Analysis of Toxicity and Clinical Outcomes in Full Versus Reduced Starting Dose Cabozantinib in Metastatic Renal Cell Carcinoma Patients

BackgroundFull dose cabozantinib for metastatic renal cell carcinoma (mRCC) is 60 mg, but adverse events (AEs) may require dose reductions. Limited data exist comparing efficacy among cabozantinib doses. We compared AEs and clinical outcomes in mRCC patients treated with full vs. reduced starting cabozantinib dose.MethodsWe performed a retrospective analysis of 87 mRCC patients treated with cabozantinib at Winship Cancer Institute from 2016 to 2019. Overall survival (OS), progression-free survival (PFS), and objective response (OR) rate measured clinical outcomes. AEs were collected from clinic notes and the most common were hypertension, mucositis/hand-foot skin reaction (HFSR), or gastrointestinal toxicity. Univariate analysis (UVA) between starting doses and AEs with clinical outcomes was performed using logistic regression model. Multivariable analysis was also performed using Cox proportional hazard model.ResultsMost patients were men (71%) with clear-cell RCC (72%). The majority were IMDC intermediate (58%) or poor (35%) risk. One third received first-line cabozantinib and 64% had ≥3 baseline metastatic sites. Most patients (68%) required dose reduction from 60 mg or started at reduced dose without escalation. Reduced dose patients were more likely to have ≥3 distant metastatic sites (70% vs. 58%) and ≥2 prior lines of systemic therapy (50% vs. 40%) compared to full dose patients. UVA revealed a trend towards shorter OS (HR: 1.78, P = .095), PFS (HR: 1.50, P = .107), and lower chance of OR (HR:0.42, P = .149) among reduced dose patients. This trend did not hold in Multivariable analysis (OS HR: 1.20, P = .636; PFS HR: 1.23, P = .4662). Mucositis/HFSR and hypertension were significantly associated with improved outcomes in UVA.ConclusionsAlthough we found a trend favoring full dose cabozantinib, this is likely due to worse baseline disease characteristics among patients starting on a reduced dose. Hypertension and mucositis/HFSR may be associated with improved outcomes. Larger studies are warranted to validate these findings.     

Primary Tumor Shrinkage and the Effect on Metastatic Disease and Outcomes in Patients With Advanced Kidney Cancer With Intermediate or Poor Prognosis Treated With Nivolumab Plus Ipilimumab or Cabozantinib

BackgroundImmune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still one of the most debated issues.Patients and MethodsThe aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes.ResultsSixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001).ConclusionExtension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.     

Predictive Impact of Early Changes in Serum C-Reactive Protein Levels in Nivolumab Plus Ipilimumab Therapy for Metastatic Renal Cell Carcinoma

BackgroundSerum C-reactive protein (CRP) is reportedly associated with metastatic renal cell carcinoma (mRCC) activity. However, in the era of immune checkpoint inhibitors, the predictive value of CRP is unclear. In this study, we investigated the predictive impact of pretreatment CRP levels and early changes in CRP levels for the treatment of mRCC with nivolumab plus ipilimumab (NIVO-IPI) therapy.MethodsForty-eight patients with mRCC treated with NIVO-IPI as a first-line therapy were retrospectively analyzed. First, patients were divided into 2 groups: initial CRP ≥ 1.0 mg/dL and < 1.0 mg/dL. Progression-free survival (PFS) was compared between the 2 groups. Second, based on the CRP change within the first 3 months of NIVO-IPI, patients were placed in the normal group (CRP remains < 1.0 mg/dL), normalized group (CRP decreased < 1.0 mg/dL), and non–normalized group (CRP remained or increased to ≥ 1.0 mg/dL). The predictive association between CRP change and PFS was evaluated.ResultsPFS was significantly lower in the high initial CRP group (n = 24, 50%) compared to the normal CRP group (n = 24, 50%) (median: 4.3 vs. 28.1 months, P = .03). As for the early CRP change, the normal (2.7 vs. 28.1, P = .0002) and normalized (2.7 vs. 11.0, P = .0094) groups showed significantly higher PFS, compared to the non–normalized group. Meanwhile, there was no significant difference between normal, and normalized groups (P = .51). The objective response rate was higher in the normal (57.1% vs. 18.7%, P = .015) and normalized (81.8 vs. 18.7%, P = .0008) groups, compared to the non–normalized group. Multivariate Cox regression analysis showed that normal [Hazard ratio (HR) = 0.15, 95% Confidence interval (CI) = 0.02-0.70, P = .026] and normalized (HR 0.21, 95% CI = 0.05-0.73, P = .015) CRP showed significant association with PFS.ConclusionIn the NIVO-IPI therapy for mRCC, early changes in CRP could predict PFS. This data may be useful for the early detection of ineffective NIVO-IPI therapy and conversion to subsequent therapies.     

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.     

Association Between Early Immune-related Adverse Events and Clinical Outcomes in Patients With Non–Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors

IntroductionPrevious studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non–small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes.Patients and MethodsWe prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS).ResultsIn the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts.ConclusionOur results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.     

Co-occurring MET Amplification Predicts Inferior Clinical Response to First-Line Erlotinib in Advanced Stage EGFR-Mutated NSCLC Patients

BackgroundIntrinsic resistance is a major obstacle in treatment of non-small cell lung cancer (NSCLC) patients with an activating mutation in the epidermal growth factor receptor (EGFR). We investigated co-occurring genetic alterations in circulating tumor DNA (ctDNA) as predictive markers of clinical response to first-line erlotinib.MethodsPretreatment plasma samples were collected from 76 patients with EGFR-mutated, advanced-stage NSCLC treated with first-line erlotinib. We isolated ctDNA from plasma for next-generation sequencing.ResultsCo-occurring oncogenic drivers were detected in 21% of pretreatment samples and correlated with decreased progression-free survival (PFS) (6.9 months vs 14.4 months; hazard ratio [HR], 2.088; 95% confidence interval [CI], 0.8119-5.370; P = .0355). Concurrent MET amplification was identified in 9 samples (12%), predicting inferior PFS (5.5 months vs 14.4 months; HR, 4.750; 95% CI, 0.5923-38.10; P = .0007) and overall survival (7.6 months vs 28.3 months; HR, 3.952; 95% CI, 0.8441-18.50; P = .0005). Co-occurring non-MET-amplification oncogenic alterations showed a tendency for shorter PFS (9.9 months vs 14.4 months; HR, 1.199; 95% CI, 0.3373-4.265; P = .7586). Clearing EGFR-mutated ctDNA during erlotinib treatment is a positive predictor of clinical outcomes. Among patients who cleared the EGFR mutation, 12% had a co-occurring oncogenic driver, with a tendency toward inferior PFS (8.7 months vs 16.1 months; HR, 1.703; 95% CI, 0.5347-5.424; P = .2508).ConclusionCo-occurring MET amplification in pretreatment ctDNA samples predict inferior clinical response to first-line erlotinib in advanced-stage, EGFR-mutated NSCLC patients. Co-occurring oncogenic alterations were associated with inferior response and may be potential predictors of clinical outcome.     

Sequential Targeted Therapy After Pazopanib Therapy in Patients With Metastatic Renal Cell Cancer: Efficacy and Toxicity

Introduction/BackgroundPatients with metastatic renal cell carcinoma (mRCC) in whom first-line therapies have failed might derive clinical benefit with sequential targeted agents. Limited data are available on the efficacy and toxicity of subsequent therapies after disease progression during pazopanib therapy.Patients and MethodsPatients with mRCC who received subsequent systemic treatment after pazopanib treatment failure were identified across 7 institutions. Pazopanib was given as first-line therapy in 28 patients and after cytokines therapy in 7 patients. Clinical outcome and toxicity analyses of 2 sequential treatment options (anti-vascular endothelial growth factor [VEGF] or mammalian target of rapamycin inhibitor [mTORi]) is presented.ResultsSubsequent therapy was anti-VEGF in 22 patients and mTORi in 13. One patient who received bevacizumab and temsirolimus combination was excluded. VEGF-targeted therapies included sorafenib (n = 10), sunitinib (n = 3), bevacizumab (n = 2), cediranib (n = 4) and cabozantinib (n = 3). Patients treated with mTORi received everolimus. Median progression-free survival was 5.6 months from the start of subsequent therapy with anti-VEGF and 2.4 months with mTORi (P = .009). Overall survival (OS) was not significantly different (P = .68). Clinical benefit (including partial response and stable disease) on subsequent therapy was observed in 15 patients (64%) and 4 patients (31%) of anti–VEGF- and everolimus-treated patients, respectively (P = .021).ConclusionIn this retrospective study, targeting VEGF was an effective strategy after disease progression during pazopanib treatment, although OS was not different among patients treated with VEGF or mTORi.     

Skin toxicity and efficacy of sunitinib and sorafenib in metastatic renal cell carcinoma: a national registry-based study

BackgroundA retrospective, registry-based analysis to assess the outcomes of metastatic renal cell cancer (mRCC) patients treated with sunitinib and sorafenib who developed dermatologic adverse events was performed.Patients and MethodsData on mRCC patients treated with sunitinib or sorafenib were obtained from the Czech Clinical Registry of Renal Cell Cancer Patients. Outcomes of patients who developed hand–foot syndrome (HFS) of any grade and/or grade 3/4 rash during the treatment were compared with patients without HFS and no, mild, or moderate rash.ResultsThe cohort included 705 patients treated with sunitinib and 365 patients treated with sorafenib. For sunitinib, the median overall survival (OS) was 43.0 months versus 31.0 months (P = 0.027) and median progression-free survival (PFS) 20.8 months versus 11.1 months (P = 0.007) for patients with versus without dermatologic toxicity, respectively. For sorafenib, the median OS and PFS were 27.9 and 24.6 months (P = 0.244), and 12.2 and 8.8 months (P = 0.050), respectively. In multivariable Cox regression, the skin toxicity was significantly associated with longer OS in the sunitinib cohort.ConclusionThe presence of skin toxicity is associated with improved OS and PFS in patients with mRCC treated with sunitinib.     

Disease Burden on PET Predicts Outcomes for Advanced NSCLC Patients Treated with First-Line Immunotherapy

BackgroundFirst-line immunotherapy (IMT), with or without cytotoxic chemotherapy, is now recommended for most patients with advanced non-small cell lung cancer (NSCLC) with no targetable mutations. We reviewed outcomes for NSCLC patients treated with first-line IMT at our institution to test the hypothesis that measures of disease burden on staging FDG-PET/CT have prognostic value.Materials and MethodsPatient, disease, and treatment details were collected. A gradient-based segmentation tool was used to delineate each PET-avid extracranial lesion. Numbers of extrathoracic lesions and metabolic tumor volumes were tabulated. Oligometastatic disease (OMD) was defined as having ≤3 extrathoracic lesions, with any number of thoracic lesions. Progression-free survival (PFS) and overall survival (OS) rates following initiation of IMT were evaluated using the Kaplan-Meier method, and predictors of PFS and OS were assessed using Cox proportional hazards models and logrank tests.ResultsOne hundred twenty-four patients met inclusion criteria, and 1143 lesions were contoured. The presence of OMD was associated with favorable PFS (median 13.1 vs. 6.9 months; P = .016) and favorable OS (median 36.5 vs. 15.4 months; P = .002). In multivariable models, OMD was associated with favorable PFS (HR = 0.64; P = .034) and favorable OS (HR = 0.61; P = .063), and metabolic tumor volumes exceeding the cohort median (88 cc) was associated with inferior OS (HR = 1.85; P = .028).ConclusionFor advanced NSCLC patients receiving first-line IMT, the presence of extrathoracic OMD and low volumetric disease burden on PET are favorable prognostic factors that could be useful stratification factors in clinical trials and may influence clinical decisions about local and systemic therapy.     

Impact of Metastasectomy on Cancer Specific and Overall Survival in Metastatic Renal Cell Carcinoma: Analysis of the REMARCC Registry

BackgroundTreatment paradigms for management of metastatic renal cell carcinoma (mRCC) are evolving. We examined impact of surgical metastasectomy on survival across in mRCC stratified by risk-group.MethodsMulticenter retrospective analysis from the Registry of Metastatic RCC database. The cohort was subdivided utilizing Motzer criteria (favorable-, intermediate-, high-risk). Primary outcome was all-cause mortality (ACM)/overall survival (OS); secondary outcome was cancer-specific mortality (CSM)/cancer-specific survival (CSS). Impact of metastasectomy was analyzed via Cox-Regression analysis adjusting for potential prognostic variables and Kaplan-Meier analysis (KMA) within each risk-group.ResultsFour hundred thirty-one patients (59 favorable-risk, 274 intermediate-risk, 98 high-risk; median follow-up 27.2 months) were analyzed. Metastasectomy was performed in 22 (37%), 66 (24%), and 32 (16%) of favorable-, intermediate- and high-risk groups (P = .012). Median number of metastases at diagnosis differed significantly (favorable-risk 2, intermediate-risk 3.4, high-risk 5.1, P < .001). On Cox-regression, high-risk (HR = 1.72, P = .002) was associated with worsened ACM, while metastasectomy was associated with improved ACM (HR = 0.56, P = .005). On KMA, median OS (months) was longer with metastasectomy in favorable- (92.7 vs. 25.8, P = .003) and intermediate-risk (26.3 vs. 20.1, P = .038), but not high-risk (P = .911) groups. Metastasectomy was associated with longer CSS in favorable- (76.1 vs. 32.8, P = .004) but not intermediate- (P = .06) and high-risk (P = .595) groups.ConclusionsMetastasectomy was independently associated with improved ACM and CSM, as well as improved CSS and OS in favorable- and intermediate-risk mRCC patients. Metastasectomy may be considered as component of multimodal management strategy in favorable and intermediate-risk subgroups. In high-risk patients, metastasectomy should be deferred except in select circumstances.     

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide,Bortezomib, and Dexamethasone

BackgroundHigher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients.Patients and methodsData from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate.ResultsThere was a trend for lower discontinuation rate (45.7% vs. 68.6%, P = .052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P = .035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P = .225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P = .024). There was significantly longer PFS (24.3 vs. 9.1 months, P = .012) and a trend for longer OS (22.4 vs. 61.3 months, P = .061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P = .941) and OS were similar in both groups.ConclusionHigher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.     

Differential Efficacy of Targeted Monoclonal Antibodies in Left-Sided Colon and Rectal Metastatic Cancers

BackgroundThe recommended first-line chemotherapy for RAS/BRAF wild-type metastatic colorectal cancer (mCRC) is bevacizumab (BEV)-containing therapy for right-sided colon cancer (R) and antiepidermal growth factor receptor antibody (anti-EGFR)-containing therapy for left-sided colon cancer (L) or rectal cancer (RE). However, anatomical or biological heterogeneity reportedly exists between L and RE. Therefore, we aimed to compare the efficacies of anti-EGFR and BEV therapies for L and RE, respectively.MethodsWe retrospectively reviewed 265 patients with KRAS (RAS)/BRAF wild-type mCRC treated with fluoropyrimidine-based doublet chemotherapy plus anti-EGFR or BEV as the first-line treatment at a single institution. They were divided into 3 groups: R, L, and RE. Overall survival (OS), progression-free survival (PFS), objective response rate, and conversion surgery rate were analyzed.ResultsForty-five patients had R (anti-EGFR/BEV: 6/39), 137 patients had L (45/92), and 83 patients had RE (25/58). In patients with R, both median (m) PFS and OS were superior with BEV therapy (mPFS, anti-EGFR vs. BEV: 8.7 vs. 13.0 months, hazard ratio [HR]: 3.90, P = .01; mOS, 17.1 vs. 33.9 months, HR: 1.54, P = .38). In patients with L, better mPFS and comparable mOS with anti-EGFR therapy were observed (mPFS, 20.0 vs. 13.4 months, HR: 0.68, P = .08; mOS, 44.8 vs. 36.0 months, HR: 0.87, P = .53), whereas, in patients with RE, comparable mPFS and worse mOS with anti-EGFR therapy were observed (mPFS, 17.2 vs. 17.8 months, HR: 1.08, P = .81; mOS, 29.1 vs. 42.2 months, HR: 1.53, P = .17).ConclusionsEfficacies of anti-EGFR and BEV therapies may differ between patients with L and RE.     

Is Axitinib Still a Valid Option for mRCC in the Second-Line Setting? Prognostic Factor Analyses From the AXIS Trial

BackgroundAxitinib resulted in significantly longer progression-free survival (PFS) versus sorafenib in patients with metastatic renal-cell carcinoma (mRCC) previously treated with sunitinib in the AXIS trial. We report post hoc analyses evaluating patient subgroups that may benefit more from axitinib in this setting.Patients and MethodsAXIS was an open-label randomized phase 3 trial (NCT00678392) in mRCC patients with disease that failed to respond to one prior systemic therapy. Univariate and multivariate analyses evaluated potential prognostic factors for improved PFS and overall survival (OS) after sunitinib. PFS and OS of axitinib versus sorafenib were assessed within subgroups identified according to these factors.ResultsOf 723 patients, 389 received first-line sunitinib; 194 and 195 were randomized to second-line axitinib and sorafenib, respectively. Identified prognostic factors were: nonbulky disease (sum of the longest diameter < 98 mm), favorable/intermediate risk disease (Memorial Sloan Kettering Cancer Center or International Metastatic Renal Cell Carcinoma Database Consortium criteria), and no bone or liver metastases. In patients with all of these prognostic factors (n = 86), significantly longer PFS was observed for axitinib versus sorafenib (hazard ratio = 0.476; 95% confidence interval, 0.263-0.863; 2-sided P = .0126). OS (hazard ratio = 0.902; 95% confidence interval, 0.457-1.780; 2-sided P = .7661) was similar between treatments. Across subgroups, PFS was generally longer in patients treated with axitinib versus sorafenib, and OS was generally similar between the two treatments.ConclusionIn patients with mRCC, axitinib remains a suitable second-line treatment option across multiple subgroups. A relevant reduction in the risk of a PFS event was observed for axitinib compared to sorafenib in selected subgroups of patients.     

Assessment of progression-free survival as a surrogate end-point for overall survival in patients with metastatic renal cell carcinoma

BackgroundTo determine suitability of progression-free survival (PFS) as a surrogate end-point for overall survival (OS), we evaluated the relationship between PFS and OS in 750 treatment-naïve metastatic renal cell carcinoma (mRCC) patients who received sunitinib or interferon-alpha (IFN-α) in a phase III study.MethodsThe relationship between PFS and post-progression survival (PPS; the difference between PFS and OS) was studied, which correctly removes inherent dependencies between PFS and OS, to properly estimate whether and to what extent PFS can serve as a surrogate for OS. A Weibull parametric model to failure time data was fit to determine whether longer PFS was significantly and meaningfully predictive of longer PPS. In a sensitivity analysis by Kaplan–Meier non-parametric method, PPS curves for three approximately equal numbered groups of patients categorised by PFS were compared by log-rank test.ResultsIn the Weibull parametric model, longer PFS was significantly predictive of longer PPS (P < 0.001). The model also allowed prediction of estimated median PPS duration from actual PFS times. In the Kaplan–Meier (non-parametric) analysis, incrementally longer PFS was also associated with longer PPS, and the PPS curves for the three PFS groups were significantly different (P < 0.0001).ConclusionsA positive relationship was found between PFS and PPS duration in individual mRCC patients randomised to first-line treatment with sunitinib or IFN-α. These results indicate that PFS can act as a surrogate end-point for OS in the first-line mRCC setting and provide clinical researchers with a potentially useful approach to estimate median PPS based on PFS.     

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study

BackgroundAxitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified.Patients and MethodsRetrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs. disease progression/refractory patients [RP]). A multivariate logistic-regression model was used to analyse clinical factors. Efficacy and safety were also analysed.ResultsIn total, 157 patients who received axitinib in second or subsequent line were evaluated (91 LR and 66 RP). Older age at start of axitinib and haemoglobin levels > LLN were independent predictive factors for LR in multivariate analyses. In LR patients, median (m) PFS was 18.1 months, median overall survival was 36.0 months and objective response rate (ORR) was 45.5%. In 59 LR patients receiving axitinib in second-line, mPFS was 18.7 months, mOS was 44.8 months and ORR was 43.9%. mOS was significantly longer in second line compared to subsequent lines (44.8 vs. 26.5 months; P = .009). In LR vs. RP, mPFS with sunitinib in first-line was correlated with mPFS with axitinib in second-line (27.2 vs. 10.9 months P < .001). The safety profile was manageable and consistent with known data.ConclusionsThis study confirms the long-term benefits of axitinib in a selected population, helping clinicians to select the best sequential approach and patients who could obtain a greater benefit from axitinib.     

Everolimus-induced pneumonitis associates with favourable outcome in patients with metastatic renal cell carcinoma

BackgroundMammalian target of rapamycin inhibitors may induce pneumonitis. We analysed the association of pneumonitis with outcomes in everolimus treated metastatic renal cell carcinoma (mRCC) patients.Patients and methodsEighty-five mRCC patients received everolimus at Helsinki University Hospital (cohort A). Computed tomography (CT) verified pneumonitis was correlated with outcome using Kaplan–Meier, Cox regression and logistic regression. An independent cohort of 148 everolimus treated mRCC patients (cohort B) at Aarhus University Hospital was assessed for validation.ResultsIn cohort A, CT-verified pneumonitis (N = 29, 34.1%) was associated with improved overall survival (OS) (24.7 versus 8.5 months; P < 0.001), progression-free survival (PFS) (5.5 versus 3.2 months; P = 0.002) and clinical benefit rate (CBR) 57.1% versus 24.1% (P = 0.003). In multivariate analyses pneumonitis was associated with improved OS (hazard ratio [HR], 0.22; 95% confidence interval [CI] 0.12–0.44; P < 0.001), PFS (HR 0.37; 95% CI 0.21–0.66; P = 0.001) and CBR (odds ratio [OR] 4.11; 95% CI 1.42–11.95; P = 0.01).In cohort B, CT-verified pneumonitis (N = 29, 19.6%) was associated with improved OS (12.9 versus 6.0 months; P = 0.02), PFS (6.0 versus 2.8 months; P = 0.02) and CBR (79.3% versus 39.5%; P < 0.001). In multivariate analyses pneumonitis was associated with improved OS (HR 0.58; 95% CI 0.36–0.94; P = 0.03), PFS (HR 0.61; 95% CI 0.39–0.95; P = 0.03) and CBR (OR 5.65; 95% CI 2.10–15.18; P = 0.001).In a combined multivariate analysis (N = 233), with pneumonitis as a time-dependent covariate, CT-verified pneumonitis was associated with longer OS (HR, 0.67; 95% CI 0.46–0.97; P = 0.03). Furthermore, in a landmark analysis, pneumonitis was associated with longer OS (17.4 versus 7.8 months; P = 0.01).ConclusionsEverolimus-induced pneumonitis is associated with improved outcome in patients with mRCC and may serve as a biomarker of everolimus efficacy.     

Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell carcinoma: Results from a large patient cohort

AimA number of targeted therapies (TTs) are effective in metastatic renal cell carcinoma (mRCC) but clinical outcomes with the sequential use of three TTs have been poorly investigated, this study evaluates their outcome.MethodsPatients with clear cells mRCC treated with three TTs were retrospectively studied. Therapies were classified as vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor (VEGFR) or mammalian target of rapamycin inhibitors (mTORi). Progression free survival (PFS), overall survival (OS) and total PFS (tPFS) – defined as the time from start of first-line to progression on third-line treatment – were estimated using the Kaplan–Meier method and curves were compared with log-rank test.ResultsA total of 2065 patients with mRCC were consecutively treated with first-line TT in 23 centres in Italy. Overall 281/2065 patients (13%) were treated with three TTs. Median OS and tPFS were 44.7 and 34.1 months, respectively and were longer in patients receiving the sequence vascular endothelial growth factor inhibitors (VEGFi)–VEGFi–mTORi compared with those receiving VEGFi–mTORi–VEGFi with a statistical difference in OS (50.7 versus 37.8 months, p = 0.004; 36.5 versus 29.3 months, p = 0.059, respectively).ConclusionsFew patients received three lines of TTs. The sequence VEGFi–VEGFi–mTORi was associated with improved survival with respect to VEGFi–mTORi–VEGFi and primary resistance to first-line was a negative predictive and prognostic factor.     

Anti-VEGF Therapy Possibly Extends Survival in Patients With Colorectal Brain Metastasis by Protecting Patients From Neurologic Disability

BackgroundColorectal brain metastases (CBMs) are rare with poor prognosis. There is still no standard systemic treatment for multiple or unresectable CBM. our study aimed to explore the impact of anti-VEGF therapy on overall survival, brain-specific disease control, and neurologic symptom burden in patients with CBM.MethodsA total of 65 patients with CBM under treatment were retrospectively enrolled and divided into anti-VEGF based systemic therapy or non–anti-VEGF based therapy. A total of 25 patients who received at least 3 cycles of anti-VEGF agent and 40 patients without anti-VEGF therapy were analyzed by endpoints of overall survival (OS), progression-free survival (PFS), intracranial PFS (iPFS) and neurogenic event-free survival (nEFS). Gene expression in paired primary metastatic colorectal cancer (mCRC), liver, lung and brain metastasis from NCBI data was analyzed using top Gene Ontology (GO) and cBioPortal.ResultsPatients who treated with anti-VEGF therapy had significantly longer OS (19.5 vs. 5.5 months, P = .009), iPFS (14.6 vs. 4.1 months, P < .001) and nEFS (17.6 vs. 4.4 months, P < .001). Patients who received anti-VEGF therapy beyond any disease progression presented with superior OS (19.7 vs. 9.4 months, P = .039). Top GO and cBioPortal analysis revealed a stronger molecular function of angiogenesis in intracranial metastasis.ConclusionsAnti-VEGF based systemic therapy showed favorable efficacy that was reflected in longer overall survival, iPFS and NEFS in patients with CBM.     

Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study

BackgroundBrigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial.Patients and MethodsThis was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases.ResultsOf the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients.ConclusionEfficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.     

Active Surveillance in Metastatic Renal Cell Carcinoma: Results From the Canadian Kidney Cancer Information System

BackgroundActive surveillance (AS) is a commonly used strategy in patients with slow-growing disease. We aimed to assess the outcomes and safety of AS in patients with metastatic renal cell carcinoma (mRCC).Patients and MethodsWe used the Canadian Kidney Cancer information system (CKCis) to identify patients with mRCC diagnosed between January 1, 2011, and December 31, 2016. The AS strategy was defined as (1) the start of systemic therapy ≥ 6 months after diagnosis of mRCC, or (2) never receiving systemic therapy for mRCC with an overall survival (OS) of ≥1 year. Patients starting systemic treatment <6 months after diagnosis of mRCC were defined as receiving immediate systemic treatment. OS and time until first-line treatment failure (TTF) were compared between the two cohorts.ResultsA total of 853 patients met the criteria for AS (cohort A). Of these, 364 started treatment >6 months after their initial diagnosis (cohort A1) and 489 never started systemic therapy (cohort A2); 827 patients received immediate systemic treatment (cohort B). The 5-year OS probability was significantly greater for cohort A than for cohort B (70% vs. 33.6%; P < .0001). After adjusting for International Metastatic RCC Database Consortium risk criteria and age, both OS (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.47-0.70; P < .0001) and TTF (HR = 0.72; 95% CI, 0.60-0.85; P = .0002) were greater in cohort A1 compared with B. For cohort A1, the median time on AS was 14.2 months (range, 6-71).ConclusionsBased on the largest analysis of AS in mRCC to date, our data suggest that a subset of patients may be safely observed without immediate initiation of systemic therapy.