Targeted agents such as the type II anti-CD20 antibody obinutuzumab and the B-cell lymphoma-2 antagonist venetoclax have shown impressive therapeutic activity in chronic lymphocytic leukaemia. The ...CLL2-BAG trial was initiated to investigate the combination of these two agents in patients with chronic lymphocytic leukaemia.
In this ongoing multicentre, open-label, investigator-initiated phase 2 trial, patients (aged ≥18 years) with chronic lymphocytic leukaemia requiring treatment according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance status of 0–2 were enrolled at 16 sites in Germany. Patients with a relevant tumour load (absolute lymphocyte count ≥25 000 cells per μL or lymph nodes with a diameter of ≥5 cm) received sequential treatment of debulking with two cycles of bendamustine (70 mg/m2 intravenously on days 1 and 2 of each of the two 28-day cycles), followed by induction and maintenance with obinutuzumab (1000 mg intravenously on days 1–2, 8, and 15 of the first induction cycle, every 4 weeks in induction cycles 2–6, and every 12 weeks in the maintenance phase) and oral venetoclax (starting in induction cycle 2 with 20 mg/day, with a weekly dose escalation over 5 weeks to the target dose of 400 mg/day). The primary endpoint was the proportion of patients achieving an overall response by investigator assessment at the end of induction treatment. All patients who received at least two induction cycles were included in the efficacy analyses and all patients who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02401503.
Between May 6, 2015, and Jan 4, 2016, 66 patients were enrolled (35 treatment naive and 31 with relapsed or refractory disease), three of whom were excluded from the efficacy analysis because they received fewer than two induction cycles. Of the remaining 63 patients in the efficacy-evaluable population, 34 patients (54%) were treatment naive and 29 (46%) had relapsed or refractory disease. At data cutoff (Feb 28, 2017), all patients had completed induction treatment. At the end of the induction, 60 (95%) of 63 patients (95% CI 87–99) had responded, including all 34 patients in the treatment-naive cohort and 26 90% of 29 relapsed or refractory patients. The most common grade 3–4 adverse events during debulking were neutropenia and anaemia (five 11% of 47 patients each), and thrombocytopenia and infection (three 6% each). The most common grade 3–4 adverse events during induction were neutropenia (29 44% of 66 patients), infection (nine 14%), thrombocytopenia (eight 12%), infusion-related reactions (five 8%), and secondary primary malignancy (four 6%). 89 serious adverse events, including 69 related to study treatment, were reported. These serious adverse events were also mainly infections (four cases in four patients during debulking and 18 cases in 11 patients during induction) and cytopenia (four cases in four patients during debulking and ten cases in seven patients in induction). Five relapsed or refractory patients died: three cases of sepsis were deemed related to study treatment, whereas two deaths from Richter's transformation were not.
The sequential application of bendamustine and obinutuzumab combined with venetoclax caused no unexpected or cumulative toxicities. The high proportion of patients who achieved overall responses, both treatment-naive and relapsed or refractory patients irrespective of physical fitness and genetic risk factors, compare favourably to established chronic lymphocytic leukaemia therapies. Further follow-up will help to define whether the remissions with eradication of minimal residual disease achieved with this combination are durable after treatment discontinuation.
F Hoffmann-La Roche and AbbVie.
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative ...effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio HR 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 25% of 297 patients in the cetuximab group vs 62 21% of 295 patients in the bevacizumab group), skin reactions (77 26% vs six 2%), and diarrhoea (34 11% vs 40 14%). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.
Trastuzumab is the only approved targeted drug for first-line treatment of human epidermal growth factor receptor 2-positive (HER2+) metastatic gastric cancer (mGC). However, not all patients respond ...and most eventually progress. The multicenter VARIANZ study aimed to investigate the background of response and resistance to trastuzumab in mGC.
Patients receiving medical treatment for mGC were prospectively recruited in 35 German sites and followed for up to 48 months. HER2 status was assessed centrally by immunohistochemistry and chromogenic in situ hybridization. In addition,
gene expression was assessed using qPCR.
Five hundred forty-eight patients were enrolled, and 77 had HER2+ mGC by central assessment (14.1%). A high deviation rate of 22.7% between central and local test results was seen. Patients who received trastuzumab for centrally confirmed HER2+ mGC (central HER2+/local HER2+) lived significantly longer as compared with patients who received trastuzumab for local HER2+ but central HER2- mGC (20.5 months, n = 60
10.9 months, n = 65; hazard ratio, 0.42; 95% CI, 8.2 to 14.4;
< .001). In the centrally confirmed cohort, significantly more tumor cells stained HER2+ than in the unconfirmed cohort, and the
amplification ratio was significantly higher. A minimum of 40% HER2+ tumor cells and a
amplification ratio of ≥ 3.0 were calculated as optimized thresholds for predicting benefit from trastuzumab.
Significant discrepancies in HER2 assessment of mGC were found in tumor specimens with intermediate HER2 expression. Borderline HER2 positivity and heterogeneity of HER2 expression should be considered as resistance factors for HER2-targeting treatment of mGC. HER2 thresholds should be reconsidered. Detailed reports with quantification of
expression and amplification levels may improve selection of patients for HER2-directed treatment.
Summary Background FIRE-3 compared first-line 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) plus cetuximab with FOLFIRI plus bevacizumab in patients with KRAS exon 2 wild-type metastatic ...colorectal cancer. The same study also reported an exploratory analysis of a subgroup of patients with tumours that were wild-type at other RAS genes ( KRAS and NRAS exons 2–4). We report here efficacy results for the FIRE-3 final RAS ( KRAS/NRAS , exons 2–4) wild-type subgroup. Moreover, new metrics of tumour dynamics were explored during a centralised radiological review to investigate how FOLFIRI plus cetuximab conferred overall survival benefit in the absence of differences in investigator-assessed objective responses and progression-free survival. Methods FIRE-3 was a randomised phase 3 trial comparing FOLFIRI plus cetuximab with FOLFIRI plus bevacizumab in the first-line treatment of patients with KRAS exon 2 wild-type metastatic colorectal cancer. The primary endpoint of the FIRE-3 study was the proportion of patients achieving an objective response according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 in the intention-to-treat population. A centralised radiological review of CT scans was done in a post-hoc analysis to assess objective response according to RECIST 1.1, early tumour shrinkage, depth of response, duration of response, and time to response in the final RAS wild-type subgroup. Comparisons between treatment groups with respect to objective response rate and early tumour shrinkage were made using Fisher's exact test (two-sided), while differences in depth of response were investigated with a two-sided Wilcoxon test. This trial is registered at ClinicalTrials.gov , number NCT00433927. Findings In the final RAS wild-type population (n=400), median overall survival was better in the FOLFIRI plus cetuximab group than the FOLFIRI plus bevacizumab group (33·1 months 95% CI 24·5–39·4 vs 25·0 months 23·0–28·1; hazard ratio 0·70 0·54–0·90; p=0·0059), although investigator-assessed objective response and progression-free survival were comparable between treatment groups. Centralised radiological review of CT-assessable patients (n=330) showed that the proportion of patients achieving an objective response (113 of 157, 72·0% 95% CI 64·3–78·8 vs 97 of 173, 56·1% 48·3–63·6; p=0·0029), frequency of early tumour shrinkage (107 of 157, 68·2% 60·3–75·4 vs 85 of 173, 49·1% 41·5–56·8; p=0·0005), and median depth of response (–48·9% –54·3 to −42·0 vs −32·3% –38·2 to −29·2; p<0·0001) were significantly better in extended RAS wild-type patients receiving FOLFIRI plus cetuximab versus those receiving FOLFIRI plus bevacizumab. No differences in duration of response and time to response were observed between treatment groups. Interpretation This analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Funding Merck KGaA and Pfizer.
Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for ...progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes.
The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated.
Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours.
FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS.
NCT00433927.
The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with
wild-type metastatic ...colorectal cancer.
Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873).
Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months
5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85;
= .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months
25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18;
= .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36;
= .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).
In
wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.
Real‐world data on the first‐line treatment of patients with advanced non‐small cell lung cancer (NSCLC) are still limited. The NEPTUN study evaluated effectiveness and safety of first‐line ...nab‐paclitaxel (Abraxane) plus carboplatin (nab‐P/C) in patients with advanced NSCLC in routine clinical practice in Germany. Patients included in our study were aged ≥18 years, diagnosed with locally advanced or metastatic NSCLC and with decision for first‐line nab‐P/C in routine clinical practice. Primary objective was 6‐month progression‐free survival rate (PFS6), secondary objectives included overall survival (OS), overall response rate (ORR) and safety. From 2016 to 2019, 408 patients from 75 sites were enrolled. PFS6 was 39.5% (95% CI: 34.2‐44.8), median PFS was 5.1 months (95% CI: 4.6‐5.6), ORR was 42.9% (95% CI: 37.7‐48.2). Median OS was 10.5 months (95% CI: 9.2‐11.6). In subgroup analyses, median OS for squamous vs non‐squamous histology was 11.5 months (95% CI: 9.2‐13.8) vs 9.8 months (95% CI: 8.1‐11.3) and for patients aged ≥70 vs <70 years median OS was 12.4 months (95% CI: 9.8‐15.1) vs 9.6 months (95% CI: 7.7‐11.1). Adverse events (AEs) related to nab‐paclitaxel were reported in 247 (66.4%) patients, while carboplatin‐related AEs were documented in 224 (60.2%) patients. Most frequently related AEs were leukopenia (22.3%) for nab‐paclitaxel and anemia (20.2%) for carboplatin. Nab‐P/C‐related deaths were reported in 2 (0.5%) patients (sepsis and neutropenic sepsis). No new or unexpected safety signals emerged. These results support the effectiveness and safety of first‐line nab‐P/C in patients with advanced NSCLC reported in the pivotal trial and highlight the clinical value of this regimen in the real‐world setting.
What's new?
Non‐small cell lung cancer (NSCLC) patients often are diagnosed in advanced stages of disease, at which point, in cases without targetable mutations, first‐line therapy typically entails platinum‐based chemotherapy. A recommended therapy is albumin‐bound paclitaxel plus carboplatin combination (nab‐P/C). Here, the authors evaluated the use of first‐line nab‐P/C therapy in a real‐world setting in patients with locally advanced or metastatic NSCLC. Results show that survival was improved among nab‐P/C‐treated patients, with better outcomes observed particularly among patients age 70 and older and in those with mild to moderate renal impairment. Improvements in tumor response, independent of histological subtype, were also observed.
Early tumor shrinkage (ETS) has been highlighted as a favorable prognostic factor related to progression‐free survival (PFS) and overall survival (OS) in cytotoxic treatment of metastatic colorectal ...cancer. Data from a randomized phase III study comparing infusional 5‐fluorouracil plus irinotecan (FUFIRI) versus irinotecan plus oxaliplatin (mIROX) were evaluated. Patient groups were analyzed according to the relative change in maximum tumor diameter between baseline and after 7 weeks of treatment. The ETS cohort was defined as a decrease of ≥20%. Additionally, the non‐ETS cohort was subdivided into “minor shrinkage” (0–19%), “tumor progression” (any increase) and development of “new metastatic lesions”. Progression‐free survival and OS were estimated in all patient subgroups. Assessment of ETS was possible in 201 patients. Early tumor shrinkage was observed in 47% (94/201) and non‐ETS in 53% (107/201) of patients. Patients with ETS had a more favorable outcome with regard to PFS (9.9 months vs 6.1 months, P = 0.029) and OS (27.5 months vs 17.8 months, P = 0.002). In the non‐ETS subgroups, patients with “minor shrinkage” (PFS 8.4 months, OS 21.6 months) showed a markedly better outcome than patients with “early tumor progression” (PFS 4.0 months, OS 15.3 months) or with “new metastatic lesions (PFS 2.2 months, OS 7.6 months). In conclusion, ETS assessment offers accelerated response evaluation when compared to RECIST. In patients treated with chemotherapy alone, ETS ≥20% is associated with excellent outcome. Non‐ETS is a heterogeneous subgroup where patients with minor shrinkage clearly benefit from treatment, and patients with early progression or development of new lesions have an unfavorable prognosis.
Secondary resection of metastases is recommended in metastatic colorectal cancer (mCRC). Data describing changes in mutational profiles of corresponding primary tumor and metastatic tissue after ...conversion treatment are limited. Next generation sequencing was performed in formalin‐fixed mCRC samples from patients of the FIRE‐3 trial (FOLFIRI plus cetuximab or bevacizumab) before treatment start (baseline) and after secondary resection of metastases (post baseline). Changes of mutational profiles and tumor mutational burden (TMB) were assessed within a post‐hoc analysis. Median overall survival (OS), progression‐free survival (PFS) and objective response rate (ORR) were compared between treatment arms. Paired tumor samples were obtained from 25 patients (19 RAS wild‐type, 6 RAS mutant by pyrosequencing). ORR (92.0% vs 58.0%) and OS (60.8 vs 35.4 months, hazard ratio = 0.39 95% CI 0.14‐1.12, P = .08) were higher for patients receiving cetuximab. After conversion therapy, 56 alterations (42 in the cetuximab and 14 in the bevacizumab arm) were newly observed in 18 patients (9 each treated with cetuximab or bevacizumab). Gains (n = 21) and losses (n = 21) of alterations occurred during cetuximab‐based treatment, while mainly gains of alterations occurred during bevacizumab (n = 10). Three of nine patients treated with cetuximab that presented a change of mutational profiles, developed resistance to cetuximab. Mutational profiles were largely comparable before and after treatment with anti‐VEGF or anti‐EGFR directed monoclonal antibodies after secondary resection. Mutations associated with resistance to anti‐EGFR antibodies were observed in only one‐third of patients.
What's new?
Secondary resection for initially unresectable metastatic colorectal cancer (mCRC) is associated with improved prognosis. Predicting opportunities for secondary resection, however, depends on the discovery of molecular changes in primary tumor and corresponding metastatic tumor tissue. Here, mutational profiles were investigated for mCRC patients in the FIRE‐3 trial, a study of FOLFIRI plus cetuximab or bevacizumab as first‐line therapy for irresectable mCRC. Of nine mCRC patients undergoing cetuximab therapy who experienced changes in tumor mutational profile, one‐third became resistant to cetuximab. For patients treated with anti‐VEGF and anti‐EGFR antibodies, mutational profiles were similar before and after treatment and following secondary resection.
Abstract Background Understanding how to sequence targeted therapies for metastatic renal cell carcinoma (mRCC) is important for maximisation of clinical benefit. Objectives To prospectively evaluate ...sequential use of the multikinase inhibitors sorafenib followed by sunitinib (So-Su) versus sunitinib followed by sorafenib (Su-So) in patients with mRCC. Design, setting, and participants The multicentre, randomised, open-label, phase 3 SWITCH study assessed So-Su versus Su-So in patients with mRCC without prior systemic therapy, and stratified by Memorial Sloan Kettering Cancer Center risk score (favourable or intermediate). Intervention Patients were randomised to sorafenib 400 mg twice daily followed, on progression or intolerable toxicity, by sunitinib 50 mg once daily (4 wk on, 2 wk off) (So-Su), or vice versa (Su-So). Outcome measurements and statistical analysis The primary endpoint was improvement in progression-free survival (PFS) with So-Su versus Su-So, assessed from randomisation to progression or death during second-line therapy. Secondary endpoints included overall survival (OS) and safety. Results and limitations In total, 365 patients were randomised (So-Su, n = 182; Su-So, n = 183). There was no significant difference in total PFS between So-Su and Su-So (median 12.5 vs 14.9 mo; hazard ratio HR 1.01; 90% confidence interval CI 0.81–1.27; p = 0.5 for superiority). OS was similar for So-Su and Su-So (median 31.5 and 30.2 mo; HR 1.00, 90% CI 0.77–1.30; p = 0.5 for superiority). More So-Su patients than Su-So patients reached protocol-defined second-line therapy (57% vs 42%). Overall, adverse event rates were generally similar between the treatment arms. The most frequent any-grade treatment-emergent first-line adverse events were diarrhoea (54%) and hand-foot skin reaction (39%) for sorafenib; and diarrhoea (40%) and fatigue (40%) for sunitinib. Conclusions Total PFS was not superior with So-Su versus Su-So. These results demonstrate that sorafenib followed by sunitinib and vice versa provide similar clinical benefit in mRCC. Patient summary We investigated if total progression-free survival (PFS) is improved in patients with advanced/metastatic kidney cancer who are treated with sorafenib and then with sunitinib (So-Su), compared with sunitinib and then sorafenib (Su-So). We found that total PFS was not improved with So-Su compared with Su-So, but both treatment options were similarly effective in patients with advanced/metastatic kidney cancer. Trial registration ClinicalTrials.gov identifier NCT00732914 , www.clinicaltrials.gov
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