Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials

BackgroundThere is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome.MethodsThis retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side.ResultsPrimary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69–2.42) and 1.38 (1.17–1.63), respectively], PFS [HRs = 1.59 (1.34–1.88) and 1.25 (1.06–1.47)], and ORR [ORs = 0.38 (0.28–0.50) and 0.56 (0.43–0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67–0.84) and 0.78 (0.70–0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87–1.45) and 1.12 (0.87–1.44) for OS and PFS, respectively; P value for interaction <0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction = 0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR = 2.12 (1.77–2.55)] compared with those with right-sided tumours [OR = 1.47 (0.94–2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm.ConclusionThis pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.     

Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study

BackgroundHomologous recombination defects in BRCA1/2-mutated tumors result in sensitivity to poly(ADP-ribose) polymerase inhibitors, which interfere with DNA damage repair. Veliparib, a potent poly(ADP-ribose) polymerase inhibitor, enhanced the antitumor activity of platinum agents and temozolomide in early phase clinical trials. This phase II study examined the safety and efficacy of intermittent veliparib with carboplatin/paclitaxel (VCP) or temozolomide (VT) in patients with BRCA1/2-mutated breast cancer.Patients and methodsEligible patients ≥18 years with locally recurrent or metastatic breast cancer and a deleterious BRCA1/2 germline mutation were randomized 1:1:1 to VCP, VT, or placebo plus carboplatin/paclitaxel (PCP). Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS) and overall response rate (ORR).ResultsOf 290 randomized patients, 284 were BRCA+, confirmed by central laboratory. For VCP versus PCP, median PFS was 14.1 and 12.3 months, respectively [hazard ratio (HR) 0.789; 95% CI 0.536–1.162; P = 0.227], interim median OS 28.3 and 25.9 months (HR 0.750; 95% CI 0.503–1.117; P = 0.156), and ORR 77.8% and 61.3% (P = 0.027). For VT (versus PCP), median PFS was 7.4 months (HR 1.858; 95% CI 1.278–2.702; P = 0.001), interim median OS 19.1 months (HR 1.483; 95% CI 1.032–2.131; P = 0.032), and ORR 28.6% (P < 0.001). Safety profile was comparable between carboplatin/paclitaxel arms. Adverse events (all grades) of neutropenia, anemia, alopecia, and neuropathy were less frequent with VT versus PCP.ConclusionNumerical but not statistically significant increases in both PFS and OS were observed in patients with BRCA1/2-mutated recurrent/metastatic breast cancer receiving VCP compared with PCP. The addition of veliparib to carboplatin/paclitaxel significantly improved ORR. There was no clinically meaningful increase in toxicity with VCP versus PCP. VT was inferior to PCP. An ongoing phase III trial is evaluating VCP versus PCP, with optional continuation single-agent therapy with veliparib/placebo if chemotherapy is discontinued without progression, in this patient population.Clinical trial informationNCT01506609     

Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy,erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial

BackgroundAfatinib has demonstrated clinical benefit in patients with non-small-cell lung cancer progressing after treatment with erlotinib/gefitinib. This phase III trial prospectively assessed whether continued irreversible ErbB-family blockade with afatinib plus paclitaxel has superior outcomes versus switching to chemotherapy alone in patients acquiring resistance to erlotinib/gefitinib and afatinib monotherapy.Patients and methodsPatients with relapsed/refractory disease following ≥1 line of chemotherapy, and whose tumors had progressed following initial disease control (≥12 weeks) with erlotinib/gefitinib and thereafter afatinib (50 mg/day), were randomized 2:1 to receive afatinib plus paclitaxel (40 mg/day; 80 mg/m²/week) or investigator's choice of single-agent chemotherapy. The primary end point was progression-free survival (PFS). Other end points included objective response rate (ORR), overall survival (OS), safety and patient-reported outcomes.ResultsTwo hundred and two patients with progressive disease following clinical benefit from afatinib were randomized to afatinib plus paclitaxel (n = 134) or single-agent chemotherapy (n = 68). PFS (median 5.6 versus 2.8 months, hazard ratio 0.60, P = 0.003) and ORR (32.1% versus 13.2%, P = 0.005) significantly improved with afatinib plus paclitaxel. There was no difference in OS. Global health status/quality of life was maintained with afatinib plus paclitaxel over the entire treatment period. The median treatment duration was 133 and 51 days with afatinib plus paclitaxel and single-agent chemotherapy, respectively; 48.5% of patients receiving afatinib plus paclitaxel and 30.0% of patients receiving single-agent chemotherapy experienced drug-related grade 3/4 adverse events. Treatment-related adverse events were consistent with those previously reported with each agent.ConclusionAfatinib plus paclitaxel improved PFS and ORR compared with single-agent chemotherapy in patients who acquired resistance to erlotinib/gefitinib and progressed on afatinib after initial benefit. LUX-Lung 5 is the first prospective trial to demonstrate the benefit of continued ErbB targeting post-progression, versus switching to single-agent chemotherapy.Trial registration numberNCT01085136 (clinicaltrials.gov).     

Randomized phase III trial of 2nd line gemcitabine and paclitaxel chemotherapy in patients with advanced bladder cancer: short-term versus prolonged treatment [German Association of Urological Oncology (AUO) trial AB 20/99]

BackgroundThe second-line chemotherapeutic treatment for metastatic urothelial cancer (UC) after failure of cisplatin-based first-line therapy needs to be improved. Based on encouraging phase II data of gemcitabine and paclitaxel (Taxol) (GP), this trial was designed to compare a short-term (arm A) versus a prolonged (arm B) second-line combination chemotherapy of GP.Patients and methodsOf 102 randomized patients, 96 were eligible for analysis. Primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rates (ORR) and toxicity.ResultsNeither OS [arm A: 7.8 (95% CI: 4.2–11.4), arm B: 8.0 (95% CI: 4.9–11.1) months] and PFS [arm A: 4.0 (95% CI: 0–8.0), arm B: 3.1 (95% CI: 1.9–4.2) months] nor ORR (arm A: 37.5%, arm B: 41.5%) were significantly different. On prolonged treatment, more patients experienced severe anemia (arm A: 6.7% versus arm B: 26.7% grade III/IV anemia; P = 0.011). In six patients, treatment was stopped during the first cycle due to disease progression or toxicity. Two patients died due to treatment-related toxic effects.ConclusionDue to rapid tumor progression and toxicity at this dosage and schedule in a multicenter setting, it was not feasible to deliver a prolonged regimen. However, a high response rate of ∼40% makes GP a promising second-line treatment option for patients with metastatic UC.     

Platinum versus platinum-combination chemotherapy in platinum-sensitive recurrent ovarian cancer: a meta-analysis using individual patient data

BackgroundThe majority of women with ovarian cancer develop recurrent disease. For patients with a platinum-free interval of >6 months, platinum-based chemotherapy is a treatment of choice. The benefit of platinum-based combination chemotherapy in randomized trials varies, and a meta-analysis was carried out to gain more secure information on the size of the benefit of this treatment.Materials and methodsWe initiated a systematic review and meta-analysis following a pre-specified protocol to determine whether combination chemotherapy is superior to single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer.ResultsA total of five potentially eligible randomized trials were identified that had used combination-platinum chemotherapy versus single-agent platinum chemotherapy in women with relapsed platinum-sensitive ovarian cancer. For one trial (190 patients), adequate contact with the investigators could not be established. Therefore, four trials that randomly assigned 1300 patients were included, with a median follow-up of 36.1 months. Overall survival (OS) analyses were based on 865 deaths and demonstrated evidence for the benefit of combination-platinum chemotherapy (HR = 0.80; 95% CI, 0.64–1.00; P = 0.05). Progression-free survival (PFS) analyses were based on 1167 events and demonstrated strong evidence for the benefit of combination-platinum chemotherapy (HR = 0.68; 95% CI, 0.57–0.81; P < 0.001). There was no evidence of a difference in the relative effect of combination-platinum chemotherapy on either OS or PFS in patient subgroups defined by previous paclitaxel (Taxol) treatment (OS, P = 0.49; PFS, P = 0.66), duration of treatment-free interval (OS, P = 0.86; PFS, P = 0.48) or the number of previous lines of chemotherapy (OS, P = 0.21; PFS, P = 0.27).ConclusionsIn this individual patient data (IPD) meta-analysis, we have demonstrated that combination-platinum chemotherapy improves OS and PFS across all subgroups. This provides the strongest evidence to date of the benefit of combination-platinum over single-agent platinum.     

Trastuzumab combined with doublet or single-agent chemotherapy as first-line therapy for HER2-positive metastatic breast cancer

Purpose

To investigate the efficacy and safety of doublet versus single-agent chemotherapy (CT) plus trastuzumab (H) as first-line therapy for human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer (MBC).

Methods

We searched for randomized clinical trials (RCTs) that evaluated the treatment effects of single-agent or doublet CT+H as first-line therapies for HER2-positive MBC. The main outcomes measured for this study included the overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). A meta-analysis and trial sequential analysis (TSA) were performed, and the study quality was evaluated using the GRADE framework. The PROSPERO registry number of our analysis is CRD42016043766.

Results

The results from four RCTs including 1044 participants were pooled. Moderate-quality evidence indicated that compared with single-agent CT+H, doublet CT+H correlated better with prolonged PFS (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.63–0.75, P < 0.0001) and OS (HR = 0.90, 95% CI 0.88–0.92, P < 0.0001). However, moderate-quality evidence revealed no significant difference between the two regimens regarding the ORR (relative risk [RR] = 1.07, 95% CI 0.98–1.17, P = 0.157), which was confirmed by TSA, indicating that the cumulative Z-curve entered the futility area. Moderate-quality evidence indicated that treatment-related grade 3 or 4 toxicities of thrombocytopenia (RR = 4.08, P = 0.000), nausea/vomiting (RR = 4.26, P = 0.002), diarrhea (RR = 2.81, P = 0.002), and stomatitis (RR = 5.02, P = 0.003) were observed more frequently with doublet CT+H than with single-agent CT+H.

Conclusions

Compared with single-agent CT, the combination of doublet CT with trastuzumab as first-line therapy for HER2-positive MBC is associated with longer PFS and OS, but more treatment-related grade 3 or 4 toxicities. Therefore, doublet CT appears to be an appropriate regimen for HER2-positive MBC with a good performance status.

     

Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer

Background

The correlation between progression-free survival (PFS) or time to progression (TTP) and overall survival (OS) has been evaluated in patients with advanced gastric cancer (AGC) who received first-line chemotherapy. No corresponding analysis has been done in patients who have undergone second-line chemotherapy.

Methods

We evaluated the correlation between PFS, TTP, objective response rate (ORR), disease control rate (DCR), and OS in patients with AGC who underwent second-line chemotherapy. Correlations were evaluated by Spearman rank correlation coefficient (ρ).

Results

Sixty-four trials, including 10 randomized studies, were selected for analysis. Median PFS/TTP moderately correlated with OS (ρ = 0.56). The correlation tended to be stronger in non-Asian trials (ρ = 0.74) than in Asian trials (ρ = 0.37). ORR and DCR did not strongly correlate with OS (ρ = 0.38 for ORR; ρ = 0.54 for DCR). The hazard ratio of PFS and OS in each of the arms of the 10 randomized studies also showed a low correlation (ρ = 0.36).

Conclusions

PFS/TTP, ORR, and DCR did not correlate sufficiently with OS to be used as surrogate endpoints in patients with AGC who have undergone second-line chemotherapy. Further research is needed based on individual patient data from ongoing randomized trials.     

Outcome of second-line treatment after first-line chemotherapy with the GONO FOLFOXIRI regimen

PurposeFOLFOXIRI demonstrated higher efficacy compared to 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) as first-line treatment of metastatic colorectal cancer. We evaluated the outcome of second-line treatments among 196 patients treated with first-line FOLFOXIRI in three consecutive trials conducted by the Gruppo Oncologico Nord Ovest group.Patients and MethodsOne hundred seventy-two of 196 patients so far progressed and 136 (79%) received second-line therapies: 32 (24%) were rechallenged with FOLFOXIRI, 52 (38%) were treated with irinotecan- or oxaliplatin-based doublets, and 52 (38%) received fluoropyrimidine plus mytomicin C or single-agent chemotherapy. Only 10 patients received bevacizumab (3) or cetuximab (7) with chemotherapy. Activity and efficacy data were collected and subgroup analyses were performed according to the regimen administered.ResultsOverall response rate (RR) was 23%; median progression-free survival (PFS) and overall survival (OS) were 5.9 and 13.2 months, respectively. At an exploratory subgroup analysis, retreatment with FOLFOXIRI was associated with longer PFS (8.2 versus 6.3 months; P = .003, hazard ratio [HR] = 0.61) and OS (19.3 versus 14.0 months; P = .02, HR = 0.57) compared with doublets; single-agent chemotherapy or fluoropyrimidine plus mytomicin C was significantly lower in terms of RR (8%), PFS (3.0 months), and OS (8.7 months) compared with FOLFOXIRI or doublets.ConclusionsFirst-line FOLFOXIRI does not impair the efficacy of second-line treatments. In some patients rechallenge with FOLFOXIRI may represent a valid option, although potential imbalances in prognostic factors due to better patient selection should be considered.     

Pooled analysis of individual patient data from capecitabine monotherapy clinical trials in locally advanced or metastatic breast cancer

We assessed the efficacy and safety of capecitabine across treatment lines, and the impact of patient and disease characteristics on outcomes using data from phase II/III trials. Individual patient data were pooled from seven Roche/Genentech-led trials conducted from 1996 to 2008 where single-agent capecitabine was the test or control regimen for metastatic breast cancer (MBC). Data were analyzed from 805 patients: 268 in the first-line metastatic setting and 537 in the second-line or later setting. Baseline characteristics were balanced across treatment lines. Patients receiving second-line or later versus first-line capecitabine had lower objective response rates (ORR: 19.0 vs. 25.0?%, respectively, odds ratio 0.70; 95?% CI: 0.5?C1.0) and significantly shorter progression-free survival (PFS: median 112.0?days [3.7?months] vs. 150.0?days [4.9?months]; p?<?0.0001) and overall survival (OS: median 396.0?days [13.0?months] vs. 666.0?days [21.9?months]; p?<?0.0001). In multivariate analysis by backward elimination, significantly improved ORR (p?=?0.0036), PFS (p?<?0.0001) and OS (p?<?0.0001) with capecitabine were demonstrated in patients with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive versus both ER and PgR-negative tumors. Hand-foot syndrome (HFS) was the most common adverse event (AE) in 63?% of patients. Overall, 7?% of patients discontinued and two patients (<1?%) died from treatment-related AEs. Significantly improved survival was observed in patients developing capecitabine-related HFS (p?<?0.0001 PFS/OS) or diarrhea (p?=?0.004 OS; p?=?0.0045 PFS) versus patients without these events. In this pooled analysis of individual patient data, first-line capecitabine was associated with improved ORR, PFS, and OS versus second or later lines. Multivariate analyses identified greater ORR, PFS, and OS with capecitabine in patients with ER and/or PgR-positive versus ER/PgR-negative tumors. Safety was in-line with previous phase III trials in MBC.     

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

BackgroundThe randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61–0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL).Patients and methodsPatients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety.ResultsOf the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59–1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68–1.05) or OS (HR = 0.96, 95% CI 0.76–1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected.ConclusionsIn this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life.ClinicalTrials.govNCT01250379.     

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

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

Phase III,randomised trial of avelumab versus physician’s choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300

BackgroundThere currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician’s choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC.Patients and methodsPatients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician’s choice of chemotherapy (paclitaxel 80 mg/m² on days 1, 8, and 15 or irinotecan 150 mg/m² on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.ResultsA total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9–1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4–2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm.ConclusionsTreatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy.Trial registrationClinicalTrials.gov: NCT02625623.     

Paclitaxel with or without trametinib or pazopanib in advanced wild-type BRAF melanoma (PACMEL): a multicentre,open-label,randomised, controlled phase II trial

BackgroundAdvanced melanoma treatments often rely on immunotherapy or targeting mutations, with few treatment options for wild-type BRAF (BRAF-wt) melanoma. However, the mitogen-activated protein kinase pathway is activated in most melanoma, including BRAF-wt. We assessed whether inhibiting this pathway by adding kinase inhibitors trametinib or pazopanib to paclitaxel chemotherapy improved outcomes in patients with advanced BRAF-wt melanoma in a phase II, randomised and open-label trial.Patients and methodsPatients were randomised (1 : 1 : 1) to paclitaxel alone or with trametinib or pazopanib. Paclitaxel was given for a maximum of six cycles, while 2 mg trametinib and 800 mg pazopanib were administered orally once daily until disease progression or unacceptable toxicity. Participants and investigators were unblinded. The primary end point was progression-free survival (PFS). Key secondary end points included overall survival (OS) and objective response rate (ORR).ResultsParticipants were randomised to paclitaxel alone (n = 38), paclitaxel and trametinib (n = 36), or paclitaxel and pazopanib (n = 37). Adding trametinib significantly improved 6-month PFS [time ratio (TR), 1.47; 90% confidence interval (CI) 1.08–2.01, P = 0.04] and ORR (42% versus 13%; P = 0.01) but had no effect on OS (P = 0.25). Adding pazopanib did not benefit 6-month PFS; (TR 1.36; 90% CI 0.96–1.93; P = 0.14), ORR, or OS. Toxicity increased in both combination arms.ConclusionIn this phase II trial, adding trametinib to paclitaxel chemotherapy for BRAF-wt melanoma improved PFS and substantially increased ORR but did not impact OS.This study was registered with the EU Clinical Trials Register, EudraCT number 2011-002545-35, and with the ISRCTN registry, number 43327231.     

Impact of Response to Prior Chemotherapy in Patients With Advanced Urothelial Carcinoma Receiving Second-Line Therapy: Implications for Trial Design

BackgroundThe prognostic impact of response to prior chemotherapy independent of performance status (PS), hemoglobin (Hb), liver metastasis (LM), and time from prior chemotherapy (TFPC) in the context of second-line therapy for advanced urothelial carcinoma (UC) is unknown.MethodsSix phase II trials evaluating second-line therapy (n = 504) were pooled. Patients who received prior therapy for metastatic disease were eligible for analysis if Hb, LM, PS, and TFPC were available. Response by Response Evaluation Criteria in Solid Tumors 1.0 to first-line therapy was recorded. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration using the Kaplan–Meier method.ResultsA total of 275 patients were evaluable for analysis. Patients received gemcitabine-paclitaxel, cyclophosphamide-paclitaxel, pazopanib, docetaxel plus vandetanib/placebo, or vinflunine (2 trials). Those with prior response (n = 111) had a median OS of 8.0 months (95% confidence interval [CI], 6.8-9.4), compared with 5.9 months (95% CI, 5.0-6.6) for those without prior response (n = 164). Those with prior response had a median PFS of 3.0 months (95% CI, 2.6-4.0) compared with 2.6 months (95% CI, 2.0-2.8) in patients without response. Multivariable analysis did not reveal a significant independent impact of prior response on PFS and OS.ConclusionsBest prior response in patients receiving prior chemotherapy for metastatic disease did not confer an independent prognostic impact with second-line therapy for advanced UC. Given that the setting of prior chemotherapy (metastatic or perioperative) has not appeared significant in a prior study, patients who received prior chemotherapy in perioperative or metastatic settings may be enrolled in the same second-line trial stratified for PS, Hb, LM, and TFPC.     

A phase II double-blind study to investigate efficacy and safety of two doses of the triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung cancer

BackgroundTo assess the efficacy, safety, tolerability and pharmacokinetics of BIBF 1120 in patients with stage IIIB/IV non-small-cell lung cancer (NSCLC).MethodsPatients with locally advanced or metastatic relapsed NSCLC in whom first- or second-line platinum-based chemotherapy failed were randomly allocated to daily 250 mg BIBF 1120 b.i.d. or 150 mg BIBF 1120 b.i.d. Primary end points were progression-free survival (PFS) and objective tumour response (RECIST). Incidence and severity of adverse events (AEs) were reported.ResultsSeventy-three patients received BIBF 1120. Median PFS was 6.9 weeks, with no significant difference between treatment arms. Median overall survival (OS) was 21.9 weeks. Eastern Cooperative Oncology Group (ECOG) 0–1 patients (n = 56) had a median PFS of 11.6 weeks and a median OS of 37.7 weeks. Tumour stabilisation was achieved in 46% of patients (ECOG 0–1 patients: 59%), with one confirmed partial response (250 mg b.i.d.). Most commonly reported drug-related AEs were nausea (57.5%), diarrhoea (47.9%), vomiting (42.5%), anorexia (28.8%), abdominal pain (13.7%) and reversible alanine transaminase (13.7%) and aspartate aminotransferase elevations (9.6%). BIBF 1120 displayed dose-linear pharmacokinetic characteristics.ConclusionContinuous treatment with BIBF 1120 was well tolerated, with no difference in efficacy between treatment arms. PFS and objective response with single-agent treatment in advanced disease warrants further exploration.     

Reduced-dose of doublet chemotherapy combined with anti-EGFR antibodies in vulnerable older patients with metastatic colorectal cancer: Data from the REVOLT study

ObjectivesTo assess the toxicity patterns and effectiveness of doublet chemotherapy when administered at reduced doses of 20% (FOLFOX or FOLFIRI) in combination with anti-EGFR antibodies (cetuximab or panitumumab) in old, vulnerable patients with metastatic colorectal cancer (mCRC).Patients and methodsWe performed a retrospective observational study of RAS and BRAF wild-type, vulnerable patients aged ≥70 years with previously untreated mCRC. The primary endpoint was safety, and secondary endpoints were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsOne hundred and eighteen patients were collected from 14 selected Italian centres. The median age was 75 (range, 70–85). Geriatric screening by G8 tool gave a score ≤ 14 in all patients. In total, 75 and 43 patients received FOLFOX or FOLFIRI, respectively, in combination with panitumumab (53%) or cetuximab (47%). The overall incidence of grade (G) 3–4 neutropenia was 11.8%, and for skin rash 11%. The most frequent adverse events were G1–2 skin rash (49.1%), G1–2 diarrhea (21.1%) and G1–2 nausea (17.7%). The ORR was 57.3%. Stable disease was observed in 29.1% of patients, with a disease control rate of 86.4%. With a median follow-up of 18 months, the median PFS was 10.0 months (95% confidence interval [CI]: 8.5–11.4), while the median OS was 18.0 months (95% CI: 16.0–19.9). No statistically significant difference was observed between the regimens in terms of ORR, PFS (p = 0.908), and OS (p = 0.832).ConclusionThis study shows that with an appropriate design, including reduced doses, vulnerable older patients best tolerate chemotherapy when combined with anti-EGFR antibodies.     

Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001–02)

BackgroundMetastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients.Patients and methodsElderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2–irinotecan or simplified LV5FU2–irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2–irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR).ResultsFrom June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2–irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75–92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66–1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67–1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75–1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55–0.92). More patients presented grade 3–4 toxicities in IRI (52.2% versus 76.3%).ConclusionIn this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2.Clinicaltrials.govNCT00303771.     

Docetaxel–cisplatin might be superior to docetaxel–capecitabine in the first-line treatment of metastatic triple-negative breast cancer

BackgroundTriple-negative breast cancer (TNBC) may be more sensitive to platinum. This study was to compare platinum-based regimen with nonplatinum regimen in the first-line treatment of advanced TNBC.Patients and methodsEligible metastatic TNBC (mTNBC) women without prior treatment for advanced disease were randomized (1 : 1) to receive either docetaxel–cisplatin (TP) or docetaxel –capecitabine (TX) q3w for up to 6 cycles, until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR) and the secondary end points included progression-free survival (PFS) and overall survival (OS). In total 53 patients were enrolled.ResultsThe median follow-up was 24 months. ORR was higher in the TP group than in the TX group (63.0% versus 15.4%, P = 0.001). PFS was more than doubled (10.9 months versus 4.8 months, P < 0.001) and median OS was also greatly improved (32.8 months versus 21.5 months, P = 0.027). Toxic effects were not different except G3/4 vomiting and G2/3 hand-foot syndrome.ConclusionsThis study suggested that cisplatin-based chemotherapy was superior to capecitabine-based regimen in the first-line treatment of mTNBC, as measured by ORR, PFS and OS. Further large-scale study should be warranted. These results are not sufficient to change clinical practice.     

Efficacy of Immune Checkpoint Inhibitors Alone or in Combination With Chemotherapy in NSCLC Harboring ERBB2 Mutations

IntroductionIn contrast to other driver mutations, no targeted therapies have yet been approved in ERBB2-mutated NSCLC (HER2mu NSCLC). Nevertheless, several compounds have revealed promising early efficacy data, which need to be evaluated in the context of current standard approaches. Although data on the efficacy of immune checkpoint inhibitors (ICIs) in second or subsequent lines of treatment remain limited and conflicting, there are virtually no data on patient outcome under ICI/platinum-doublet combinations in the first-line setting.MethodsWe retrospectively evaluated outcomes of patients with HER2mu NSCLC treated with ICI alone or in combination with chemotherapy within the German National Network Genomic Medicine Lung Cancer consortium by means of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsICI either in combination with chemotherapy or as monotherapy was applied as first-line treatment in 27 patients, whereas 34 received single-agent ICI in second or subsequent lines. Patient characteristics were in line with previously published data. In treatment-naive patients receiving ICI in combination with chemotherapy, the ORR, median PFS, and OS rate at 1 year were 52%, 6 months, and 88%, respectively. In second or subsequent lines, ICI monotherapy was associated with an ORR of 16%, a median PFS of 4 months, and a median OS of 10 months.ConclusionsICIs are effective as monotherapy and in combination with platinum-doublet chemotherapy. Therefore, ICI-based treatments may be found as the current standard of care and benchmark for targeted therapies in HER2mu NSCLC.     

Six-Month Progression-Free Survival as the Primary Endpoint to Evaluate the Activity of New Agents as Second-line Therapy for Advanced Urothelial Carcinoma

ObjectiveSecond-line systemic therapy for advanced urothelial carcinoma (UC) has substantial unmet needs, and current agents show dismal activity. Second-line trials of metastatic UC have used response rate (RR) and median progression-free survival (PFS) as primary endpoints, which may not reflect durable benefits. A more robust endpoint to identify signals of durable benefits when investigating new agents in second-line trials may expedite drug development. PFS at 6 months (PFS6) is a candidate endpoint, which may correlate with overall survival (OS) at 12 months (OS12) and may be applicable across cytostatic and cytotoxic agents.MethodsTen second-line phase II trials with individual patient outcomes data evaluating chemotherapy or biologics were combined for discovery, followed by external validation in a phase III trial. The relationship between PFS6/RR and OS12 was assessed at the trial level using Pearson correlation and weighted linear regression, and at the individual level using Pearson chi-square test with Yates continuity correction.ResultsIn the discovery dataset, a significant correlation was observed between PFS6 and OS12 at the trial (R² = 0.55, Pearson correlation = 0.66) and individual levels (82%, Қ = 0.45). Response correlated with OS12 at the individual level less robustly (78%, Қ = 0.36), and the trial level association was not statistically significant (R² = 0.16, Pearson correlation = 0.37). The correlation of PFS6 (81%, Қ = 0.44) appeared stronger than the correlation of response (76%, Қ = 0.17) with OS12 in the external validation dataset.ConclusionsPFS6 is strongly associated with OS12 and appears more optimal than RR to identify active second-line agents for advanced UC.