First-line Setting For Patients Research Articles

Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population

PurposeCompLEEment-1 is a phase 3b trial in an expanded patient population with hormone receptor-positive (HR +), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC), the largest current trial of cyclin-dependent kinase 4 and 6 inhibitors in ABC.MethodsPatients treated with ≤ 1 line of prior chemotherapy and no prior endocrine therapy for ABC received ribociclib 600 mg/day (3-weeks-on/1-week-off) plus letrozole 2.5 mg/day and additionally monthly goserelin/leuprolide in men and pre-/perimenopausal women. Eligibility criteria allowed inclusion of patients with stable CNS metastases and an Eastern Cooperative Oncology Group performance status of 2. Primary objectives were safety and tolerability, and secondary objectives were efficacy and quality of life (QoL).ResultsOverall, 3,246 patients were evaluated (median follow-up 25.4 months). Rates of all-grade and grade ≥ 3 treatment-related adverse events (AEs) were 95.2% and 67.5%, respectively. Treatment-related discontinuations due to all grade and grade ≥ 3 AEs occurred in 12.9% and 7.3% of patients, respectively. Rates of all-grade AEs of special interest (AESI) were as follows: neutropenia (74.5%), increased alanine aminotransferase (16.2%), increased aspartate aminotransferase (14.1%), and QTcF prolongation (6.7%); corresponding values for grade ≥ 3 AESI were 57.2%, 7.7%, 5.7%, and 1.0%, respectively. Median time to progression was 27.1 months (95% confidence interval, 25.7 to not reached). Patient QoL was maintained during treatment.ConclusionSafety and efficacy data in this expanded population were consistent with the MONALEESA-2 and MONALEESA-7 trials and support the use of ribociclib plus letrozole in the first-line setting for patients with HR + , HER2– ABC.Trial registrationlinicalTrials.gov NCT02941926.

Challenges of Immunotherapy in Stage IV Non-Small-Cell Lung Cancer.

Treatment for metastatic non-small-cell lung carcinoma has seen important advances in recent years with the introduction of targeted therapies and immunotherapy. Immune checkpoint inhibitors, which target the programmed death 1 receptor and programmed death ligand-1, alone or in combination with platinum-based chemotherapy, have become standard of care in the first-line setting for patients with advanced non-small-cell lung carcinoma without targetable driver mutations. However, several clinical questions have now since emerged. Physicians treating lung cancer lack guidance when treating patients who have a poor performance status, patients who are receiving corticosteroids, and those known for pre-existing autoimmune disorders. Furthermore, data are scarce on rechallenging a patient with immune checkpoint inhibitors after the occurrence of a significant immune-related adverse event. In this review, we aim to shed light on these topics.

First-line Daratumumab in Addition to Chemotherapy for Newly Diagnosed Multiple Myeloma Patients Who are Transplant Ineligible: A Cost-Effectiveness Analysis

Daratumumab is a standard-of-care treatment for newly diagnosed multiple myeloma (NDMM). According to the ALCYONE trial, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) provides significantly longer overall survival and progression-free survival than bortezomib, melphalan, and prednisone (VMP) in patients with NDMM. However, considering the high price of daratumumab, it is necessary to conduct further research on its efficacy and cost. This study evaluated the cost-effectiveness, from the US payer perspective, of D-VMP vs VMP in the first-line setting for patients with NDMM who are not eligible for autologous stem cell transplantation. A Markov model was developed to estimate the lifetime cost and effectiveness of VMP with or without daratumumab as the first-line therapy for patients with NDMM. Univariable sensitivity analysis and probabilistic sensitivity analysis were performed to address the model robustness and uncertainty. Expected value of perfect information analysis was conducted to explore the uncertainty of decision-making and future costs. D-VMP provides an additional 2.417 quality-adjusted life years (QALYs), at a cost of $30,893 per QALY. Sensitivity analysis revealed that the transition probability of progression-free survival in D-VMP strategy, the price of daratumumab, and body weight of the patient influenced the model results most strongly. Probabilistic sensitivity analysis showed that D-VMP versus VMP has a 90.8% probability of being cost-effective at the $150,000/QALY willingness-to-pay (WTP) threshold. The population expected value of perfect information was $2150 million at a WTP threshold of $50,000/QALY and $1481 million at $100,000/QALY. In this study, D-VMP was estimated to be cost-effective compared with VMP for patients with NDMM at a WTP threshold of $150,000/QALY.

Residual of circulating tumor DNA (ctDNA) indicated therapeutic efficacy of sintilimab plus docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

e21207 Background: The synergetic effect of ICIs plus chemotherapy has been demonstrated in first line setting for patients with advanced NSCLC. As previously reported, sintilimab plus docetaxel in advanced Chinese NSCLC pts who had failed first-line chemotherapy showed encouraging efficacy and tolerable safety profile. This exploratory study aims to investigate putative biomarker(s) predicting therapeutic response and long-term outcome for eligible patients. Methods: Advanced NSCLC pts who had failed standard platinum doublet without receiving any ICIs before would receive docetaxel (75mg/m2, day 1) plus sintilimab (200mg, day 3) every 3 weeks for 4-6 cycles followed by sintilimab maintenance until disease progression, unacceptable toxicity, or up to 2 years. Thirty-nine eligible patients received comprehensive genomic profiling of circulating tumor DNA (ctDNA) via a 448-gene panel before treatment. ctDNA from twenty-three patients were dynamically assessed after two courses (at 6th week). Eventually, 22 patients were enrolled into analysis, one patient was lost. White blood cells were used to filter germline variants from ctDNA sequencing data. Results: Of 22 patients with paired ctDNA profiling results at 6th week, 11 patients (50%) were defined as ctDNA residual due to presence of ≥2 somatic variants; Another 11 patients (50%) who had ≤1 somatic variant were defined as non-ctDNA residual. Significant difference of best objective response rate (ORR) (63.64% vs 0%, P=0.0039, two-sided Fisher’s Exact Testing for non-ctDNA residual vs ctDNA residual patients) was observed between these two populations. And numerically higher disease control rate (DCR) was seen in non-ctDNA residual patients (100% vs 63.64%, non-ctDNA residual vs ctDNA residual). Further, patients with ctDNA residual after 2 courses of sintilimab plus docetaxel (at 6th week) displayed higher risk of disease progression [Hazard Ratio (95%CI), 9.91(2.09-46.97), P=0.0038] and inferior prognosis (median PFS, ctDNA residual vs non-ctDNA residual, 3.0 months vs NR, P=0.0007). In addition, mutations of EGFR and LRP1B were enriched in ctDNA residual group. Especially, LRP1B gene mutations associated with shorter PFS period, which should be further investigated. Conclusions: Residual of ctDNA at 6th week was able to indicate inferior response to sintilimab plus docetaxel in patients with previously treated advanced NSCLC. Further validation of ctDNA residual as a robust predictive biomarker is warranted. [Table: see text]

Phase 2 Study of Nivolumab Plus Bevacizumab Plus Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer

Phase 2 Study of Nivolumab Plus Bevacizumab Plus Paclitaxel in Patients with HER2-Negative Metastatic Breast Cancer

Abstract PS10-05: Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial

Abstract Background: CompLEEment-1 (NCT02941926) is an ongoing Phase IIIb trial of ribociclib (RIB) in combination with letrozole (LET) in the first-line setting for patients (pts) with HR+, HER2- ABC, reflecting a real-world clinical setting by including a more diverse pt population than those included in the pivotal MONALEESA trials. Here we report further analyses of the primary endpoint of safety from the completed Core Phase of the trial. Methods: CompLEEment-1 included women of any menopausal status and men with HR+, HER2- ABC treated with ≤1 line of prior chemotherapy and no prior hormonal therapy for advanced disease. Pts received RIB (600 mg QD, 3 weeks on/1 week off) in combination with LET (2.5 mg QD, continuous). Premenopausal women and men received a luteinizing hormone-releasing hormone agonist (3.6 mg goserelin or 7.5 mg leuprolide, Q28D). The primary endpoints were safety and tolerability. Updated analyses included dose reduction/interruption or treatment discontinuation due to adverse events (AEs), clinical impact of AEs of special interest (AESI), and exposure-adjusted incidence/occurrence rates (IRs) for AESI. Results: At data cutoff (November 8, 2019) 3,246 pts had been evaluated (median follow-up of 25.4 months), and median duration of exposure to RIB was 17.5 months; 1,301 (40.1%) pts completed Core Phase treatment, 415 of whom moved to the Extension Phase. Overall, 1,945 (59.9%) pts permanently discontinued treatment, mostly due to progressive disease (34.2%) and AEs (15.5%). Treatment-related AEs were reported in 3,091 (95.2%) pts, leading to dose modification in 2,235 (68.9%) pts. Dose modification occurred most often in pts with grade ≥3 neutropenia (dose interruption, 1,671 [51.5%] pts; dose reduction, 480 [14.8%] pts); treatment discontinuation occurred most frequently in pts with grade ≥3 increased alanine aminotransferase (ALT; 116 [3.6%] pts) or aspartate aminotransferase (AST; 68 [2.1%] pts). Grade ≥3 neutropenia occurred in 1,856 (57.2%) pts, with the median time to first occurrence of 4.1 weeks and median duration of first occurrence of 1.1 weeks. As measured by laboratory values, grade ≥2 increased ALT and AST occurred in 453 (14.0%) and 380 (11.7%) pts, respectively. Grade ≥2 QTcF prolongation was infrequent, occurring in 101 (3.1%) pts, leading 8 (0.2%) pts to discontinue from treatment. AESI rarely led to hospitalization (0 to 0.3%) and none were fatal. Exposure-adjusted IRs for AESI per 100 patient-years of exposure show that with increasing RIB exposure, the IR and the event rates for AESI decreased by a factor of ×2 to ×8 from 0-1 years compared with 1-2 years (Table 1). Conclusions: AEs associated with RIB + LET combination therapy were manageable, consistent with previous Phase III trials of RIB + LET - and adjusted IRs for AESI notably decreased from Year 1 to Year 2 of treatment. These data further support the use of RIB + LET for first-line treatment of HR+, HER2- ABC in both men and women of any menopausal status and in a broader and more diverse patient population. Table 1. Exposure-adjusted IRs for selected AESI per 100 patient-years of exposure0-1 years1-2 yearsAESIIR per 100 PTYaEvents per 100 PTYbIR per 100 PTYaEvents per 100 PTYbNeutropenia276.76410.2292.43200.83ALT increased20.3741.663.796.32AST increased17.5133.272.944.61QTcF prolongation8.4410.221.081.26aIR per 100 PTY: n/100 PTY, number of patients with an event divided by the corresponding sum of the exposure duration for patients, where duration of exposure in patient treatment-years (PTY) is counted up to the first qualifying event (or duration of exposure in time interval for patients without an event).bEvents per 100 PTY: n/100 PTY, number of events divided by the corresponding sum of the exposure duration, where duration of exposure in patient treatment-years (PTY) is duration of exposure in time interval. Citation Format: Janice Lu, Paul Cottu, Miguel Martín, Claudio Zamagni, Aleix Prat, Stephen Chia, Guy Jerusalem, Senthil Rajappa, Constanta Timcheva, Lyudmila Zhukova, Katie Zhou, Jiwen Wu, Lakshmi Menon-Singh, Michelino De Laurentiis. Ribociclib + letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2−) advanced breast cancer (ABC): Expanded safety analysis of the phase IIIb CompLEEment-1 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-05.

PD-L1 testing in urothelial bladder cancer: essentials of clinical practice.

While immunotherapy has become an increasingly attractive strategy in patients with urothelial bladder cancer, the need for a biomarker to identify patients whose cancer is the most likely to respond has never been more crucial. This review systematically evaluates evidence regarding PD-L1 as a predictive biomarker of response to anti-PD(L)1 monoclonal antibodies in patients with urothelial bladder carcinoma, and discusses its current limits in routine clinical practice. We performed a critical review of PubMed/Medline according to the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) statement. Prospective clinical trials evaluating anti-PD(L)1 monoclonal antibodies in urothelial bladder carcinoma together with retrospective studies evaluating PD-L1 expression in patients with bladder cancer were included. Evidence data related to PD-L1 as a predictive biomarker of response to immune checkpoint blockade monotherapy across clinical trials are detailed in this review. The different companion diagnostic assays, and the methods for PD-L1 scoring in urothelial bladder carcinoma are reported. Additionally, the issues related to the implementation of PD-L1 testing in clinical practice are discussed. PD-(L)1 monoclonal antibodies atezolizumab and pembrolizumab are restricted to patients with PD-L1 positive status in the first-line setting in patients with advanced or metastatic urothelial bladder carcinoma who are ineligible to cisplatin-based chemotherapy. Importantly, the use of anti-PD(L)1 mAb in the other clinical settings is not based on PD-L1 status, but rather on patients' clinical characteristics. Further identification of biomarkers with high negative predictive value will also be of utmost importance to identify patients who may not respond to such immunotherapies.

Cost-effectiveness analysis of adding ramucirumab to the first-line erlotinib treatment for untreated EGFR-mutated metastatic non-small cell lung cancer in China

ObjectiveTo investigate the cost-effectiveness of ramucirumab plus erlotinib compared with placebo plus erlotinib in the first-line setting for patients with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) from the Chinese...

Systemic Therapy and Sequencing Options in Advanced Hepatocellular Carcinoma

The treatment landscape for advanced hepatocellular carcinoma (HCC) has recently changed and become relatively confusing. Head-to-head comparisons between most of the available agents have not been performed and are less likely to be examined in a prospective fashion in the future. Therefore, a network meta-analysis (NMA) is helpful to compare different agents from across different trials. To evaluate comparative effectiveness of different systemic treatments in advanced patients with HCC across lines of therapy. We searched various databases for abstracts and full-text articles published from database inception through March 2020. We included phase 3 trials evaluating different vascular endothelial growth factor inhibitors (VEGFis), checkpoint inhibitors (CPIs), or their combinations in advanced HCC, in the first-line or refractory setting. The reporting of this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The overall effect was pooled using the random effects model. Outcomes of interest included overall (OS) and progression-free survival (PFS). Fourteen trials (8 in the first-line setting and 6 in the second-line setting) at low risk of bias were included. The 8 trials in the first-line setting encompassed a total of 6290 patients, with an age range of 18 to 89 years. The 5 trials included in the second-line analysis encompassed a total of 2653 patients, with an age range of 18 to 91 years. Network meta-analysis showed the combination of atezolizumab and bevacizumab was superior in patients with HCC treated in the first-line setting compared with lenvatinib (HR, 0.63; 95% CI, 0.44-0.89), sorafenib (HR, 0.58; 95% CI, 0.42-0.80), and nivolumab (HR, 0.68; 95% CI, 0.48-0.98). In the refractory setting, NMA showed that all studied drugs had PFS benefit compared with placebo. However, this only translated into OS benefit with regorafenib (HR, 0.62; 95% CI, 0.51-0.75) and cabozantinib (HR, 0.76; 95% CI, 0.63-0.92) compared with placebo. In the NMA of patients with α-fetoprotein (AFP) levels of 400 ng/mL or greater, regorafenib, cabozantinib, and ramucirumab showed PFS and OS benefit compared with placebo with no superiority of an active drug compared with any others. This systematic review and NMA of 14 trials found that atezolizumab and bevacizumab in combination is now considered the standard of care in the first-line setting in patients with advanced HCC. Regorafenib and cabozantinib are preferred options in refractory patients, with ramucirumab as an additional option in those with levels of AFP of 400 ng/mL or higher. Future trials should focus on other potential combinations and best treatment strategy in patients with prior VEGFi/CPI exposure.

Ensartinib as Treatment for ALK-Rearranged NSCLC

Ensartinib as Treatment for ALK-Rearranged NSCLC

Cost-Effectiveness of Pembrolizumab plus Axitinib Versus Sunitinib as First-Line Therapy in Advanced Renal Cell Carcinoma in the U.S.

The data from the phase III clinical trial KEYNOTE-426 indicated that pembrolizumab plus axitinib compared with sunitinib could generate clinical benefits in patients with previously untreated advanced renal cell carcinoma (RCC). Given the incremental clinical benefits, we examined the potential cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in the first-line setting for patients with advanced RCC from the U.S. payers' perspective. Cost and health outcomes were estimated at a willingness-to-pay (WTP) threshold of $100,000 to $150,000 per quality-adjusted life-year (QALY). One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters, and additional subgroup analyses were performed as well. Upon our analyses, the total treatment costs in the pembrolizumab plus axitinib and sunitinib groups were $522,796 and $348,424 and the QALYs gained 2.90 and 1.72, respectively. In the base-case analysis, compared with receiving sunitinib, patients with advanced RCC receiving pembrolizumab plus axitinib gained 1.18 more QALYs at an incremental cost-effectiveness ratio of $148,676/QALY. The results of subgroup analyses demonstrated that pembrolizumab plus axitinib was most cost-effective for patients who had one organ with metastasis. First-line treatment with pembrolizumab plus axitinib, compared with sunitinib, is a cost-effective strategy when the value of WTP is from $100,000 to $150,000 per QALY in patients with advanced RCC. For patients with one-organ metastasis and those in International Metastatic Renal Cell Carcinoma Database Consortium poor risk group, first-line treatment with pembrolizumab plus axitinib is more cost-effective than others. This was the first study to examine the cost-effectiveness of pembrolizumab plus axitinib versus sunitinib in advanced renal cell carcinoma (RCC). This study found that first-line treatment with pembrolizumab plus axitinib is a cost-effective strategy when the value of willingness-to-pay is from $100,000 to $150,000 per quality-adjusted life-year in patients with advanced RCC from the U.S. payers' perspective.

Metastazavusio nesmulkiųjų ląstelių plaučių vėžio su ROS1 geno translokacija gydymo galimybės tirozino kinazės inhibitoriais

ROS1 geno translokacija nustatoma apie 1–4 proc.nesmulkiųjų ląstelių plaučių vėžio (NSLPV) atvejų. ALK (anaplazinės limfomos receptoriaus tirozino kinazė) ir ROS1 (ROS 1 onkogeno tirozino kinazės receptorius) teigiamo metastazavusio NSLPV atveju rekomenduojamas pirmos eilės gydymas tirozino kinazės inhibitoriais (TKI). Krizotinibas – tai geriamasis pirmosios kartos ALK, ROS1 ir MET receptorių TKI, kuris tapo pirmuoju pirmaeilio ALK atžvilgiu teigiamo NSLPV gydymo standartu klinikinėje praktikoje. PROFILE 1001 tyrimo duomenimis, pacientams, sergantiems metastazavusiu ROS1 teigiamu NSLPV, bendro išgyvenamumo mediana, vartojant krizotinibą, siekia kiek daugiau nei ketverius metus. Svarbu tai, kad krizotinibas saugus vartoti ilgą laiką, o pasitaikantis nepageidaujamas poveikis yra trumpalaikis.

Безпосередні та віддалені результати першої лінії поліхіміотерапії у хворих на метастатичний тричі негативний рак грудної залози. Остаточний аналіз рандомізованого дослідження

The objective: was to evaluate the efficacy of the first line chemotherapy in patients with metastatic triple negative breast cancer (TNBC). Materials and methods. Open randomized study was performed including 122 patients with metastatic TNBC. The efficacy and safety of the first line chemotherapy of regimens АТ (n=59) – group 1, patients received doxorubicine 60 мг/м2 and paclitaxel 175 мг/м2 and ТР (n=63) – group 2, patients received paclitaxel 175 мг/м2 and carboplatin AUC 5 were evaluated. Results. The median duration of response was 9.5 months (4.5–13.25 months) in patients received AT regimen and 8.5 months (4.7–12.25 months), in TP regimen; no statistically significant differences were observed, р=0.836. The median progression free survival was 7 months (95% CI 5–26 months) in group 1 and 7.5 months (95% CI 6–35 months) in group 2, p=0.85. Both chemotherapy regimens (AT and TP) had mild or moderate toxicity profiles (grade 1 or 2 in most patients). No significant difference in gastrointestinal toxicity was observed. The incidence of grade 3–4 neutropenia was higher in patients of group 2 (TP regimen): 42.8% versus 27% (р<0.05). Conclusions. Both regimens of chemotherapy (AT and TP) are appropriate to use in the first line setting in patients with metastatic TNBC. Key words: metastatic triple negative breast cancer, chemotherapy, progression free survival, chemotherapy toxicity.

Nab-paclitaxel and atezolizumab for the treatment of PD-L1-positive, metastatic triple-negative breast cancer: review and future directions

ABSTRACTIntroduction: Breast cancer is the most common malignancy in women in the United States and triple-negative breast cancer (TNBC) accounts for 15–20%. The standard of care for metastatic TNBC has been limited to cytotoxic chemotherapy with modest efficacy. TNBC is associated with high levels of tumor-infiltrating lymphocytes and PD-L1 expression, supporting the investigation of immune checkpoint inhibitors in this breast cancer subtype.Areas covered: This review summarizes the clinical data supporting the use of atezolizumab and nab-paclitaxel in the treatment of metastatic PD-L1-positive TNBC. It examines the pharmacology and toxicity profile of the combination in patients with metastatic TNBC.Expert opinion: The addition of atezolizumab to nab-paclitaxel prolonged progression-free survival in both the intention-to-treat and PD-L1-positive subgroups in the first-line setting in patients with metastatic TNBC. The IMpassion 130 trial led to FDA-approval of this combination in patients with PD-L1-positive, metastatic TNBC and represents the first approval of immunotherapy for TNBC. This work supports ongoing investigations of other immunotherapy combinations in TNBC, predictive biomarker development, and immunotherapy in patients with early-stage TNBC. Immunotherapy combinations in TNBC have the potential to lead to improved survival in this group of patients with high-risk disease.

Phase II study of panitumumab monotherapy in chemotherapy-naïve frail or elderly patients with unresectable, RAS wild-type colorectal cancer: OGSG 1602.

106 Background: Single agent of panitumumab (Pmab) is expected to be well tolerated and to improve survival in first-line setting in patients (pts) who are not eligible for intensive chemotherapy, although the efficacy and safety of Pmab for chemotherapy-naïve frail or elderly Japanese pts with wild-type (wt) RAS unresectable colorectal cancer (CRC) have not been yet studied. Methods: We conducted a multi-center phase II study. Pts aged over 76 years, or over 65 who were considered unsuitable for intensive chemotherapy. Pmab 6 mg/kg was administered intravenously every 2 weeks. The primary endpoint was disease control rate (DCR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and the incidence of grade 3 or 4 toxicities. Sample size was set to 36 with exact p-value of 0.05, a power of 0.90, the null of hypothesis of 45% and alternative hypothesis of 70% based on the Clopper-Pearson method. Results: A total 36 pts were enrolled in February 2017 to August 2018. Two pts were excluded; one was a lack of image examination at baseline, and the other was a lack of measurable lesion. The median age was 81 (67-88), with 29 pts (85%) being aged over 76 years. There were 33 (92%) pts with performance status (PS) 0/1, while two (6%) and one (3%) pts were PS 2/3, respectively. Twenty-eight pts (78%) had left-sided CRC, while eight pts had right-sided CRC. The RR was 50.0% (95%CI, 32.4-67.6) including three cases (8.8%) of complete response, and SD was 26.5%, yielding 76.5% of DCR (p < 0.001, 90% confidence interval [CI], 61.5-87.7). The RR with left sided tumor was 65% (95%CI, 44.3-82.8), while that pts with right-sided tumor was 0% (95%CI, 0.0-36.9)(p = 0.003). The major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 17%), hypomagnesemia (n = 4, 11%), fatigue (n = 3, 8%), paronychia (n = 3, 6%), and hyponatremia (n = 3, 6%). The grade 3 hematologic toxicities was neutropenia (n = 1, 3%). Conclusions: Pmab monotherapy showed the favolable efficacy and feasibility in the frail or elderly pts with RAS wt, unresectable CRC. The survival analysis including OS, PFS and TTF is awaiting. Clinical trial information: UMIN000024528.

Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis.

Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79-0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69-1.01), p = 0.06 and OR = 1.46 (95% CI 0.90-2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16-66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23-3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28-1.87, p < 0.00001). The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

Cost-effectiveness analysis of pembrolizumab plus chemotherapy for previously untreated metastatic non-small cell lung cancer in the USA

ObjectivesEvaluating the cost-effectiveness of pembrolizumab plus standard chemotherapy in the first-line setting for patients with metastatic non-small cell lung cancer (NSCLC) from the US payer perspective.DesignA Markov model was constructed...

PRISM protocol: a randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

BackgroundThe combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy.MethodsThe PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored.DiscussionThe combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established.Trial registrationPRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017).Trial statusAt the time of submission, PRISM is open to recruitment and data collection is ongoing.

Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis

ObjectiveTo compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC).DesignSystematic review and network meta-analysis.Data sourcesPubMed,...

EGFR-TKIs plus bevacizumab demonstrated survival benefit than EGFR-TKIs alone in patients with EGFR-mutant NSCLC and multiple brain metastases

IntroductionPrevious studies suggested that epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKIs) plus bevacizumab could significantly prolong progression-free survival (PFS) than EGFR-TKI alone as first-line setting for patients with EGFR-mutant non-small-cell lung cancer (NSCLC). However, whether this combination could benefit patients with multiple brain metastases (BrMs) remains undetermined. MethodsA total of 208 patients with EGFR-mutant NSCLC and multiple BrM (number >3, at least one of lesions was measurable) were retrospectively identified. Kaplan-Meier curves with two-sided log-rank tests and Cox proportional hazards model with calculated hazard ratios and 95% confidence intervals were used to determine the survival difference. ResultsOf all patients, 149 patients received EGFR-TKIs monotherapy and 59 received EGFR-TKIs plus bevacizumab as first-line setting. EGFR-TKIs plus bevacizumab was associated with a significantly higher intracranial objective response rate (ORR, 66.1% vs. 41.6%, P = 0.001), systemic ORR (74.6% vs. 57.1%, P = 0.019), longer intracranial PFS (14.0 vs. 8.2 months; P < 0.001) and systemic PFS (14.4 vs. 9.0 months; P < 0.001). Importantly, addition of bevacizumab also had a significantly longer overall survival (OS, 29.6 vs. 21.7 months; P < 0.001). Multivariate analysis consistently revealed that addition of bevacizumab was independently associated with prolonged intracranial and systemic PFS, and OS. No unexpected serious adverse effects were observed. ConclusionsEGFR-TKIs plus bevacizumab prolonged not only PFS but also OS in patients with EGFR-mutant NSCLC and multiple BrMs when compared with EGFR-TKIs alone, indicating that this combination could be an alternative therapeutic option for those patients.