• N Chemical and physical data C 6484 H 10042 N 1732 O 2023 S 36 145781.6 g/mol N Y Cetuximab is an (EGFR) inhibitor used for the treatment of metastatic, metastatic non-small cell and. Cetuximab is a chimeric (mouse/human) given by intravenous infusion that is distributed under the trade name Erbitux in the U.S. And Canada by the drug company and outside the U.S.

And Canada by the drug company. In Japan, Merck KGaA, Bristol-Myers Squibb and Eli Lilly have a co-distribution. In July 2009, the approved cetuximab (Erbitux) for treatment of colon cancer with wild-type, since it had little or no effect in colorectal tumors harboring a mutation (this also applied to the EGFR antibody ). This was the first genetic test to guide treatment of cancer. In July 2012, the FDA approved a real time test for KRAS, the therascreen KRAS test.

Contents • • • • • • • • • • • • • • • • Medical uses [ ] A diagnostic immunohistochemistry assay (EGFR pharmDx) can be used to detect EGFR expression in the tumor material. Approximately 75% of patients with metastatic colorectal cancer have an EGFR-expressing tumor and are therefore considered eligible for treatment with cetuximab or, according to FDA guidelines. Unfortunately, there is evidence that immunohistochemical EGFR receptor testing does not predict response to either cetuximab or panitumumab, so that this has been called a 'misleading biomarker' that has nevertheless caused insurers and even health systems to deny payment for EGFR antibody treatment for patients who lack a positive tumor EGFR histochemical test. Head and neck cancer [ ] Cetuximab was approved by the in March 2006 for use in combination with for treating of the head and neck () or as a single agent in patients who have had prior platinum-based therapy. Side effects [ ] One of the more serious side effects of cetuximab therapy is the incidence of. This rash rarely leads to dose reductions or termination of therapy.

It is generally reversible. Further severe infusion reactions include but are not limited to: fevers, chills,,,, rash, hypotension, nausea, vomiting, headache, shortness of breath, wheezing, angioedema, dizziness,, and cardiac arrest. Therefore, pretreatment with (30 to 60) min before administration is standard of care. Other common side effects include photosensitivity, due to magnesium wasting, and less commonly pulmonary and cardiac toxicity. Alpha-gal allergy [ ] Certain geographic regions have a high rate of anaphylactic reactions to cetuximab upon the first exposure to the medication.

Original Article. Cisplatin and Fluorouracil Alone or with Docetaxel in Head and Neck Cancer. Posner, M.D., Diane M. Hershock, M.D., Ph.D., Cesar R.

This is unusual because exposure to the allergen must occur before the development of an allergy. Fewer than 1% of people in the northeast United States reacted, while greater than 20% in the southeast did.

The is believed to result from tick bites. Are native to the regions of the US where reactions occurred and were found to be the vector. Cetuximab is produced in the mouse myeloma cell line SP2/0 and thus contains the alpha-gal oligosaccharide, as do all mammals other than primates. Mechanism of action [ ] Cetuximab is a chimeric (mouse/human) monoclonal antibody which binds to and inhibits EGFR.

KRAS Testing [ ] The gene encodes a small G protein on the EGFR pathway. Cetuximab and other EGFR inhibitors only work on tumors in which KRAS is not mutated. KRAS mutational analysis is commercially available from a number of laboratories. In July 2009, the US Food and Drug Administration (FDA) updated the labels of two anti-EGFR monoclonal antibody drugs ( (Vectibix) and cetuximab (Erbitux)) indicated for treatment of metastatic colorectal cancer to include information about KRAS mutations. Studies have indicated that detection of KRAS gene mutations helps physicians identify patients that are unlikely to respond to treatment with targeted EGFR inhibitors, including cetuximab and panitumumab. Accordingly, genetic testing to confirm the absence of KRAS mutations (and so the presence of the KRAS wild-type gene), is now clinically routine before the start of treatment with EGFR inhibitors. MCRC patients with wild-type KRAS tumors have been shown to benefit from a response rate of over 60% and a decreased risk for progression of over 40% when treated with Erbitux as 1st-line therapy.

[ ] Around 65% of mCRC patients have the KRAS wild-type gene. [ ] History [ ], Ester Hurwitz and co-workers published observations on EGFR inhibition in 1988. Yeda Research, on behalf of the in Israel, challenged the Aventis-owned patent, licensed by, for the use of anti- antibodies in combination with chemotherapy, to slow the growth of certain tumors which was filed in 1989. The court ruled that Yeda is sole owner of the patent in the U.S., while Yeda and Sanofi-Aventis co-own the patent's foreign counterparts. Society and culture [ ] Manufacture [ ] • is responsible for the manufacture and supply of Erbitux in bulk-form active pharmaceutical ingredient (API) for clinical and commercial use in the U.S. And Canada, and purchases the API for commercial use from Eli Lilly. • manufactures Erbitux for supply in its territory (outside the U.S.

And Canada) as well as for Japan. Distribution [ ] • Erbitux is marketed in the U.S. And Canada by Bristol-Myers Squibb. Eli Lilly has the option to co-promote Erbitux in the U.S. Eli Lilly receives royalties from Bristol-Myers Squibb.

• Outside the U.S. And Canada, Erbitux is commercialized by Merck KGaA.

Eli Lilly receives royalties from Merck KGaA. • A separate agreement grants co-exclusive rights among Merck, Bristol-Myers Squibb and Eli Lilly in Japan and expires in 2032. Sales [ ] Cetuximab is given by and costs up to $30,000 for eight weeks of treatment per patient. Merck KGaA had 887 million euros ($1.15 billion) in Erbitux sales in 2012, from head and neck as well as bowel cancer, while Bristol-Myers Squibb generated $702 million in sales from the drug. Erbitux was the eighth best-selling cancer drug of 2013, with sales of $1.87 billion. Biosimilars [ ] Erbitux had 2013 worldwide sales of US$1.9 billion making it a lucrative target for developers.

Additionally the patent protection for Erbitux in Europe expired in June 2014, and in the U.S. And in Japan the protection will expire in 2016. However biosimilars of Erbitux are not expected until 2018. As of 2014 biosimilars of cetuximab were in development by several companies. Insider trading [ ]. Main article: Cetuximab failed to get FDA approval in 2001, which caused the stock price of the developer to drop dramatically.

Prior to the announcement, several executives sold stock, and the SEC launched an investigation into. This resulted in a widely publicized criminal case, which resulted in prison terms for media celebrity, ImClone chief executive officer and Stewart's broker at, Peter Bacanovic.

Programs Help Mortgage Debt Ratios there. Research [ ] The efficacy of cetuximab was explored in a clinical trial of advanced published in 2013; cetuximab showed no survival benefit. References [ ].

Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck Robert L. Ferris, M.D., Ph.D., George Blumenschein, Jr., M.D., Jerome Fayette, M.D., Ph.D., Joel Guigay, M.D., A.

Dimitrios Colevas, M.D., Lisa Licitra, M.D., Kevin Harrington, Ph.D., F.R.C.P., F.R.C.R., Stefan Kasper, M.D., Everett E. Vokes, M.D., Caroline Even, M.D., Francis Worden, M.D., Nabil F. Saba, M.D., Lara C. Iglesias Docampo, M.D., Robert Haddad, M.D., Tamara Rordorf, M.D., Naomi Kiyota, M.D., Ph.D., Makoto Tahara, M.D., Ph.D., Manish Monga, M.D., Mark Lynch, Ph.D., William J. Geese, Ph.D., Justin Kopit, Ph.D., James W. Shaw, Pharm.D., Ph.D., M.P.H., and Maura L. Gillison, M.D., Ph.D.

N Engl J Med 2016; 375:1856-1867 DOI: 10.1056/NEJMoa1602252. Methods In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. Results The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy.

Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group.

Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. Figure 1 Overall Survival, Progression-free Survival, and Treatment Effect on Overall Survival According to Subgroup. Panel A shows the Kaplan–Meier curves for overall survival among all the patients who underwent randomization and were assigned to receive either nivolumab or standard therapy.

In the planned interim analysis, the boundary for statistical significance for overall survival required the P value to be less than 0.0227. Panel B shows the Kaplan–Meier curves for progression-free survival among all the patients who underwent randomization. Symbols indicate censored observations.

Hazard ratios (and confidence intervals) were computed with the use of a stratified Cox proportional-hazards model, and the P values were from a stratified log-rank test. Panel C shows a forest plot of unstratified hazard ratios for death in the analysis of the treatment effect according to demographic and clinical subgroups at baseline. Hazard ratios were not calculated for subgroups that included fewer than 20 patients across the two groups.

Platinum-refractory disease in the context of primary therapy refers to cancer progression within 6 months after platinum therapy administered in the context of primary or adjuvant therapy (a post hoc derived analysis). Figure 2 Overall Survival According to Baseline PD-L1 Status and Quality of Life and Symptom Burden. Kaplan–Meier curves for overall survival according to tumor programmed death 1 ligand 1 (PD-L1) expression of 1% or higher and of less than 1% are shown in Panels A and B, respectively. Symbols indicate censored observations. Hazard ratios (and 95% confidence intervals) were computed with the use of a Cox proportional-hazards model.

Panel C shows the results of multivariable analyses of adjusted mean changes from baseline in patient-reported outcomes at weeks 9 and 15, stratified according to treatment group, for 129 patients with questionnaire responses. Least-squares mean estimates were based on analyses of covariance of changes in scores from baseline with adjustment for treatment group, visit, status with respect to previous cetuximab use, and baseline score. Physical, role, and social functioning were assessed by means of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30), and pain, sensory problems, and social-contact problems were assessed by means of the EORTC head-and-neck–specific module (QLQ-H&N35).

All scales range from 0 to 100 and were scored such that higher values indicated better functioning or lower symptom burden. A clinically meaningful score change was regarded as one of 10 points (dashed lines) or more. I bars indicate 95% confidence intervals.

Squamous-cell carcinoma of the head and neck is a major cause of cancer-associated illness and death, with more than 600,000 cases diagnosed annually worldwide. Most patients present with locoregionally advanced disease, and more than 50% have recurrence within 3 years. Patients with squamous-cell carcinoma of the head and neck who have cancer progression within 6 months after platinum-based chemotherapy administered in the context of primary or recurrent disease have a median survival of 6 months or less. No therapeutic options prolong survival among these patients.

The recurrence and metastasis of squamous-cell carcinoma of the head and neck are facilitated by immune evasion, which is mediated in part by expression of the programmed death ligands (PD-L1 and PD-L2) of the T-cell–suppressive immune-checkpoint receptor programmed death 1 (PD-1). Nivolumab, a fully human IgG4 anti–PD-1 monoclonal antibody, has shown antitumor efficacy in multiple tumor types. We designed a randomized trial to investigate whether overall survival would be longer with nivolumab therapy than with standard therapy, among patients with platinum-refractory squamous-cell carcinoma of the head and neck. Trial Design and Treatments Patients were randomly assigned in a 2:1 ratio to receive intravenous nivolumab (Opdivo, Bristol-Myers Squibb) or a standard, single-agent therapy of the investigator’s choice, with stratification according to receipt of previous cetuximab therapy (yes or no).

Nivolumab was administered at a dose of 3 mg per kilogram of body weight every 2 weeks. Standard therapy consisted of weekly intravenous administration of methotrexate at a dose of 40 to 60 mg per square meter of body-surface area, docetaxel at a dose of 30 to 40 mg per square meter, or cetuximab at a dose of 250 mg per square meter after a loading dose of 400 mg per square meter. End Points and Assessments The primary end point was overall survival, which was defined as the time from randomization to the date of death from any cause. Secondary end points were progression-free survival (time from randomization to the date of disease progression or death) and the rate of objective response according to RECIST, version 1.1. Additional prespecified end points included the time to response; associations between PD-L1 level and human papillomavirus (HPV) status and overall survival, progression-free survival, and response rate; safety; and quality-of-life assessments. Tumor response was assessed by investigators according to RECIST, version 1.1, every 6 weeks beginning at week 9. Patients were treated until an unacceptable level of drug-related toxic effects occurred or until disease progression.

However, nivolumab treatment could be continued beyond disease progression, as assessed clinically or radiographically, if the investigator assessed that it was providing clinical benefit. Patients were followed for overall survival every 3 months until death, loss to follow-up, or withdrawal of consent.

At each treatment visit and for 100 days after receipt of the last dose, acute toxic effects were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. Adverse events with potential immunologic causes were classified as select adverse events. The criteria for a dose delay or the discontinuation of nivolumab or standard therapy because of treatment-related adverse events were specified in the, available with the full text of this article at NEJM.org. Dose modifications were not permitted for nivolumab but were specified for methotrexate, docetaxel, and cetuximab on the basis of the type and grade of the toxic effect. Patient-reported outcomes, including symptoms and health-related quality of life, were exploratory end points and were evaluated with the use of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire–Core 30 module (QLQ-C30) and the head-and-neck–specific module (QLQ-H&N35). Scores for these modules range from 0 to 100, with higher scores indicating better functioning or well-being or higher symptom burden, although scales measuring symptom burden were reverse-scored to facilitate presentation.

The proportion of patients reporting health problems was assessed with the use of the three-level version of the European Quality of Life–5 Dimensions (EQ-5D-3L) questionnaire. Patients also completed the EQ-5D-3L visual-analogue scale, for which scores range from 0 to 100 and higher scores indicate better perceived health status. Biomarker Analysis Fresh or archived pretreatment tumor specimens were obtained after the last therapy and before trial entry from 90.6% of the patients. For patients with oropharyngeal cancer, tumor HPV status, assessed by means of p16 immunohistochemical testing, was required to be documented by local or central analysis and was defined as positive if diffuse staining was present in at least 70% of the tumor cells. Immunochemical testing for p16 was not performed for nonoropharyngeal cancers because of the low prevalence of HPV-positive tumors and poor specificity for HPV status at these anatomical sites. Tumor PD-L1 membrane expression was evaluated centrally by means of immunohistochemical testing (Dako North America) with the use of a rabbit antihuman PD-L1 antibody (clone 28–8, Epitomics) and was scored at prespecified expression levels, including levels of 1% or more, 5% or more, and 10% or more in a minimum of 100 tumor cells that could be evaluated. Trial Oversight This trial was registered with the National Cancer Institute and was approved by the institutional review board at each participating institution.

Written informed consent was obtained from all the patients before enrollment. The trial was designed by the academic authors in collaboration with the sponsor (Bristol-Myers Squibb).

The first and last authors attest to the accuracy and completeness of the data and analyses and vouch for adherence of the trial to the. Medical-writing support, funded by the sponsor, was provided by inScience Communications and Chrysalis Medical Communications. Patients and Treatment From June 2014 through August 2015, we randomly assigned 240 patients to receive nivolumab and 121 to receive standard therapy (Fig. S1 in the, available at NEJM.org).

Previous treatment included radiotherapy in 91.4% of the patients and two or more lines of systemic therapy in 54.5%. The treatment groups were balanced with respect to most demographic and clinical characteristics ( Table 1 Characteristics at Baseline and Previous Therapy.

), although the standard-therapy group included higher percentages of patients 65 years of age or older and of patients who had never smoked. Tumor p16 status was reported, per, for 178 patients (113 patients in the nivolumab group and 65 in the standard-therapy group), and 26.2% of the patients in the nivolumab group and 24.0% in the standard-therapy group had positive p16 status. Of 361 patients who underwent randomization, 347 (96.1%) received one or more doses of assigned therapy (236 patients in the nivolumab group and 111 in the standard-therapy group). Standard therapies that were administered included methotrexate (in 46 patients), docetaxel (in 52), and cetuximab (in 13). The median duration of treatment was 1.9 months in each group. Data on dose delays and reductions according to treatment group are provided in Table S1 in the. At the time of analysis, 41 of 236 patients (17.4%) were still receiving nivolumab and 3 of 111 (2.7%) were still receiving standard therapy.

Efficacy Among 361 patients who underwent randomization, 133 deaths (55.4% of patients) occurred in the nivolumab group and 85 deaths (70.2% of patients) occurred in the standard-therapy group. The median duration of follow-up for overall survival was 5.1 months (range, 0 to 16.8). The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the standard-therapy group. Overall survival was significantly longer with nivolumab than with standard therapy, and nivolumab-treated patients had a risk of death that was 30% lower than the risk among patients assigned to standard therapy (hazard ratio, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01) ( Figure 1 Overall Survival, Progression-free Survival, and Treatment Effect on Overall Survival According to Subgroup. Panel A shows the Kaplan–Meier curves for overall survival among all the patients who underwent randomization and were assigned to receive either nivolumab or standard therapy. In the planned interim analysis, the boundary for statistical significance for overall survival required the P value to be less than 0.0227.

Panel B shows the Kaplan–Meier curves for progression-free survival among all the patients who underwent randomization. Symbols indicate censored observations. Hazard ratios (and confidence intervals) were computed with the use of a stratified Cox proportional-hazards model, and the P values were from a stratified log-rank test. Panel C shows a forest plot of unstratified hazard ratios for death in the analysis of the treatment effect according to demographic and clinical subgroups at baseline.

Hazard ratios were not calculated for subgroups that included fewer than 20 patients across the two groups. Platinum-refractory disease in the context of primary therapy refers to cancer progression within 6 months after platinum therapy administered in the context of primary or adjuvant therapy (a post hoc derived analysis). The delayed separation of the Kaplan–Meier curves for overall survival is indicative of nonproportionality, and the hazard ratio should be thought of as an average over time. The estimated rate of overall survival at 1 year among patients treated with nivolumab (36.0%; 95% CI, 28.5 to 43.4) was more than double the rate with standard therapy (16.6%; 95% CI, 8.6 to 26.8).

Nivolumab was associated with longer median overall survival than all the options for standard therapy: methotrexate (median, 4.6 months; hazard ratio for death, 0.64; 95% CI, 0.43 to 0.96), docetaxel (median, 5.8 months; hazard ratio, 0.82; 95% CI, 0.53 to 1.28), and cetuximab (median, 4.1 months; hazard ratio, 0.47; 95% CI, 0.22 to 1.01). Across prespecified demographic and clinical subgroups, the estimate of the hazard ratio for death in the analysis of overall survival with nivolumab versus standard therapy was less than 1 (, and Fig. No significant difference between groups was observed with regard to the rate of progression-free survival (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). Gta Iv Hot Coffee Mod How To Install. The crossing of the Kaplan–Meier curves is indicative of nonproportionality. The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) in the nivolumab group versus 2.3 months (95% CI, 1.9 to 3.1) in the standard-therapy group ( ).

However, a late separation in the Kaplan–Meier curves was observed, and the estimated rates of progression-free survival at 6 months were 19.7% (95% CI, 14.6 to 25.4) in the nivolumab group and 9.9% (95% CI, 5.0 to 16.9) in the standard-therapy group. The response rate among nivolumab-treated patients was 13.3% (95% CI, 9.3 to 18.3), including 6 complete responses and 26 partial responses.

In the standard-therapy group, the response rate was 5.8% (95% CI, 2.4 to 11.6), including 1 complete response and 6 partial responses. The median time to response was 2.1 months with nivolumab versus 2.0 months with standard therapy. Tumor reductions were more durable with nivolumab, as indicated by the tumor-burden plots over time for patients who had either a partial response or a complete response (Fig. PD-L1 Expression and p16 Status A prespecified, exploratory analysis was performed to evaluate the consistency of the treatment effect in subgroups defined according to tumor PD-L1 expression level (≥1% vs. Safety The most common treatment-related adverse events are shown in Table 3 Treatment-Related Adverse Events Occurring in at Least 5% of the Patients in Either Group. (see also Tables S4, S5, and S6 in the ).

The rates of treatment-related adverse events of any grade were similar in the two groups, but fewer events of grade 3 or 4 were reported in the nivolumab group than in the standard-therapy group (occurring in 13.1% vs. 35.1% of patients). In the nivolumab group, the most frequent adverse events of any grade were fatigue, nausea, rash, decreased appetite, and pruritus. Among the select adverse events, gastrointestinal events were less common with nivolumab than with standard therapy (occurring in 6.8% vs. 14.4% of the patients; primarily diarrhea), whereas adverse events of the skin were more common with nivolumab (in 15.7% vs. 12.6%; primarily rash and pruritus), as were adverse events of the endocrine system (in 7.6% vs. 0.9%; primarily hypothyroidism).

Pneumonitis was observed in 2.1% of the patients treated with nivolumab. Two treatment-related deaths were reported in the nivolumab group (pneumonitis and hypercalcemia in one patient each), and one patient in the standard-therapy group died from a treatment-related lung infection. Patient-Reported Outcomes Patient-reported quality-of-life measures were similar at baseline among patients randomly assigned to the nivolumab group and those assigned to the standard-therapy group (Table S7 in the ). Analyses were limited to data collected through week 15 owing to a low number of responses to the questionnaires in the standard-therapy group after that time point (Table S8 in the ). Patients in the standard-therapy group reported clinically meaningful worsening of physical, role, and social functioning (as assessed by means of the QLQ-C30), as well as of pain, sensory problems, and social-contact problems (as assessed by means of the QLQ-H&N35). Conversely, among patients treated with nivolumab, these measures remained nearly stable or showed slight improvements.

P values showed significant between-group differences at both week 9 and week 15 for most comparisons ( ). Additional patient-reported outcome data, including health problems and evaluations of health as measured by the EQ-5D-3L questionnaire, are provided in Table S9 in the. Discussion Among patients with recurrent squamous-cell carcinoma of the head and neck who had disease progression after platinum-based chemotherapy, treatment with nivolumab resulted in significantly longer survival than treatment with standard therapy. Patients who were treated with nivolumab had stability in several measures of quality of life, whereas the patients who received standard therapy had declines in these measures.

Our exploratory biomarker analysis indicated that patients who were treated with nivolumab appeared to have longer overall survival than those treated with standard therapy, regardless of tumor PD-L1 expression or p16 status. Although we observed preliminary evidence that patients with a tumor PD-L1 expression level of 1% or more or p16-positive tumors (or both) may have a greater magnitude of effect from nivolumab therapy than those whose PD-L1 level was less than 1% or who had p16-negative tumors, the interactions were not significant and were not corrected for multiple comparisons. The response data from this trial are consistent with those from a previous phase 1b trial of anti–PD-1 therapy.

In conclusion, nivolumab prolonged survival, as compared with standard therapy, among patients with platinum-refractory squamous-cell carcinoma of the head and neck. Nivolumab was associated with fewer toxic effects of grade 3 or 4 than standard therapy (13.1% vs.

35.1%) and with maintenance of quality of life among patients with a treatment-refractory cancer that otherwise has serious adverse effects on quality of life as it leads to death. Supported by Bristol-Myers Squibb. Provided by authors are available with the full text of this article at NEJM.org. Ferris and Gillison contributed equally to this article. This article was published on October 9, 2016, at NEJM.org.