Temporal Trends and Outcomes Among Patients Admitted for Immune-Related Adverse Events: A Single-Center Retrospective Cohort Study from 2011 to 2018

BackgroundThe aim of this study was to characterize severe immune‐related adverse events (irAEs) seen among hospitalized patients and to examine risk factors for irAE admissions and clinically relevant outcomes, including length of stay, immune checkpoint inhibitor (ICI) discontinuation, readmission, and death.MethodsPatients who received ICI therapy (ipilimumab, pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, or any ICI combination) at Massachusetts General Hospital (MGH) and were hospitalized at MGH following ICI initiation between January 1, 2011, and October 24, 2018, were identified using pharmacy and hospital admission databases. Medical records of all irAE admissions were reviewed, and specialist review with defined criteria was performed. Demographic data, relevant clinical history (malignancy type and most recent ICI regimen), and key admission characteristics, including dates of admission and discharge, immunosuppressive management, ICI discontinuation, readmission, and death, were collected.ResultsIn total, 450 admissions were classified as irAE admissions and represent the study''s cohort. Alongside the increasing use of ICIs at our institution, the number of patients admitted to MGH for irAEs has gradually increased every year from 9 in 2011 to 92 in 2018. The hospitalization rate per ICI recipient has declined over that same time period (25.0% in 2011 to 8.5% in 2018). The most common toxicities leading to hospitalization in our cohort were gastrointestinal (30.7%; n = 138), pulmonary (15.8%; n = 71), hepatic (14.2%; n = 64), endocrine (12.2%; n = 55), neurologic (8.4%; n = 38), cardiac (6.7%; n = 30), and dermatologic (4.4%; n = 20). Multivariable logistic regression revealed statistically significant increases in irAE admission risk for CTLA‐4 monotherapy recipients (odds ratio [OR], 2.02; p < .001) and CTLA‐4 plus PD‐1 combination therapy recipients (OR, 1.88; p < .001), relative to PD‐1/PD‐L1 monotherapy recipients, and patients with multiple toxicity had a 5‐fold increase in inpatient mortality.ConclusionThis study illustrates that cancer centers must be prepared to manage a wide variety of irAE types and that CTLA‐4 and combination ICI regimens are more likely to cause irAE admissions, and earlier. In addition, admissions for patients with multi‐organ involvement is common and those patients are at highest risk of inpatient mortality.Implications for Practice The number of patients admitted to Massachusetts General Hospital for immune‐related adverse events (irAEs) has gradually increased every year and the most common admissions are for gastrointestinal (30.7%), pulmonary (15/8%), and hepatic (14.2%) events. Readmission rates are high (29% at 30 days, 49% at 180 days) and 64.2% have to permanently discontinue immune checkpoint inhibitor therapy. Importantly, multiple concurrent toxicities were seen in 21.6% (97/450) of irAE admissions and these patients have a fivefold increased risk of inpatient death.     

Impact of prior treatment with immune checkpoint inhibitors on dacarbazine efficacy in metastatic melanoma

Background Despite its low efficacy, chemotherapy with dacarbazine remains an option in metastatic melanoma patients after failure of immune checkpoint inhibitors (ICI) ± targeted therapy. Some observations suggested an increased efficacy of chemotherapy in melanoma or lung cancer patients previously treated with ICI; we aimed to evaluate the efficacy of dacarbazine in a controlled-group study of patients pre-treated or not with ICI.Methods We retrospectively collected data from all consecutive patients treated with dacarbazine for advanced cutaneous melanoma without brain metastasis, in our skin cancer centre between June 2006 and September 2019. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rates (ORR), overall survival (OS) and safety of dacarbazine.Results Among 72 patients, 17 (23.6%) received dacarbazine after ICI and 55 (76.3%) without prior ICI. Despite less favourable prognostic factors in patients ICI-pre-treated, median PFS was 4.27 months (range 0.89–43.69) in this group versus 2.04 months (range 1.25–39.25) P = 0.03 in non-ICI-pre-treated patients; ORR were 35.3% and 12.7%, respectively. The median OS and the occurrence of adverse events were similar in both groups.Conclusion Dacarbazine seems to offer a short-lived benefit in patients with progressive advanced disease despite ICI (±targeted therapy), and could be an alternative before considering best supportive care.Subject terms: Melanoma, Immunization     

Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors

Background Approximately 50% of cancer patients eventually develop a syndrome of prolonged weight loss (cachexia), which may contribute to primary resistance to immune checkpoint inhibitors (ICI). This study utilised radiomics analysis of ¹⁸F-FDG-PET/CT images to predict risk of cachexia that can be subsequently associated with clinical outcomes among advanced non-small cell lung cancer (NSCLC) patients treated with ICI.Methods Baseline (pre-therapy) PET/CT images and clinical data were retrospectively curated from 210 ICI-treated NSCLC patients from two institutions. A radiomics signature was developed to predict the cachexia with PET/CT images, which was further used to predict durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) following ICI.Results The radiomics signature predicted risk of cachexia with areas under receiver operating characteristics curves (AUCs) ≥ 0.74 in the training, test, and external test cohorts. Further, the radiomics signature could identify patients with DCB from ICI with AUCs≥0.66 in these three cohorts. PFS and OS were significantly shorter among patients with higher radiomics-based cachexia probability in all three cohorts, especially among those potentially immunotherapy sensitive patients with PD-L1-positive status (p < 0.05).Conclusions PET/CT radiomics analysis has the potential to predict the probability of developing cachexia before the start of ICI, triggering aggressive monitoring to improve potential to achieve more clinical benefit.Subject terms: Prognostic markers, Predictive markers     

Real‐World Clinical Outcomes in Biological Subgroups of Breast Cancer in the Hospital District of Southwest Finland

BackgroundComparing breast cancer survival trends globally, Finland is among the top three countries in Europe. However, outcome data on breast cancer subgroups in the Finnish population are limited. This retrospective, registry‐based study aimed to assess patient characteristics and clinical outcomes of different breast cancer subgroups in early (EBC) and metastatic breast cancer (MBC) in a real‐life clinical setting.Materials and MethodsThe study consisted of 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005–2018. Patients were divided into four mutually exclusive groups: human epidermal growth factor receptor 2 positive (HER2+), triple negative, HER2−/hormone receptor positive (HR+), and HER2 and/or HR status unknown, and further into patients with EBC and MBC. Overall survival (OS) was assessed as a clinical outcome, as well as the following real‐world (rw) clinical outcomes: disease‐free survival (rwDFS), progression‐free survival (rwPFS), and distant recurrence‐free interval (rwDRFI).ResultsWithin EBC, 5‐year survival was the highest (88%) in HER2−/HR+, followed by 85% in HER2+, and 75% in triple negative. The rwDFS varied significantly in EBC (5‐year rwDFS HER2 ‐/HR+, HER2+, triple negative: 87%, 80%, 71% respectively). In MBC, median survival was 2 years for both HER2−/HR+ and HER2+ and markedly shorter for triple negative (0.8 years). Independent predictors of mortality were age (hazard ratio [HR], 1.1), other subgroups than HER2−/HR+ (HR, 1.2–1.9), metastatic disease (HR, 9.8), and other malignancies (HR, 2.7).ConclusionThis registry‐based study demonstrates significant differences in breast cancer outcomes on the subgroup level, as well as poorer outcomes compared with clinical trials, giving complementary insight on clinical characteristics in an unselected patient population.Implications for PracticeThis retrospective, registry‐based study assessed the clinical outcomes of different breast cancer subgroups in 6,977 adult, female patients with breast cancer diagnosed in Southwest Finland during 2005–2018. Results demonstrated significant variation in the survival between subgroups in both early breast cancer and metastatic breast cancer, as well as differences between unselected patients representing the standard of care and randomized clinical trials. Although, according to the global comparison of survival trends, the net survival of patients with breast cancer in Finland is generally high, there is great variation between subgroups. These real‐life breast cancer data provide tools to further evaluate medical need in different breast cancer subgroups.     

Weekly Carboplatin and Paclitaxel: A Retrospective Comparison with the Three‐Weekly Schedule in First‐Line Treatment of Ovarian Cancer

BackgroundConventional first‐line combination therapy for ovarian cancer comprises 6 cycles of adjuvant or neoadjuvant carboplatin (AUC5‐6) with paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). Weekly scheduling of paclitaxel may maximize its antiangiogenic effect and reduce adverse effects. We compared the efficacy and safety of PC‐3W with a modified protocol of weekly paclitaxel 80 mg/m² and weekly carboplatin AUC2 administered on days 1, 8, and 15 in a 28‐day cycle (i.e., with 1 week off‐treatment [PC‐W]).Materials and MethodsMedical records of consecutive patients treated between 2000 and 2018 were reviewed; 707 patients were analyzed for demographic and clinical characteristics, effectiveness and toxicity.ResultsPC‐3W was administered to 402 patients (median age, 60.5 years) and PC‐W to 305 patients (median age, 62.5 years). Most patients (91.4%) were diagnosed at stage III–IV. Notwithstanding a higher proportion of residual disease and older patients in the PC‐W group, median progression‐free survival was 21.4 months and 13.2 months for PC‐W and PC‐3W, respectively; median overall survival was 75.2 and 54.0 months for PC‐W and PC‐3W, respectively. Cox proportional hazards model indicated improved survival for patients treated with PC‐W (hazard ratio, 0.54). Similar results were observed for older patients diagnosed at ≥75 years. PC‐W demonstrated a better safety profile, with lower incidence of neuropathy, neutropenia, and alopecia.ConclusionPC‐W is as active and better tolerated than the standard PC‐3W regimen. PC‐W may serve as an alternative option for elderly or frail patients.Implications for PracticeWeekly scheduling of paclitaxel 80 mg/m² and carboplatin AUC2, administered on days 1, 8, and 15 in a 28‐day cycle (PC‐W) for first‐line therapy for advanced ovarian cancer, is as active and better tolerated than the standard regimen of carboplatin and paclitaxel (175 mg/m²) every 3 weeks (PC‐3W). It is possible that the weekly holiday on day 21 in the PC‐W regimen may ensure better completion rates (which may result in treatment delays for toxicity in PC‐3W). The results of this retrospective analysis highlight the weekly regimen as a valid treatment option, especially for elderly patients and those with significant comorbidities.     

Baseline Modified Glasgow Prognostic Score Associated with Survival in Metastatic Urothelial Carcinoma Treated with Immune Checkpoint Inhibitors

BackgroundThe modified Glasgow prognostic score (mGPS), a clinical tool that incorporates albumin and C‐reactive protein, has proven useful in the prognostication of multiple cancers. Several immune checkpoint inhibitors (ICIs) have been approved for the treatment of metastatic urothelial cell carcinoma (mUC), but a prognostic biomarker is needed. We investigated the impact of mGPS on survival outcomes in patients with mUC receiving ICIs.Materials and MethodsWe retrospectively reviewed patients with mUC treated with ICIs (programmed cell death protein 1 or programmed cell death ligand 1 inhibitors) at Winship Cancer Institute from 2015 to 2018. Overall survival (OS) and progression‐free survival (PFS) were measured from the start date of ICI until death or clinical or radiographic progression, respectively. mGPS was defined as a summary score with one point given for C‐reactive protein >10 mg/L and/or albumin <3.5 g/dL. Univariate (UVA) and multivariate (MVA) analyses were carried out using Cox proportional hazard model. These outcomes were also assessed by Kaplan‐Meier analysis.ResultsA total of 53 patients were included with a median follow‐up 27.1 months. The median age was 70 years, with 84.9% male and 20.8% Black. Baseline mGPS was 0 in 43.4%, 1 in 28.3% and 2 in 28.3%. Increased mGPS at the time of ICI initiation was associated with poorer OS and PFS in UVA, MVA, and Kaplan‐Meier analyses.ConclusionThe mGPS may be a useful prognostic tool in patients with mUC when treatment with ICI is under consideration. These results warrant a larger study for validation.Implications for PracticeThe ideal prognostic tool for use in a busy clinical practice is easy‐to‐use, cost‐effective, and capable of accurately predicting clinical outcomes. There is currently no universally accepted risk score in metastatic urothelial cell carcinoma (mUC), particularly in the immunotherapy era. The modified Glasgow prognostic score (mGPS) incorporates albumin and C‐reactive protein and may reflect underlying chronic inflammation, a known risk factor for resistance to immune checkpoint inhibitors (ICIs). This study found that baseline mGPS is associated with survival outcomes in patients with mUC treated with ICIs and may help clinicians to prognosticate for their patients beginning immunotherapy.     

Efficacy of local therapy for oligoprogressive disease after programmed cell death 1 blockade in advanced non‐small cell lung cancer

Immune checkpoint inhibitors (ICIs) have dramatically changed the strategy used to treat patients with non‐small‐cell lung cancer (NSCLC); however, the vast majority of patients eventually develop progressive disease (PD) and acquire resistance to ICIs. Some patients experience oligoprogressive disease. Few retrospective studies have evaluated clinical efficacy in patients with oligometastatic progression who received local therapy after ICI treatment. We conducted a retrospective analysis of advanced NSCLC patients who received PD‐1 inhibitor monotherapy with nivolumab or pembrolizumab to evaluate the effects of ICIs on the patterns of progression and the efficacy of local therapy for oligoprogressive disease. Of the 307 patients treated with ICIs, 148 were evaluated in our study; 42 were treated with pembrolizumab, and 106 were treated with nivolumab. Thirty‐eight patients showed oligoprogression. Male sex, a lack of driver mutations, and smoking history were significantly correlated with the risk of oligoprogression. Primary lesions were most frequently detected at oligoprogression sites (15 patients), and 6 patients experienced abdominal lymph node (LN) oligoprogression. Four patients showed evidence of new abdominal LN oligometastases. There was no significant difference in overall survival (OS) between the local therapy group and the switch therapy group (reached vs. not reached, P = .456). We summarized clinical data on the response of oligoprogressive NSCLC to ICI therapy. The results may help to elucidate the causes of ICI resistance and indicate that the use of local therapy as the initial treatment in this setting is feasible treatment option.     

Safety of Immune Checkpoint Inhibitors in Patients with Cancer and Hepatitis C Virus Infection

BackgroundThe safety of immune checkpoint inhibitors (ICIs) in patients with hepatitis C virus (HCV) infection has not been studied in many cancers, as these patients were excluded from most ICI trials. This poses a degree of uncertainty when a patient with HCV is being considered for ICIs in the absence of data to inform potential adverse events (AEs).Materials and MethodsThis was a single‐institution retrospective chart review of patients with active or resolved HCV who were treated with ICIs for cancer of any type and stage from January 2012 to December 2019, with emphasis on AE rates.ResultsWe identified 40 patients, 30 men and 10 women. Median age was 64 years. Cancer types were non‐small cell lung cancer (18; 45%), hepatocellular carcinoma (12; 30%), head and neck cancer (4; 10%), small cell lung cancer (3; 7.5%), renal cell carcinoma (1; 2.5%), colon cancer (1; 2.5%), and melanoma (12.5%). Hepatitis C was untreated in 17 patients (42.5%), treated in 14 (35%), and spontaneously resolved in 9 (22.5%). AEs observed were grade 3 pneumonitis in one patient (2.5%) on pembrolizumab; grade 3 colitis in one patient (2.5%) on nivolumab; hepatotoxicity in two patients (5%) on nivolumab: one patient with grade 1 and the other with grade 2; grade 1–2 fatigue in three patients (7.5%); and hypothyroidism in one patient (2.5%).ConclusionAdverse events rates in patients with untreated and resolved HCV treated with ICI for a variety of cancers were comparable with AEs rates reported in clinical trials for patients without HCV.Implications for PracticeThe safety of immune checkpoint inhibitors (ICIs) in patients with cancer with hepatitis C virus (HCV) infection is a major concern because of the lack of prospective safety data for most cancers. HCV is prevalent worldwide, and the occurrence of cancer where ICI is indicated is not uncommon. This study was a retrospective review of all patients with HCV who received ICI for a variety of cancers in the authors’ institution over 8 years, and the results are presented in this article. The results may help inform clinical decisions and the design of future clinical trials.     

Risk of COVID-19 in Patients with Cancer Receiving Immune Checkpoint Inhibitors

ObjectiveThe aim of this study was to determine the rate of coronavirus disease‐19 (COVID‐19) among patients with cancer treated with immune checkpoint inhibitors (ICIs).Materials and MethodsThis was a retrospective study of 1,545 patients with cancer treated with ICIs between July 1, 2019, and February 29, 2020, and 20,418 age‐, sex‐, and cancer category‐matched controls in a large referral hospital system. Confirmed COVID‐19 case and mortality data were obtained with Massachusetts Department of Public Health from March 1 through June 19, 2020.ResultsThe mean age was 66.6 years, and 41.9% were female. There were 22 (1.4%) and 213 (1.0%) COVID‐19 cases in the ICI and control groups, respectively. When adjusting for demographics, medical comorbidities, and local infection rates, ICIs did not increase COVID‐19 susceptibility.ConclusionICIs did not increase the rate of COVID‐19. This information may assist patients and their oncologists in decision‐making surrounding cancer treatment during this pandemic.     

All in the Levels—Programmed Death‐Ligand 1 Expression as a Biomarker for Immune Checkpoint Inhibitor Response in Patients with Gastrointestinal Cancer

Immune checkpoint inhibitors (ICIs) benefit patients with rare subsets of gastrointestinal (GI) cancer. Significant interest exists to identify predictive biomarkers that may increase the applicability of ICI therapy for these patients. Programmed death ligand 1 (PD‐L1) is one such candidate; however, this biomarker has well‐chronicled limitations. Combined positive score (CPS) ≥1 is the minimum PD‐L1 expression threshold necessary for patients with gastric or gastroesophageal junction (GEJ) cancer to qualify for treatment with pembrolizumab; however, studies suggest that patients with higher CPS scores may derive greater benefit. We present the cases of two patients, both with low tumor mutational burden, microsatellite stable, and CPS ≥70 GI tumors (cholangiocarcinoma and GEJ cancer), who have achieved excellent tumor control with pembrolizumab. We postulate that, by testing for CPS in all patients with GI cancer and identifying a CPS threshold predictive of ICI response, PD‐L1 expression could identify the patiets with GI cancer, in tissue agnostic fashion, who could benefit from ICI therapy.     

Results with Floxuridine,Actinomycin D,Etoposide, and Vincristine in Gestational Trophoblastic Neoplasias with International Federation of Gynecology and Obstetrics Scores ≥5

Background5‐fluorouracil‐based multiagent chemotherapy has been used as the primary treatment for high‐risk gestational trophoblastic neoplasia (GTN) in China for a few decades. This study aims to assess the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who had International Federation of Gynecology and Obstetrics (FIGO) scores ≥5.Materials and MethodsA total of 207 patients with GTN who had FIGO scores ≥5 were treated with FAEV as first‐line chemotherapy at Peking Union Medical College Hospital between January 2002 and December 2017. Complete remission (CR), resistance, survival, toxicity, and reproductive outcomes were analyzed.ResultsOf the 207 patients treated with FAEV, 9 (4.3%) required a change of chemotherapy owing to toxicity and 1 (0.5%) died of cerebral hernia 5 weeks after commencing treatment. The remaining 197 patients were assessable to determine the response to FAEV; among them, 168 (85.3%) achieved CR with FAEV and 29 (14.7%) developed resistance to FAEV. The 5‐year overall survival rate of the entire cohort was 97.4%. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 28.4%, 6.8%, and 6.2% of cycles, respectively. No acute toxicity‐related deaths occurred. Five patients developed acute myeloid leukemia 10–50 months after exposure to chemotherapy; another patient developed duodenal cancer 2 years after completing therapy. Sixty‐one patients who preserved fertility wanted to become pregnant; 56 of them conceived.ConclusionThe FAEV regimen is an effective primary treatment for patients with GTN who have FIGO scores ≥5 and has predictable and manageable toxicity.Implications for PracticeThe most commonly used multiagent chemotherapy for high‐risk gestational trophoblastic neoplasia (GTN) is etoposide, methotrexate and actinomycin D/cyclophosphamide and vincristine (EMA/CO) worldwide. However, 5‐fluorouracil‐based multiagent chemotherapy has been used as a primary treatment for high‐risk GTN in China for a few decades. This study evaluated the efficacy and toxicity of floxuridine, actinomycin D, etoposide, and vincristine (FAEV) as a primary treatment for patients with GTN who have International Federation of Gynecology and Obstetrics (FIGO) scores ≥5. The study''s data demonstrated that FAEV as a primary treatment achieved favorable outcomes for patients with FIGO scores ≥5. Toxicities that result from the FAEV regimen are predictable and manageable. The FAEV regimen may provide another option for the treatment of GTN.     

Clinical Application of the FoundationOne CDx Assay to Therapeutic Decision-Making for Patients with Advanced Solid Tumors

BackgroundImplementation of personalized medicine requires the accessibility of tumor molecular profiling in order to allow prioritization of appropriate targeted therapies for individual patients. Our aim was to study the role of comprehensive genomic profiling assays that may inform treatment recommendations for patients with solid tumors.Materials and MethodsWe performed a prospective study to evaluate the feasibility of application of the FoundationOne CDx panel—which detects substitutions, insertions and deletions, and copy number alterations in 324 genes, select gene rearrangements, and genomic signatures including microsatellite instability and tumor mutation burden (TMB)—to patients with advanced or recurrent solid tumors before its approval in Japan.ResultsA total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%. The median turnaround time was 41 days (range, 21–126 days). The most common known or likely pathogenic variants were TP53 mutations (n = 113), PIK3CA mutations (n = 33), APC mutations (n = 32), and KRAS mutations (n = 29). Among the 153 patients assessed for TMB, the median TMB was 4 mutations/Mb, and tumors with a high TMB (≥10 mutations/Mb) were more prevalent for lung cancer (11/32) than for other solid tumor types (9/121, Fisher''s exact test p < .01). No clear trend toward increased efficacy for immune checkpoint inhibitor (ICI) monotherapy or ICI combination chemotherapy in patients with a high programmed cell death–ligand 1 tumor proportion score or a high TMB was apparent. Among the 174 patients found to harbor known or likely pathogenic actionable alterations, 24 individuals (14%) received matched targeted therapy.ConclusionThe FoundationOne CDx assay was performed with formalin‐fixed, paraffin‐embedded tumor specimens with a success rate of >95%. Such testing may inform the matching of patients with cancer with investigational or approved targeted drugs.Implications for PracticeThis prospective cohort study was initiated to investigate the feasibility and utility of clinical application of FoundationOne CDx. A total of 181 samples were processed for genomic testing between September 2018 and June 2019, with data being successfully obtained for 175 of these samples, yielding a success rate of 96.7%, and 24 individuals (14%) received matched targeted therapy.     

A Multicenter Analysis of Immune Checkpoint Inhibitors as Adjuvant Therapy Following Treatment of Isolated Brain Metastasis

BackgroundThe objective of this work was to characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy.Materials and MethodsPatients from four medical centers were included if they presented with isolated brain metastases treated with local therapy and received adjuvant treatment with ICIs.ResultsEleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n = 8) and/or stereotactic radiosurgery (SRS; n = 6), were included. Ipilimumab/nivolumab was the adjuvant ICI used in four patients, of whom one recurred (25%) and none died, compared with three of seven (43%) who recurred and two of seven (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial.ConclusionPatients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI therapy, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.     

Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer

The pleiotropic protein hepatocyte growth factor (HGF) is the only known ligand of the tyrosine kinase mesenchymal–epithelial transition (cMET) receptor. The HGF/cMET pathway mediates invasion and migration of ovarian cancer cells, and upregulation of HGF/cMET pathway components has been associated with poor prognosis. This study investigated the clinical relevance of circulating HGF in serum of patients with ovarian cancer. Serum HGF (sHGF) was determined by enzyme‐linked immunosorbent assay in a total of 471 serum samples from 82 healthy controls and 113 patients with ovarian cancer (88.5% with ≥ FIGO III). Patient samples were collected at primary diagnosis and at four follow‐up time points throughout treatment and at disease recurrence. Patients with ovarian cancer showed elevated median sHGF levels at primary diagnosis, and sHGF levels transiently increased after surgery and normalized in the course of chemotherapy, even dropping below initial baseline. Higher levels of sHGF were an independent predictor for shorter overall survival (OS) (a) at primary diagnosis (HR = 0.41, 95% CI: 0.22–0.78, P = 0.006), (b) at longitudinal follow‐up time points (after surgery and before/during/after chemotherapy), (c) along the patients’ individual dynamics (HR = 0.21, 95% CI: 0.07–0.63, P = 0.005), and (d) among a subgroup analysis of patients with BRCA1/2 wild‐type ovarian cancer. This is the first study proposing sHGF as an independent prognostic biomarker for ovarian cancer at primary diagnosis and in the course of platinum‐based chemotherapy, irrespective of the postoperative residual disease after surgical debulking. sHGF could be implemented into clinical diagnostics as a CA125 auxiliary tumor marker for individualized prognosis stratification and sHGF‐guided therapy monitoring.     

Phase II Study of Panitumumab Monotherapy in Chemotherapy‐Naïve Frail or Elderly Patients with Unresectable RAS Wild‐Type Colorectal Cancer: OGSG 1602

Lessons Learned

• Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild‐type unresectable colorectal cancer.
• It is especially effective for left‐sided tumors; therefore, panitumumab as first‐line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin‐based or irinotecan‐based combination regimens.

BackgroundFirst‐line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy‐naïve frail or elderly patients with unresectable RAS wild‐type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first‐line treatment.MethodsWe conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression‐free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities.ResultsThirty‐six patients (median age: 81 [range, 67–88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty‐three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty‐eight patients (77.8%) had left‐sided CRC, whereas eight (22.2%) had right‐sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4–67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5–87.7). The RR of patients with left‐ and right‐sided tumors was 65.4% (95% CI, 44.3–82.8) and 0.0% (95% CI, 0.0–36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%).ConclusionPanitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress.     

Weekly Paclitaxel-Induced Neurotoxicity in Breast Cancer: Outcomes and Dose Response

BackgroundPaclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose‐reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose‐reduction on post‐treatment neuropathy outcomes.Patients and MethodsBreast cancer patients receiving paclitaxel (80mg/m²) weekly for 12‐weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group‐Neurotoxicity; FACTGOG‐Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12‐months post completion. The impact of dose‐reduction on post‐treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel‐treated patients.ResultsSignificant neuropathy was present by 6‐weeks across patient‐reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT‐GOG‐Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT‐GOG‐Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT‐GOG‐Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT‐GOG‐Ntx: 45.3 ± 0.9, p < .05).ConclusionWeekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose.Implications for PracticeWeekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long‐term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule‐specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.     

Fibroblast growth factor receptor 3 alterations and response to immune checkpoint inhibition in metastatic urothelial cancer: a real world experience

Background FGFR3-altered urothelial cancer (UC) correlates with a non-T cell-inflamed phenotype and has therefore been postulated to be less responsive to immune checkpoint blockade (ICB). Preclinical work suggests FGFR3 signalling may suppress pathways such as interferon signalling that alter immune microenvironment composition. However, correlative studies examining clinical trials have been conflicting as to whether FGFR altered tumours have equivalent response and survival to ICB in patients with metastatic UC. These findings have yet to be validated in real world data, therefore we evaluated clinical outcomes of patients with FGFR3-altered metastatic UC treated with ICB and investigate the underlying immunogenomic mechanisms of response and resistance.Methods 103 patients with metastatic UC treated with ICB at a single academic medical center from 2014 to 2018 were identified. Clinical annotation for demographics and cancer outcomes, as well as somatic DNA and RNA sequencing, were performed. Objective response rate to ICB, progression-free survival, and overall survival was compared between patients with FGFR3-alterations and those without. RNA expression, including molecular subtyping and T cell receptor clonality, was also compared between FGFR3-altered and non-altered patients.Results Our findings from this dataset confirm that FGFR3-altered (n = 17) and wild type (n = 86) bladder cancers are equally responsive to ICB (12 vs 19%, p = 0.73). Moreover, we demonstrate that despite being less inflamed, FGFR3-altered tumours have equivalent T cell receptor (TCR) diversity and that the balance of a CD8 T cell gene expression signature to immune suppressive features is an important determinant of ICB response.Conclusions Our work in a real world dataset validates prior observations from clinical trials but also extends this prior work to demonstrate that FGFR3-altered and wild type tumours have equivalent TCR diversity and that the balance of effector T cell to immune suppression signals are an important determinant of ICB response.Subject terms: Bladder cancer, Cancer immunotherapy     

Postoperative Adjuvant Therapy Versus Surgery Alone for Stage IIB–III Esophageal Squamous Cell Carcinoma: A Phase III Randomized Controlled Trial

BackgroundRetrospective studies have shown that adjuvant treatment improves survival of patients with stage IIB–III esophageal squamous cell carcinoma, but there is no evidence from prospective trials so far.Materials and MethodsPatients with pathological stage IIB–III esophageal squamous cell carcinoma were randomly assigned to receive surgery alone (SA), postoperative radiotherapy (PORT), or postoperative concurrent chemoradiotherapy (POCRT). PORT patients received 54 Gy in 27 fractions; the POCRT group received 50.4 Gy in 28 fractions, plus concurrent chemotherapy with paclitaxel (135–150 mg/m²) and cisplatin or nedaplatin (50–75 mg/m²) every 28 days. The primary endpoint was disease‐free survival (DFS), and the secondary endpoint was overall survival (OS).ResultsA total of 172 patients were enrolled (SA, n = 54; PORT, n = 54; POCRT, n = 64). The 3‐year DFS was significantly better in PORT/POCRT patients than in SA patients (53.8% vs. 36.7%; p = .020); the 3‐year OS was also better in PORT/POCRT patients (63.9% vs. 48.0%; p = .025). The 3‐year DFS for SA, PORT, and POCRT patients were 36.7%, 50.0%, 57.3%, respectively (p = .048). The 3‐year OS for SA, PORT, and POCRT patients were 48.0%, 60.8%, 66.5%, respectively (p = .048).ConclusionPORT/POCRT (especially POCRT) may significantly improve DFS and OS in stage IIB–III esophageal squamous cell carcinoma.Implications for PracticeThe results of this phase III study indicated that postoperative radiotherapy/postoperative concurrent chemoradiotherapy (PORT/POCRT) could significantly improve disease‐free survival and overall survival in stage IIB–III esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. In‐field and out‐of‐field recurrences were comparable between the POCRT and PORT groups, which demonstrates the rationality and safety of the radiation field used in this study. The postoperative regimens in this trial might be accepted as standard treatment options for pathological stage IIB–III esophageal cancer. Larger sample size prospective randomized trials to identify the value are warranted.     

Immune Checkpoint Inhibitor–Induced Myocarditis with Myositis/Myasthenia Gravis Overlap Syndrome: A Systematic Review of Cases

BackgroundThe development of immune checkpoint inhibitors (ICIs) represents a paradigm shift in the treatment of cancers. Despite showing remarkable efficacy, these agents can be associated with life‐threatening immune‐related adverse events. In recent years, several cases of myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS) have been reported. However, given the rarity, the clinical features and outcomes of these cases remain poorly understood. We, therefore, attempted to systematically review and summarize all cases of IM3OS reported in the literature.Materials and MethodsStudies reporting IM3OS were identified in Embase and MEDLINE. Only case reports and case series published in journals or presented at conferences were included. We conducted a systematic review according to the PRISMA Harms guidelines.ResultsA total of 60 cases were eligible. The patients’ median age was 71 years, and the majority (67%) were males; melanoma was the most common indication for ICIs (38%). The most‐reported symptoms were fatigue (80%) and muscle weakness (78%). The median number of doses to the development of IM3OS was one. The average creatine kinase level was 9,645 IU/L. Cardiac arrhythmias occurred in 67% of patients, and 18% had depressed ejection fraction. Initial treatment consisted of immunosuppression with high‐dose steroids and supportive therapies. Sixty percent of the patients died in hospital because of acute complications.ConclusionIM3OS can be associated with significant mortality and morbidity. Prospective studies are needed to understand the optimal approach to diagnose and manage these patients and to develop biomarkers to predict the occurrence and severity of this rare but serious condition.Implications for PracticeClinicians should suspect coexisting myositis and/or myasthenia gravis in all patients with immune checkpoint inhibitor‐induced myocarditis, given their propensity to occur together. Early recognition and prompt treatment with the help of a multidisciplinary team might help improve the outcomes of this life‐threatening condition.