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.
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.
Summary Background Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent ...lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas. Methods We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m2 on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m2 , doxorubicin 50 mg/m2 , and vincristine 1·4 mg/m2 on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m2 on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov , number NCT00991211 , and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335. Findings 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25–57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69·5 months 26·1 to not yet reached vs 31·2 months 15·2–65·7; hazard ratio 0·58, 95% CI 0·44–0·74; p<0·0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0·0001), haematological toxicity (77 30% vs 173 68%; p<0·0001), infections (96 37% vs 127 50%); p=0·0025), peripheral neuropathy (18 7% vs 73 29%; p<0·0001), and stomatitis (16 6% vs 47 19%; p<0·0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 16% vs 23 9%; p=0·024). Interpretation In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects. Funding Roche Pharma AG, Ribosepharm/Mundipharma GmbH.
Summary Background Fludarabine-based chemoimmunotherapy with rituximab is frequently used in patients with indolent and mantle-cell lymphomas who relapse after alkylating chemotherapy. We aimed to ...compare the efficacy and safety of rituximab with bendamustine or fludarabine in patients with relapsed, indolent, non-Hodgkin lymphoma and mantle-cell lymphoma. Methods For this randomised, non-inferiority, open-label, phase 3 trial, we recruited patients from 55 centres in Germany, who were subsequently randomised centrally according to prespecified randomisation lists with permuted blocks of randomly variable block size to rituximab (375 mg/m2 , day 1) plus either bendamustine (90 mg/m2 , days 1 and 2) or fludarabine (25 mg/m2 , days 1–3) every 28 days for a maximum of six 28-day cycles. Patients were aged 18 years or older with a WHO performance status of 0–2 and had relapsed or refractory indolent or mantle-cell lymphoma; patients refractory to regimens that included rituximab, bendamustine, or purine analogue drugs were excluded. Patients were stratified by histological subtypes of lymphoma and by their latest previous therapies. Treatment allocation was not masked. The primary endpoint was progression-free survival and the final analysis was completed per protocol. Non-inferiority of bendamustine plus rituximab versus fludarabine plus rituximab was defined as a difference of less than 15% in 1-year progression-free survival. The protocol was amended in July, 2006, after approval of rituximab maintenance (375 mg/m2 every 3 months for up to 2 years), which was then given to patients achieving a response to either trial treatment. This study is registered with ClinicalTrials.gov , number NCT01456351 (closed to enrolment, follow-up is ongoing). Findings Between Oct 8, 2003, and Aug 5, 2010, we randomly assigned 230 patients to treatment groups (116 bendamustine plus rituximab, 114 fludarabine plus rituximab). 11 patients were excluded for protocol violations and were not followed up further (two in the bendamustine plus rituximab group and nine in the fludarabine plus rituximab group). Thus, 219 patients were included in the per-protocol analysis (114 bendamustine plus rituximab, 105 fludarabine plus rituximab). 1-year progression-free survival with bendamustine plus rituximab was 0·76 (95% CI 0·68–0·84) and 0·48 (0·39–0·58) with fludarabine plus rituximab (non-inferiority p<0·0001). At a median follow-up of 96 months (IQR 73·2–112·9), median progression-free survival with bendamustine plus rituximab was 34·2 months (95% CI 23·5–52·7) and 11·7 months (8·0–16·1) with fludarabine plus rituximab (hazard ratio HR 0·54 95% CI 0·38–0·72, log-rank test p<0·0001). Safety outcomes were similar in both groups, with 46 serious adverse events recorded (23 in the bendamustine plus rituximab group and 23 in the fludarabine plus rituximab group), most commonly myelosuppression and infections. Interpretation In combination with rituximab, bendamustine was more effective than fludarabine, suggesting that bendamustine plus rituximab may be the preferred treatment option for patients with relapsed indolent and mantle-cell lymphomas. Funding Roche Pharma AG, Ribosepharm GmbH, Mundipharma GmbH, Studiengruppe indolente Lymphome (StiL).
This study investigated the impact of comorbidity in 555 patients with chronic lymphocytic leukemia enrolled in two trials of the German Chronic Lymphocytic Leukemia Study Group on first-line ...treatment with fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Patients with two or more comorbidities and patients with less than two comorbidities differed in overall survival (71.7 versus 90.2 months; P<0.001) and progression-free survival (21.0 versus 31.5 months; P<0.01). After adjustment for other prognostic factors and treatment, comorbidity maintained its independent prognostic value in a multivariate Cox regression analysis. Chronic lymphocytic leukemia was the major cause of death in patients with two or more comorbidities. Disease control in patients with two or more comorbidities was better with fludarabine plus cyclophosphamide than with fludarabine treatment, but not with fludarabine compared to chlorambucil treatment. These results give insight into interactions between comorbidity and therapy of chronic lymphocytic leukemia and suggest that durable control of the hematologic disease is most critical to improve overall outcome of patients with increased comorbidity. The registration numbers of the trials reported are NCT00276848 and NCT00262795.
The AIO KRK-0104 randomized phase II trial investigated the efficacy and safety of cetuximab combined with capecitabine and irinotecan (CAPIRI) or capecitabine and oxaliplatin (CAPOX) in the ...first-line treatment of metastatic colorectal cancer (mCRC).
A total of 185 patients with mCRC were randomly assigned to cetuximab (400 mg/m(2) day 1, followed by 250 mg/m(2) weekly) plus CAPIRI (irinotecan 200 mg/m(2), day 1; capecitabine 800 mg/m(2) twice daily days 1 through 14, every 3 weeks; or cetuximab plus CAPOX (oxaliplatin 130 mg/m(2) day 1; capecitabine 1,000 mg/m(2) twice daily day 1 through 14, every 3 weeks). The primary study end point was objective response rate (ORR).
In the intention-to-treat patient population (n = 177), ORR was 46% (95% CI, 35 to 57) for CAPIRI plus cetuximab versus 48% (95% CI, 37 to 59) for CAPOX plus cetuximab. Analysis of the KRAS gene mutation status was performed in 81.4% of the intention to treat population. Patients with KRAS wild-type in the CAPIRI plus cetuximab arm showed an ORR of 50.0%, a PFS of 6.2 months and an OS of 21.1 months. In the CAPOX plus cetuximab arm, an ORR of 44.9%, a PFS of 7.1 months and an OS of 23.5 months were observed. While ORR and PFS were comparable in KRAS wild-type and mutant subgroups, a trend toward longer survival was associated with KRAS wild-type. Both regimens had manageable toxicity profiles and were safe.
This randomized trial demonstrates that the addition of cetuximab to CAPIRI or CAPOX is effective and safe in first-line treatment of mCRC. In the analyzed regimens, ORR and PFS did not differ according to KRAS gene mutation status.
The management of recurrent ovarian cancer remains controversial. Single-agent topotecan is an established treatment option, and preliminary evidence suggests improved tumor control by combining ...topotecan with etoposide or gemcitabine.
Women with relapsed ovarian cancer after primary surgery and platinum-based chemotherapy were randomly assigned to topotecan monotherapy 1.25 mg/m(2)/d, topotecan 1.0 mg/m(2) plus oral etoposide 50 mg/d, or topotecan 0.5 mg/m(2)/d plus gemcitabine 800 mg/m(2) on day 1 and 600 mg/m(2) on day 8 every 3 weeks. Patients were stratified for platinum-refractory and platinum-sensitive disease according to a recurrence-free interval of less or more than 12 months, respectively. The primary end point was overall survival. Secondary end points included progression-free survival, objective response rates, toxicity, and quality of life (as measured by the European Organisation for Research and Treatment of Cancer EORTC 30-item Quality-of-Life Questionnaire).
The trial enrolled 502 patients with a mean age of 60.5 years (+/- 10.2 years), 208 of whom were platinum resistant. Median overall survival was 17.2 months (95% CI, 13.5 to 21.9 months) with topotecan, 17.8 months (95% CI, 13.7 to 20.0 months) with topotecan plus etoposide (log-rank P = .7647), and 15.2 months (95% CI, 11.3 to 20.9 months) with topotecan plus gemcitabine (log-rank P = .2344). Platinum-sensitive patients lived significantly longer than platinum-refractory patients (21.9 v 10.6 months). The median progression-free survival was 7.0, 7.8, and 6.3 months, respectively. Objective response rates were 27.8%, 36.1%, and 31.6%, respectively. Patients under combined treatment were at higher risk of severe thrombocytopenia.
Nonplatinum topotecan combinations do not provide a survival advantage over topotecan alone in women with relapsed ovarian cancer.
To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and ...2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P<0.0001). Univariate Cox regression analysis demonstrated that patients who did receive antibody treatment had a 1.42-fold higher risk of death (hazard ratio, 1.42; 95% confidence interval: 1.185-1.694). Therapies administered at relapse were very heterogeneous. Only 55 of 368 patients (14.9%) who started second-line treatment >24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901.
We explored the association of early tumor shrinkage (ETS) and non‐ETS with efficacy of first‐line and consecutive second‐line treatment in patients with KRAS wild‐type metastatic colorectal cancer ...treated in FIRE‐3. Assessment of tumor shrinkage was based on the sum of longest diameters of target lesions, evaluated after 6 weeks of treatment. Shrinkage was classified as ETS (shrinkage by ≥ 20%), mETS (shrinkage by 0 to <20%), mPD (minor progression >0 to <20%) and PD (progression ≥20%). Overall survival (OS) was 33.2 (95% CI 28.0–38.4) months in ETS patients, while non‐ETS was associated with less favorable outcome (mETS 24.0 (95% CI 21.2–26.9) months, mPD 19.0 (95% CI 13.0–25.0) months, PD 12.8 (95% CI 11.1–14.5) months). Differences in PFS of first‐line therapy were less pronounced. ETS subgroups defined in first‐line therapy also correlated with efficacy of second‐line therapy. Progression‐free survival in second‐line (PFS2nd) was 6.5 months (5.8–7.2) for ETS, and was 5.6 (95% CI 4.7–6.5) months for mETS, 4.9 (95% CI 3.7–6.1) months for mPD and 3.3 (95% CI 2.3–4.3) months for PD. PFS of first‐line and PFS2nd showed a linear correlation (Bravais–Pearson coefficient: 0.16, p = 0.006). While ETS is associated with the most favorable outcome, non‐ETS represents a heterogeneous subgroup with distinct characteristics of less favorable initial tumor response to treatment. This is the first analysis to demonstrate that early tumor response observed during first‐line FOLFIRI‐based therapy may also relate to efficacy of second‐line treatment. Early response parameters may serve as stratification factors in trials recruiting pretreated patients.
What's new?
Early tumor shrinkage (ETS) is linked to favorable survival in metastatic colorectal cancer (mCRC). However, ETS occurs in only some patients, for reasons that remain unknown while non‐ETS patients represent a heterogeneous subgroup. Here, ETS and non‐ETS subgroups were examined in KRAS wild‐type mCRC patients enrolled in FIRE‐3, a trial comparing first‐line FOLFIRI (5‐fluorouracil, leucovorin, and irinotecan) plus cetuximab with FOLFIRI plus bevacizumab. Efficacy of first‐line FOLFIRI‐based therapy differed in ETS and non‐ETS subgroups, with the latter generally experiencing less‐favorable initial tumor responses. Patients who benefited from first‐line therapy tended to also benefit from second‐line therapy, supporting a role for efficacy parameters in mCRC patient stratification.
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