival benefit in Japanese patients with favorable-risk metastatic RCC in the era of targeted therapy. Further prospective study is needed.

Long-Term Follow-up of 228 Hairy Cell Leukemia Patients Treated with Pentostatin or Cladribine with 15.4 Years Median Time from Diagnosis.

Background: In a previous review of hairy cell leukemia (HCL) patients we found no difference in efficacy between cladribine and pentostatin [Else et al, Cancer 104:2442- 8; 2005]. With longer follow-up (median 15.4 years since diagnosis) we aimed to find whether efficacy remained equivalent and whether factors associated with relapse could be identified retrospectively.Methods: We reviewed data retrospectively from 228 HCL patients, treated between 1986–2005 with either single-agent pentostatin (n=187) or cladribine (n=41), at a median of 15.4 (range 1–38) years from diagnosis.Results: Patient demographics were similar for both treatment groups, apart from a male:female ratio of 4.5:1 (pentostatin) versus 2:1 (cladribine) (p=0.02). No statistically significant differences were found between treatment groups after first-line therapy. Complete response (CR) rates were 82% (pentostatin) and 76% (cladribine). After a median followup since treatment of 13 years (pentostatin) and 9 years (cladribine), 43% of pentostatin and 37% of cladribine patients had relapsed. Relapse rates at 5, 10 and 15 years were 25%, 42% and 47% (pentostatin) and 35%, 44% and 44% (cladribine). Overall, patients who reached 5 years remission had only a 30% risk of relapsing by 15 years. Median progression-free survival (PFS) was 10 years. After relapse (n=75) or non-response (n=5), 24 patients received single-agent pentostatin and 56 cladribine, with CR rates of 63% and 75% respectively (not significant). Eleven patients subsequently relapsed after pentostatin and 18 after cladribine. Ten years after second-line treatment the rate of relapse was 53% and 39% for the two agents respectively (not significant) and second-line PFS was marginally shorter after pentostatin than after cladribine (p=0.04). Relapse rates and PFS were no different between those switching treatment (n=51) and those re-treated with the same agent (n=29). There were 45 deaths altogether, of which only 8 were HCL-related. With non-HCL-related deaths censored, overall survival from first treatment was 95% (pentostatin) and 100% (cladribine) at both 10 and 15 years (not significant). Compared with all others, the 95 patients (42%) whose disease progressed (who failed to respond to treatment, relapsed, or died of HCL-related causes) were more likely to have haemoglobin <10g/dl (p=0.01) and platelets <100x109/l (p=0.002). The median first-line PFS of patients with haemoglobin <10g/dl and/or platelets <100x109/l was 8 years versus 16 years for all others (p<0.001).Conclusions and Recommendations: The long-term outcome for HCL patients was similar, whether treated with pentostatin or cladribine. The risk of dying of HCL-related causes was less than 5% and, among those surviving 15 years after treatment, 52% had still not relapsed. As in chronic lymphocytic leukaemia Binet stage C, patients with a low haemoglobin and/or platelet count appeared to fare worse. Further research will elucidate the factors underlying this difference in long-term prognosis. The outcome for relapsed patients may improve with the combination of either pentostatin or cladribine with the monoclonal antibody rituximab (Else et al, Cancer 110:2240–7; 2007).