Elotuzumab, lenalidomide, bortezomib, dexamethasone, and autologous haematopoietic stem-cell transplantation for newly diagnosed multiple myeloma (GMMG-HD6): results from a randomised, phase 3 trial.

BACKGROUND: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma. METHODS: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1-2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, and on days 1 and 11 for cycles 3-4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1-28 for cycles 1-3; thereafter, up to 15 mg orally on days 1-28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1-6, and on day 1 for cycles 7-26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed. FINDINGS: Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7-55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61-77), 69% (61-76), 66% (58-74), and 67% (59-75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both. INTERPRETATION: Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma. FUNDING: Bristol Myers Squibb/Celgene and Chugai.

User-Centered Development of a Mobile App to Assess the Quality of Life of Patients With Cancer: Iterative Investigation and Usability Testing.

BACKGROUND: The treatment for cancer can have a negative impact not only on physical well-being but also on mental health and the quality of life (QoL). Health apps enable the monitoring of different parameters, but to date, there are only few that support patients with cancer and none that focuses on the assessment of QoL. Furthermore, patients as stakeholders are often only integrated at the late stage of the development process, if at all. OBJECTIVE: The aim of this research was to develop and evaluate a smartphone app (Lion-App) to enable patients with cancer to autonomously measure the QoL with an iterative, user-centered approach. METHODS: Patients with cancer were involved in a 3-stage process from conceptualization to the point when the app was available on the tester's private device. First, focus groups with members (N=21) of cancer support groups were conducted to understand their expectations and needs. Thereafter, individual tests were performed. After developing a prototype that incorporated findings from the focus groups, a second test cycle was conducted, followed by a beta test lasting 2 months. In our app, the QoL can be assessed via a patient diary and an integrated questionnaire. Through all stages, usability was evaluated using the modular extended version of the User Experience Questionnaire (UEQ+), including the calculation of a key performance indicator (KPI). If possible, the impact of sex on the results was evaluated. As part of the beta test, usage rates as well as age-dependent differences were also assessed. RESULTS: A total of 21 participants took part in the initial 3 focus groups. In the subsequent usability testing (N=18), 17 (94%) participants rated their impression through the UEQ+, with a mean KPI of 2.12 (SD 0.64, range: -3 to 3). In the second usability test (N=14), the mean KPI increased to 2.28 (SD=0.49). In the beta test, the usage rate of 19 participants was evaluated, of whom 14 (74%) also answered the UEQ+ (mean KPI 1.78, SD 0.84). An influence of age on the number of questionnaire responses in Lion-App was observed, with a decrease in responses with increasing age (P=.02). Sex-dependent analyses were only possible for the first usability test and the beta test. The main adjustments based on user feedback were a restructuring of the diary as well as integration of a shorter questionnaire to assess the QoL. CONCLUSIONS: The iterative, user-centered approach for development and usability testing resulted in positive evaluations of Lion-App. Our app was rated as suitable for everyday use to monitor the QoL of patients with cancer. Initial results indicated that the sex and age of participants seem to play only a minor role.

The INFINITY study protocol: a retrospective cohort study on decision making and clinical impact of biomarker-driven precision oncology in routine clinical practice.

BACKGROUND: Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap. METHODS: INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome. DISCUSSION: INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications. TRIAL REGISTRATION: The study is registered at ClinicalTrials.gov, NCT04389541.

Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia. METHODS: This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed. FINDINGS: Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections. INTERPRETATION: The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia. FUNDING: Pfizer and Amgen.

Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies.

UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1non-M41) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome.

Liquid profiling of circulating tumor DNA in colorectal cancer: steps needed to achieve its full clinical value as standard care.

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real-world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long-term implementation in clinical workflows.

Comorbidities, Rather Than Older Age, Are Strongly Associated With Higher Utilization of Healthcare in Colorectal Cancer Survivors.

BACKGROUND: Colorectal cancer (CRC) survivors generally have a higher healthcare utilization (HCU) than the general population due to cancer burden. However, it is unclear which factors are associated with this increased uptake. Our study aimed to (1) compare CRC-related and non-CRC visits to general practitioners (GPs) and medical specialists (MSs) by comorbidities, and (2) assess whether HCU differs by demographic, clinical, and psychological factors. METHODS: We used data from a German population-based cohort of 1,718 survivors of stage I-III CRC diagnosed in 2003 through 2010 who provided information on HCU at 5-year follow-up. Multivariable linear regression was used to calculate least-square means of CRC-related and non-CRC HCU according to the Charlson comorbidity index and comorbidity cluster, adjusting for relevant demographic, clinical, and psychological characteristics. RESULTS: A higher comorbidity level was associated with more CRC-related MS visits and non-CRC GP visits. In addition to being strongly associated with non-CRC GP visits, comorbidity clusters were associated with CRC-related GP and MS visits, but their association varied by specific cardiometabolic comorbidities. HCU was less dependent on prognostic factors for CRC, such as age and tumor stage, but was strongly associated with disease recurrence, depression, and emotional functioning. CONCLUSIONS: Comorbidities, rather than age or tumor stage, were related to HCU, suggesting that CRC survivors use healthcare mainly for reasons other than cancer 5 years postdiagnosis. Improved communication between primary and tertiary healthcare providers could enhance the medical care of cancer survivors with complex health needs and thereby also reduce healthcare costs.

Advantages and Challenges of Using ctDNA NGS to Assess the Presence of Minimal Residual Disease (MRD) in Solid Tumors.

The ability to detect minimal residual disease (MRD) after a curative-intent surgery or treatment is of paramount importance, because it offers the possibility to help guide the clinical decisions related adjuvant therapy. Thus, the earlier MRD is detected, the earlier potentially beneficial treatment can be proposed to patients who might need it. Liquid biopsies, and in particular the next-generation sequencing of circulating tumor DNA (ctDNA) in the blood, have been the focus of an increasing amount of research in the past years. The ctDNA detection at advanced cancer stages is practicable for several solid tumors, and complements molecular information on acquired therapy resistance. In the context of MRD, it is by definition more challenging to detect ctDNA, but it is technically achievable and provides information on treatment response and probability of relapse significantly earlier than standard imaging methods. The clinical benefit of implementing this new technique in the routine is being tested in interventional clinical trials at the moment. We propose here an update of the current use of ctDNA detection by NGS as a tool to assess the presence of MRD and improve adjuvant treatment of solid tumors. We also discuss the main limitations and medium-term perspectives of this process in the clinic.

Assessment of SARS-CoV-2 Infection among Healthcare Workers of a German COVID-19 Treatment Center.

To date, more than 160 million people have been infected with COVID-19 worldwide. In the present study, we investigated the history of SARS-CoV-2 infection among 3067 healthcare workers (HCW) in a German COVID-19 treatment center during the early phase of the pandemic (July 2020) based on the seroprevalence of SARS-CoV-2 antibodies and self-reported previous PCR results. The results demonstrate a low prevalence of SARS-CoV-2 infection (n = 107 [3.5%]) with no increased risk for employees with a high level of patient exposure in general or working in COVID-19-confined areas in particular. This suggests that the local hygiene standards implemented in our hospital during the first wave of COVID-19 pandemic were effective in preventing patient-to-HCW transmission. No evidence for highly mobile staff serving as a vector for SARS-CoV-2 transmission could be found. In addition, impairment of smell and/or taste was strongly associated with SARS-CoV-2 history.

Neoadjuvant nivolumab for patients with resectable HPV-positive and HPV-negative squamous cell carcinomas of the head and neck in the CheckMate 358 trial.

BACKGROUND: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting. METHODS: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria. RESULTS: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR. CONCLUSIONS: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.

Quality of Life as an Indicator for Care Delivery in Clinical Oncology Using FHIR.

INTRODUCTION: Health-related quality of life (HR-QoL) as a parameter for patient well-being is becoming increasingly important.[1] Nevertheless, it is mainly used as an endpoint in studies rather than as an indicator for adjustments in therapy. In this paper we will present an approach to gradually integrate quality of life (QoL) as a control element into the care delivery of oncology. CONCEPT: Acceptance, usability, interoperability and data protection were identified and integrated as key indicators for the development. As an initial approach, a questionnaire tool was developed to provide patients a simplified answering of questionnaires and physicians a clearer presentation of the results. IMPLEMENTATION: As communication standard HL7 FHIR was used and known security concepts like OpenID Concept were integrated. In a usability study, first results were achieved by asking patients in the waiting room to answer a questionnaire, which will be discussed with the physician in the appointment. This study was conducted in 2019 at theSLK Clinics Heilbronn and achieved 86% participation of all respondents with an average age of 67 years. DISCUSSION: Although the evaluation study could prove positive results in usability and acceptance, it is necessary to aim for longitudinal surveys in order to include QoL as a control element in the therapy. However, a longitudinal survey through questionnaires leads to decreasing compliance and increasing response bias. [2] For this reason, the concept needs to be expanded. With sensors a continuous monitoring can be carried out and the data can be mapped to the individual, interpreted by machine learning. CONCLUSION: Questionnaires are a concept that has been successfully applied in studies for years. However, since care delivery poses different challenges, the integration of new concepts is inevitable. The authors are currently working on an extension of the use of questionnaires with patient generated data through sensors.

Uptake Rates of Novel Therapies and Survival Among Privately Insured Versus Publicly Insured Patients With Colorectal Cancer in Germany.

BACKGROUND: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany. METHODS: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively. RESULTS: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I-III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20-4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis. CONCLUSIONS: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.

Neoadjuvant Nivolumab for Patients With Resectable Merkel Cell Carcinoma in the CheckMate 358 Trial.

PURPOSE: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC. METHODS: In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies. RESULTS: Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation. CONCLUSION: Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.

Magnitude of the Age-Advancement Effect of Comorbidities in Colorectal Cancer Prognosis.

BACKGROUND: Comorbidities and old age independently compromise prognosis of patients with colorectal cancer (CRC). The impact of comorbidities could thus be considered as conveying worse prognosis already at younger ages, but evidence is lacking on how much worsening of prognosis with age is advanced to younger ages in comorbid versus noncomorbid patients. We aimed to quantify, for the first time, the impact of comorbidities on CRC prognosis in "age advancement" of worse prognosis. METHODS: A total of 4,602 patients aged ≥30 years who were diagnosed with CRC in 2003 through 2014 were recruited into a population-based study in the Rhine-Neckar region of Germany and observed over a median period of 5.1 years. Overall comorbidity was quantified using the Charlson comorbidity index (CCI). Hazard ratios and age advancement periods (AAPs) for comorbidities were calculated from multivariable Cox proportional hazards models for relevant survival outcomes. RESULTS: Hazard ratios for CCI scores 1, 2, and ≥3 compared with CCI 0 were 1.25, 1.53, and 2.30 (P<.001) for overall survival and 1.20, 1.48, and 2.03 (P<.001) for disease-free survival, respectively. Corresponding AAP estimates for CCI scores 1, 2, and ≥3 were 5.0 (95% CI, 1.9-8.1), 9.7 (95% CI, 6.1-13.3), and 18.9 years (95% CI, 14.4-23.3) for overall survival and 5.5 (95% CI, 1.5-9.5), 11.7 (95% CI, 7.0-16.4), and 21.0 years (95% CI, 15.1-26.9) for disease-free survival. Particularly pronounced effects of comorbidity on CRC prognosis were observed in patients with stage I-III CRC. CONCLUSIONS: Comorbidities advance the commonly observed deterioration of prognosis with age by many years, meaning that at substantially younger ages, comorbid patients with CRC experience survival rates comparable to those of older patients without comorbidity. This first derivation of AAPs may enhance the empirical basis for treatment decisions in patients with comorbidities and highlight the need to incorporate comorbidities into prognostic nomograms for CRC.

Treatment selection bias for chemotherapy persists in colorectal cancer patient cohort studies even in comprehensive propensity score analyses.

INTRODUCTION: Propensity score methods are increasingly used to address confounding related to treatment selection in observational studies. Studies estimating the effect of chemotherapy in colon cancer (CC) patients, however, often lacked information on pertinent comorbidities and functional status (FS). We assessed to what extent comorbidities and FS impact treatment decisions in colorectal cancer patients and explain the benefit of chemotherapy in stage III CC patients. METHODS: Stage II-III colorectal cancer patients diagnosed in 2003-2014 and recruited into a population-based study were included (N=1102). Associations of comorbidity and FS with treatment patterns were examined with multivariable logistic regression. The contribution of lower comorbidity and higher FS to the benefit of chemotherapy was estimated with propensity score weighted Cox models in 430 stage III CC patients who were followed over a median time of 4.7 years. RESULTS: In stage II (high-risk) and III CC patients, Charlson comorbidity scores 1, 2 and 3+ were associated with 57%, 66% and 70% lower odds of chemotherapy use, respectively. In combination with older age and poor FS, comorbidity was associated with 97% and 83% decreased odds of adjuvant chemotherapy use in CC and rectal cancer patients, respectively. In stage III CC patients, lower comorbidity and higher FS explained 38% and 24% of the overall and disease-specific survival benefits of chemotherapy, respectively. Selection bias was observed even in the comprehensive models, as chemotherapy was still associated with substantially higher non-disease-specific survival (hazard ratio (HR): 0.66; 95% confidence interval (CI): 0.46-0.92), especially in patients <75 years (HR: 0.33; 95% CI: 0.17-0.63). CONCLUSION: Lower comorbidity and higher FS of recipients of chemotherapy explain approximately 40% of the benefits of chemotherapy in stage III CC patients. Regardless of how comprehensive propensity score analyses might be in observational studies, treatment selection bias might persist and affect estimates of treatment effects.

FOLFOXIRI Plus Panitumumab As First-Line Treatment of RAS Wild-Type Metastatic Colorectal Cancer: The Randomized, Open-Label, Phase II VOLFI Study (AIO KRK0109).

PURPOSE: This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, open-label, phase II trial in patients with untreated RAS wild-type (WT) metastatic colorectal cancer. PATIENTS AND METHODS: The primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI [mFOLFOXIRI] plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival. RESULTS: A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3% v 60.6%; odds ratio, 4.469; 95% CI, 1.61 to 12.38; P = .004). The secondary resection rate was improved with the addition of panitumumab (33.3% v 12.1%; P = .02). Progression-free survival was similar in the study arms, whereas overall survival showed a trend in favor of the panitumumab-containing arm (hazard ratio for death, 0.67; 95% CI, 0.41 to 1.11; P = .12). CONCLUSION: The addition of panitumumab to mFOLFOXIRI in patients with RAS WT metastatic colorectal cancer improved the ORR and rate of secondary resection of metastases and represents a treatment option in selected and fit patients in need of highly active first-line therapy. Future studies should determine whether the addition of panitumumab to mFOLFOXIRI prolongs survival.

Decreasing Use of Chemotherapy in Older Patients With Stage III Colon Cancer Irrespective of Comorbidities.

BACKGROUND: Chemotherapy underuse in elderly patients (aged ≥75 years) with colon cancer has been reported in previous studies. However, these studies were mostly registry-based and limited in their potential to consider underlying reasons of such undertreatment. This study aimed to evaluate patient and hospital determinants of chemotherapeutic treatment in patients with stage III colon cancer, with a particular focus on age and underlying reasons for nontreatment of elderly patients. METHODS: A total of 629 patients with stage III colon cancer who were diagnosed in 2003 through 2012 and recruited into a population-based study in the Rhine-Neckar region of Germany were included. Information on sociodemographic and lifestyle factors, comorbidities, and treatment was collected from patient interviews and physicians. Patient (with an emphasis on age) and hospital factors were evaluated for their associations with administration of adjuvant chemotherapy overall and of oxaliplatin specifically using multivariable logistic regression. RESULTS: Administration of chemotherapy decreased from 94% in patients aged 30 to 64 years to 51% in those aged ≥75 years. A very strong decline in chemotherapy use with age persisted even after comprehensive adjustment for multiple patient factors-including comorbidities-and hospital factors and was also seen among patients without any major comorbidities. Between 2005 and 2008, and 2009 and 2012, chemotherapy administration in patients aged ≥75 years decreased from 60% to 41%. Among chemotherapy recipients, old age was also strongly associated with higher odds of nonadministration of oxaliplatin. The 2 most commonly reported reasons for chemotherapy nonreceipt among the study population were patient refusal (30%) and old age (24%). CONCLUSIONS: Age was the strongest predictor of chemotherapy underuse, irrespective of comorbidities and even in patients without comorbidities. Such underuse due just to older age in otherwise healthy patients deserves increased attention in clinical practice to ensure that elderly patients also get the best possible care. Patients' refusal as the most frequent reason for chemotherapy nonreceipt also warrants further investigation to exclude misinformation as underlying cause.

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial.

BACKGROUND: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours. METHODS: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m2 epirubicin and 60 mg/m2 cisplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644. FINDINGS: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group. INTERPRETATION: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX. FUNDING: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation.