Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be ...negative predictive biomarkers for anti-EGFR therapy.
In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.
Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval CI, 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.
Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).
Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with ...chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC.
In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status.
KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio HR, 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy.
This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
Panitumumab is approved for RAS wild‐type metastatic colorectal cancer and was evaluated in Phase III (PRIME, NCT00364013) and Phase II (PEAK, NCT00819780) first‐line randomised studies. This ...retrospective analysis of these trials investigated efficacy and toxicity of panitumumab‐based maintenance after oxaliplatin discontinuation in RAS wild‐type patients. First‐line regimens were FOLFOX4 ± panitumumab in PRIME and mFOLFOX6 plus panitumumab or mFOLFOX6 plus bevacizumab in PEAK. Outcomes included median progression‐free survival (PFS) and overall survival (OS), from randomisation and oxaliplatin discontinuation, and toxicity. Overall, median duration of panitumumab plus 5‐fluorouracil/leucovorin (5‐FU/LV) maintenance was 21 (interquartile range: 11–41) weeks; that of 5‐FU/LV ± bevacizumab maintenance was 16 (6–31) weeks. Median OS from randomisation was 40.2 (95% confidence interval: 30.3–50.4) and 39.1 (34.2–63.0) months for panitumumab plus 5‐FU/LV maintenance and 24.1 (17.7–33.0) and 28.9 (21.0–32.0) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. Median PFS from randomisation was 16.6 (11.3–23.6) and 15.4 (11.6–18.4) months for panitumumab plus 5‐FU/LV maintenance and 12.6 (9.4–16.2) and 13.1 (9.5–16.6) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively. From oxaliplatin discontinuation, median OS was 33.9 (24.7–42.8) and 33.5 (24.5–54.9) months for panitumumab plus 5‐FU/LV maintenance and 16.4 (12.4–24.1) and 23.3 (15.7–26.3) months for 5‐FU/LV ± bevacizumab maintenance in PRIME and PEAK, respectively; PFS was 11.7 (7.8–19.2) and 9.7 (5.8–14.8) months and 7.1 (5.6–10.2) and 7.0 (3.9–10.6) months, respectively. The most frequently reported adverse events were rash, fatigue and diarrhoea. Maintenance of panitumumab plus 5‐FU/LV after oxaliplatin discontinuation was well tolerated and may be an acceptable treatment paradigm for patients demonstrating a good response to first‐line treatment. Prospective studies are warranted.
What's new?
Panitumumab is an anti‐EGFR antibody used in the treatment of RAS wild‐type metastatic colorectal cancer. But is it useful for long‐term therapy in these patients, especially after more toxic therapies like oxaliplatin are discontinued? In this retrospective analysis, the authors found that a maintenance regimen including panitumumab was well tolerated and may be associated with better outcomes than non‐panitumumab strategies. Patients who received panitumumab‐based maintenance therapy were also more likely to have had a good response to first‐line treatment. The results from this study indicate that further, prospective studies are warranted.
In the phase IV, open-label, single-arm study NCT01203917, first-line gefitinib 250 mg/d was effective and well tolerated in Caucasian patients with epidermal growth factor receptor (EGFR) ...mutation-positive non–small-cell lung cancer (previously published). Here, we report EGFR mutation analyses of plasma-derived, circulating-free tumor DNA.
Mandatory tumor and duplicate plasma (1 and 2) baseline samples were collected (all screened patients; n = 1060). Preplanned, exploratory analyses included EGFR mutation (and subtype) status of tumor versus plasma and between plasma samples. Post hoc, exploratory analyses included efficacy by tumor and plasma EGFR mutation (and subtype) status.
Available baseline tumor samples were 1033 of 1060 (118 positive of 859 mutation status known; mutation frequency, 13.7%). Available plasma 1 samples were 803 of 1060 (82 positive of 784 mutation status known; mutation frequency, 10.5%). Mutation status concordance between 652 matched tumor and plasma 1 samples was 94.3% (95% confidence interval CI, 92.3–96.0) (comparable for mutation subtypes); test sensitivity was 65.7% (95% CI, 55.8–74.7); and test specificity was 99.8% (95% CI, 99.0–100.0). Twelve patients of unknown tumor mutation status were subsequently identified as plasma mutation-positive. Available plasma 2 samples were 803 of 1060 (65 positive of 224 mutation status-evaluable and -known). Mutation status concordance between 224 matched duplicate plasma 1 and 2 samples was 96.9% (95% CI, 93.7–98.7). Objective response rates are as follows: mutation-positive tumor, 70% (95% CI, 60.5–77.7); mutation-positive tumor and plasma 1, 76.9% (95% CI, 65.4–85.5); and mutation-positive tumor and mutation-negative plasma 1, 59.5% (95% CI, 43.5–73.7). Median progression-free survival (months) was 9.7 (95% CI, 8.5–11.0; 61 events) for mutation-positive tumor and 10.2 (95% CI, 8.5–12.5; 36 events) for mutation-positive tumor and plasma 1.
The high concordance, specificity, and sensitivity demonstrate that EGFR mutation status can be accurately assessed using circulating-free tumor DNA. Although encouraging and suggesting that plasma is a suitable substitute for mutation analysis, tumor tissue should remain the preferred sample type when available.
Summary Background The phase 3 LUME-Lung 1 study assessed the efficacy and safety of docetaxel plus nintedanib as second-line therapy for non-small-cell lung cancer (NSCLC). Methods Patients from 211 ...centres in 27 countries with stage IIIB/IV recurrent NSCLC progressing after first-line chemotherapy, stratified by ECOG performance status, previous bevacizumab treatment, histology, and presence of brain metastases, were allocated (by computer-generated sequence through an interactive third-party system, in 1:1 ratio), to receive docetaxel 75 mg/m2 by intravenous infusion on day 1 plus either nintedanib 200 mg orally twice daily or matching placebo on days 2–21, every 3 weeks until unacceptable adverse events or disease progression. Investigators and patients were masked to assignment. The primary endpoint was progression-free survival (PFS) by independent central review, analysed by intention to treat after 714 events in all patients. The key secondary endpoint was overall survival, analysed by intention to treat after 1121 events had occurred, in a prespecified stepwise order: first in patients with adenocarcinoma who progressed within 9 months after start of first-line therapy, then in all patients with adenocarcinoma, then in all patients. This trial is registered with ClinicalTrials.gov , number NCT00805194. Findings Between Dec 23, 2008, and Feb 9, 2011, 655 patients were randomly assigned to receive docetaxel plus nintedanib and 659 to receive docetaxel plus placebo. The primary analysis was done after a median follow-up of 7·1 months (IQR 3·8–11·0). PFS was significantly improved in the docetaxel plus nintedanib group compared with the docetaxel plus placebo group (median 3·4 months 95% CI 2·9–3·9 vs 2·7 months 2·6–2·8; hazard ratio HR 0·79 95% CI 0·68–0·92, p=0·0019). After a median follow-up of 31·7 months (IQR 27·8–36·1), overall survival was significantly improved for patients with adenocarcinoma histology who progressed within 9 months after start of first-line treatment in the docetaxel plus nintedanib group (206 patients) compared with those in the docetaxel plus placebo group (199 patients; median 10·9 months 95% CI 8·5–12·6 vs 7·9 months 6·7–9·1; HR 0·75 95% CI 0·60–0·92, p=0·0073). Similar results were noted for all patients with adenocarcinoma histology (322 patients in the docetaxel plus nintedanib group and 336 in the docetaxel plus placebo group; median overall survival 12·6 months 95% CI 10·6–15·1 vs 10·3 months 95% CI 8·6–12·2; HR 0·83 95% CI 0·70–0·99, p=0·0359), but not in the total study population (median 10·1 months 95% CI 8·8–11·2 vs 9·1 months 8·4–10·4; HR 0·94, 95% CI 0·83–1·05, p=0·2720). Grade 3 or worse adverse events that were more common in the docetaxel plus nintedanib group than in the docetaxel plus placebo group were diarrhoea (43 6·6% of 652 vs 17 2·6% of 655), reversible increases in alanine aminotransferase (51 7·8% vs six 0·9%), and reversible increases in aspartate aminotransferase (22 3·4% vs three 0·5%). 35 patients in the docetaxel plus nintedanib group and 25 in the docetaxel plus placebo group died of adverse events possibly unrelated to disease progression; the most common of these events were sepsis (five with docetaxel plus nintedanib vs one with docetaxel plus placebo), pneumonia (two vs seven), respiratory failure (four vs none), and pulmonary embolism (none vs three). Interpretation Nintedanib in combination with docetaxel is an effective second-line option for patients with advanced NSCLC previously treated with one line of platinum-based therapy, especially for patients with adenocarcinoma. Funding Boehringer Ingelheim.
Tumor lymphocytic infiltration (TLI) has differing prognostic value among various cancers. The objective of this study was to assess the effect of TLI in lung cancer.
A discovery set (one trial, n = ...824) and a validation set (three trials, n = 984) that evaluated the benefit of platinum-based adjuvant chemotherapy in non-small-cell lung cancer were used as part of the LACE-Bio (Lung Adjuvant Cisplatin Evaluation Biomarker) study. TLI was defined as intense versus nonintense. The main end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs associated with TLI were estimated through a multivariable Cox model in both sets. TLI-histology and TLI-treatment interactions were explored in the combined set.
Discovery and validation sets with complete data included 783 (409 deaths) and 763 (344 deaths) patients, respectively. Median follow-up was 4.8 and 6 years, respectively. TLI was intense in 11% of patients in the discovery set compared with 6% in the validation set (P < .001). The prognostic value of TLI in the discovery set (OS: HR, 0.56; 95% CI, 0.38 to 0.81; P = .002; DFS: HR, 0.59; 95% CI, 0.42 to 0.83; P = .002; SDFS: HR, 0.56; 95% CI, 0.38 to 0.82; P = .003) was confirmed in the validation set (OS: HR, 0.45; 95% CI, 0.23 to 0.85; P = .01; DFS: HR, 0.44; 95% CI, 0.24 to 0.78; P = .005; SDFS: HR, 0.42; 95% CI, 0.22 to 0.80; P = .008) with no heterogeneity across trials (P ≥ .38 for all end points). No significant predictive effect was observed for TLI (P ≥ .78 for all end points).
Intense lymphocytic infiltration, found in a minority of tumors, was validated as a favorable prognostic marker for survival in resected non-small-cell lung cancer.
The classification for invasive lung adenocarcinoma by the International Association for the Study of Lung Cancer, American Thoracic Society, European Respiratory Society, and WHO is based on the ...predominant histologic pattern-lepidic (LEP), papillary (PAP), acinar (ACN), micropapillary (MIP), or solid (SOL)-present in the tumor. This classification has not been tested in multi-institutional cohorts or clinical trials or tested for its predictive value regarding survival from adjuvant chemotherapy (ACT).
Of 1,766 patients in the IALT, JBR.10, CALGB 9633 (Alliance), and ANITA ACT trials included in the LACE-Bio study, 725 had adenocarcinoma. Histologies were reclassified according to the new classification and then collapsed into three groups (LEP, ACN/PAP, and MIP/SOL). Primary end point was overall survival (OS); secondary end points were disease-free survival (DFS) and specific DFS (SDFS). Hazard ratios (HRs) and 95% CIs were estimated through multivariable Cox models stratified by trial. Prognostic value was estimated in the observation arm and predictive value by a treatment effect interaction with histologic subgroups. Significance level was set at .01 for pooled analysis.
A total of 575 patients were included in this analysis. OS was not prognostically different between histologic subgroups, but univariable DFS and SDFS were worse for MIP/SOL compared with LEP or ACN/PAP subgroup (P < .01); this remained marginally significant after adjustment. MIP/SOL patients (but not ACN/PAP) derived DFS and SDFS but not OS benefit from ACT (OS: HR, 0.71; 95% CI, 0.51 to 0.99; interaction P = .18; DFS: HR, 0.60; 95% CI, 0.44 to 0.82; interaction P = < .01; and SDFS: HR, 0.59; 95% CI, 0.42 to 0.81; interaction P = .01).
The new lung adenocarcinoma classification based on predominant histologic pattern was not predictive for ACT benefit for OS, but it seems predictive for disease-specific outcomes.
Panitumumab, a fully human monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has demonstrated significant improvements in progression-free survival (PFS) in patients with ...wild-type KRAS metastatic colorectal cancer (mCRC) in studies 20050203 (first line), 20050181 (second line), and 20020408 (monotherapy). Mutations in KRAS codons 12 and 13 are recognized biomarkers that predict lack of response to anti-EGFR antibody therapies. This retrospective analysis of three randomized phase III studies assessed the prognostic and predictive impact of individual mutant KRAS codon 12 and 13 alleles.
Patients were randomly assigned 1:1 to FOLFOX4 (infusional fluorouracil, leucovorin, and oxaliplatin) in study 20050203, FOLFIRI (fluorouracil, leucovorin, and irinotecan) in study 20050181, or best supportive care in study 20020408 with or without panitumumab 6.0 mg/kg once every 2 weeks. In all, 441 (20050203), 486 (20050181), and 126 (20020408) patients with mutant KRAS codon 12 or 13 alleles were included in the analysis.
No mutant KRAS allele in patients treated on the control arm emerged as a consistent prognostic factor for PFS or overall survival (OS). In addition, no mutant KRAS allele was consistently identified as a predictive factor for PFS or OS in patients receiving panitumumab treatment. Significant interactions for individual mutant KRAS alleles were observed only in study 20050203 with G13D negatively and G12V positively associated with OS in the panitumumab-containing arm. Pooled analysis indicated that only G12A was associated with a negative predictive effect on OS.
In this retrospective analysis, results across three treatment regimens suggest that patients with mutant KRAS codon 12 or 13 mCRC tumors are unlikely to benefit from panitumumab therapy. Currently, panitumumab therapy should be limited to patients with wild-type KRAS mCRC.
A regimen consisting of 5‐fluorouracil/leucovorin plus oxaliplatin (FOLFOX‐6) is widely used in France in the first‐line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to ...demonstrate the non‐inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX‐6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX‐6 for 6 months. The primary endpoint was overall response rate (ORR) in the per‐protocol (PP) population; however, progression‐free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX‐6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX‐6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non‐inferiority margin of 15%. In the intent‐to‐treat population, median progression‐free survival was 8.8 months with XELOX and 9.3 months with FOLFOX‐6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX‐6 patients. We conclude that XELOX is non‐inferior in terms of efficacy to FOLFOX‐6 in the first‐line treatment of MCRC, but has a different toxicity profile.
Several recent trials have shown a significant overall survival (OS) benefit from postoperative cisplatin-based chemotherapy in patients with non-small-cell lung cancer (NSCLC). The aim of the Lung ...Adjuvant Cisplatin Evaluation was to identify treatment options associated with a higher benefit or groups of patients who particularly benefit from postoperative chemotherapy.
Individual patient data were collected and pooled from the five largest trials (4,584 patients) of cisplatin-based chemotherapy in completely resected patients that were conducted after the 1995 NSCLC meta-analysis. The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analyzed using hazard ratios (HRs) and log-rank tests stratified by trial.
With a median follow-up time of 5.2 years, the overall HR of death was 0.89 (95% CI, 0.82 to 0.96; P = .005), corresponding to a 5-year absolute benefit of 5.4% from chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, P = .04; HR for stage IA = 1.40; 95% CI, 0.95 to 2.06; HR for stage IB = 0.93; 95% CI, 0.78 to 1.10; HR for stage II = 0.83; 95% CI, 0.73 to 0.95; and HR for stage III = 0.83; 95% CI, 0.72 to 0.94). The effect of chemotherapy did not vary significantly (test for interaction, P = .11) with the associated drugs, including vinorelbine (HR = 0.80; 95% CI, 0.70 to 0.91), etoposide or vinca alkaloid (HR = 0.92; 95% CI, 0.80 to 1.07), or other (HR = 0.97; 95% CI, 0.84 to 1.13). Chemotherapy effect was higher in patients with better performance status. There was no interaction between chemotherapy effect and sex, age, histology, type of surgery, planned radiotherapy, or planned total dose of cisplatin.
Postoperative cisplatin-based chemotherapy significantly improves survival in patients with NSCLC.
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