Low CD49d expression in newly diagnosed chronic lymphocytic leukaemia may be associated with high-risk features and reduced treatment-free-intervals.

This study was carried out to assess the prognostic power of low CD49d expression (≥10%) in newly diagnosed CLL patients using a previously described cohort. Eighty-five patients were included. Median age at diagnosis; 70 years (43-88); CD49d was expressed in 33/85 (38.8%); 23/33 (69.7%) at ≥30% referred to as 'HiCD49d' and 10/33 (30.3%) between 10 and 30% with a bimodal pattern on scatterplot analysis referred to as 'LoCD49d'. Eleven patients (12.9%) presented as Binet stage B, of whom 8 (72.7%) were CD49d+ (HiCD49d 7/8; LoCD49d 1/8). Seven of 81 patients (8.6%) were NOTCH1 mutated and all were CD49d+ (p ≤ .01). IgVH analysis was performed on 29 (87.8%) of the CD49d+ cases, of whom 21 (72.4%) were unmutated and 8 (27.6%) were mutated. CD38+/CD49d+ accounted for 11/20 (55%) (CD38+/HiCD49D: 9/11; CD38+/LoCD49D: 2/11). At 42 months, treatment had been initiated in 18/85 (21%) patients, of these 10/33 (30.3%) were CD49d+ versus 8/52 (15.4%) of the CD49d- group. The median treatment free interval for the CD49d+ group was 11 months (HiCD49d; 14.5 months, LoCD49d; 11 months) compared to 21.5 months for the CD49d- group. These findings suggest that the predictive value of CD49d expression is retained at expression levels down to 10%.

Treatment effect of palbociclib plus endocrine therapy by prognostic and intrinsic subtype and biomarker analysis in patients with bone-only disease: a joint analysis of PALOMA-2 and PALOMA-3 clinical trials.

PURPOSE: This analysis evaluated the relationship between treatment-free interval (TFI, in PALOMA-2)/disease-free interval (DFI, in PALOMA-3) and progression-free survival (PFS) and overall survival (OS, in PALOMA-3), treatment effect in patients with bone-only disease, and whether intrinsic subtype affects PFS in patients receiving palbociclib. METHODS: Data were from phase 3, randomized PALOMA-2 and PALOMA-3 clinical studies of hormone receptor‒positive/human epidermal growth factor receptor 2‒negative (HR+ /HER2-) advanced breast cancer (ABC) patients receiving endocrine therapy plus palbociclib or placebo. Subpopulation treatment effect pattern plot (STEPP) analysis evaluated the association between DFI and PFS and OS. PFS by luminal subtype and cyclin-dependent kinase (CDK) 4/6 or endocrine pathway gene expression levels were evaluated in patients with bone-only disease; median PFS and OS were estimated by the Kaplan-Meier method. RESULTS: Median durations of TFI were 37.1 and 30.9 months (PALOMA-2) and DFI were 49.2 and 52.0 months (PALOMA-3) in the palbociclib and placebo groups, respectively. Among the PALOMA-2 biomarker population (n = 454), 23% had bone-only disease; median PFS was longer with palbociclib versus placebo (31.3 vs 11.2 months; hazard ratio, 0.41; 95% CI 0.25‒0.69). The interaction effect of bone-only versus visceral disease subgroups on median PFS with palbociclib was not significant (P = 0.262). Among the PALOMA-3 biomarker population (n = 302), 27% had bone-only disease. STEPP analyses showed that palbociclib PFS benefit was not affected by DFI, and that palbociclib OS effect may be smaller in patients with short DFIs. Among patients who provided metastatic tumor tissues (n = 142), regardless of luminal A (hazard ratio, 0.23; 95% CI 0.11‒0.47; P = 0.0000158) or luminal B (hazard ratio, 0.26; 95% CI 0.12‒0.56; P = 0.000269) subtype, palbociclib improved PFS versus placebo. CONCLUSIONS: These findings support palbociclib plus endocrine therapy as standard of care for HR+ /HER2- ABC patients, regardless of baseline TFI/DFI or intrinsic molecular subtype, including patients with bone-only disease. TRIAL REGISTRATION: Pfizer (clinicaltrials.gov:NCT01740427, NCT01942135).

Treatment Outcome of Second-Line Chemotherapy for Gynecologic Carcinosarcoma.

INTRODUCTION: Carcinosarcoma is a rare cancer, and its prognosis is poor. There are few reports on the prognostic factors of patients with carcinosarcoma who receive second-line chemotherapy. OBJECTIVE: To investigate the outcome and prognostic factors of patients who received second-line chemotherapy for gynecologic carcinosarcoma. METHODS: We retrospectively investigated patients with ovarian or uterine carcinosarcoma, who were treated at two institutions from July 2006 to March 2018. All patients who had received second-line chemotherapy for advanced or recurrent disease were eligible. The efficacy of second-line chemotherapy and prognostic factors were evaluated. RESULTS: Forty-six patients were eligible. Combination chemotherapy was used in approximately half (52.2%) of the patients. The response rate and disease control rate of second-line chemotherapy were 32.6 and 60.9%, respectively. The median follow-up period was 11.0 (range, 8.8-107.5) months. The median progression-free survival and overall survival were 6.3 (95% CI, 3.2-7.5) months and 12.9 (95% CI, 7.8-16.0) months, respectively. In the multivariate analysis of overall survival, a treatment-free interval >180 days was a significant good prognostic factor. The median overall survival was 7.8 (95% CI, 5.1-10.5) months in the <180 days group and 16.4 (95% CI, 13.1-130.6) months in the >180 days group (p = 0.0052; hazard ratio, 0.26; 95% CI, 0.10-0.66), respectively. CONCLUSION: The outcome of gynecologic carcinosarcoma in the second-line setting is poor, especially in patients with a short treatment-free interval.

Persistence and treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany.

AIMS: The goal of this study was to analyze persistence and the treatment-free interval in patients being prescribed biological drugs in rheumatology practices in Germany. METHODS: Patients who received a first prescription of biological drugs between 2008 and 2016 in 21 rheumatologists in Germany were included in this study (index date). The main outcome was the rate of persistence with biological drugs as a function of the duration of the treatment-free interval used to define discontinuation. The secondary outcomes were the duration of the treatment-free interval, the probability of restarting therapy, and their respective association with age, gender, and diagnosis (i.e., rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis). RESULTS: A total of 4925 patients were included in this study. After 5 years of follow-up, the rate of persistence was 32.6%, 51.1%, and 65.7% if discontinuation was defined as a gap of 90, 180, and 360 days respectively. The majority of patients restarted therapy between 91 and 180 days after the discontinuation date. Advanced age was associated with a decreased probability of restarting biological therapy after a treatment-free interval of at least 91 days, with odds ratios ranging from 0.34 in people aged 61-70 years to 0.66 in those aged 31-40 years (reference value: ≤ 30 years). Finally, patients over 70 and those suffering from ankylosing spondylitis had shorter treatment-free intervals compared to those 30 years or younger (adjusted difference of - 117 days) and those suffering from rheumatoid arthritis (- 48 days) respectively. CONCLUSION: Persistence varied widely depending on the definition of discontinuation, with the majority of nonpersistent patients restarting biological therapy shortly after discontinuation.

Temozolomide rechallenge in recurrent glioblastoma: when is it useful?

AIM: To identify patients with recurrent glioblastoma after temozolomide (TMZ) concurrent with and adjuvant to radiotherapy who could benefit from TMZ rechallenge at the time of disease progression. METHODS: We retrospectively evaluated 106 glioblastoma patients who had nonprogressive disease at first magnetic resonance imaging after completion of TMZ concurrent with and adjuvant to radiotherapy, a treatment-free interval (TFI) of at least 8 weeks and received TMZ rechallenge or a nitrosourea at the time of progression. RESULTS: In patients with TFI ≥5 months, median survival was 17.7 and 11.6 months and median progression-free survival was 8.1 and 5.8 months in the TMZ and nitrosourea group, respectively. Longer TFI was associated with reduced risk for death (p = 0.002) and for disease progression (p = 0.005). CONCLUSION: TFI ≥5 months represents a predictor of retained TMZ sensitivity.

Survival after secondary cytoreductive surgery and chemotherapy compared with chemotherapy alone for first recurrence in patients with platinum-sensitive epithelial ovarian cancer and no residuals after primary treatment. A registry-based study.

INTRODUCTION: The aim of this study was to investigate whether secondary cytoreductive surgery and platinum-based chemotherapy improved survival among patients with recurrent, platinum-sensitive epithelial ovarian cancer compared with those who received platinum-based chemotherapy alone, and to identify possible predictors for selection to secondary cytoreductive surgery. MATERIAL AND METHODS: We included 397 patients who had a primary diagnosis of FIGO stage I-IV epithelial ovarian cancer recorded in the Cancer Registry of Norway between 1 January 2002 and 31 December 2012, received primary surgery with no residuals followed by platinum-based chemotherapy, had first recurrence six or more months after completion of primary platinum-based chemotherapy, and received secondary treatment with either secondary cytoreductive surgery and platinum-based chemotherapy (secondary cytoreductive surgery+platinum-based chemotherapy group) or platinum-based chemotherapy alone (platinum-based chemotherapy group). Outcomes were progression-free survival to second recurrence or death and overall survival. Hazard ratios were estimated using multivariable Cox regression. RESULTS: There were 75 patients in the secondary cytoreductive surgery+platinum-based chemotherapy group in whom complete resection was achieved for 60 (80%), and 322 patients in the platinum-based chemotherapy group. Both progression-free survival (hazard ratio 0.45, 95% confidence interval 0.32-0.62) and overall survival (hazard ratio 0.50, 95% confidence interval 0.32-0.70) were improved in the secondary cytoreductive surgery+platinum-based chemotherapy compared with the platinum-based chemotherapy group. A survival benefit was only seen in patients with no residuals at secondary cytoreductive surgery. CONCLUSIONS: In selected epithelial ovarian cancer patients with no residuals after primary surgery and a recurrent, platinum-sensitive tumor, the complete resection of recurrent tumor at secondary cytoreductive surgery improves progression-free survival and overall survival. Our results suggest that a long treatment-free interval and non-disseminated lesions (three or fewer lesions) on radiological images could be useful predictors for complete resection at secondary cytoreductive surgery.

When nonplatinum is the answer: the role of trabectedin plus pegylated liposomal doxorubicin in recurrent ovarian cancer.

Trabectedin + pegylated liposomal doxorubicin (PLD) offers a well tolerated and effective nonplatinum, nontaxane alternative for treatment of ovarian cancer patients with a treatment-free interval after platinum beyond 6 months, especially for those relapsing between 6 and 12 months and those who are not candidates to receive platinum-based therapy. Using the nonplatinum trabectedin + PLD combination gives patients time to recover from platinum-related toxicities and may restore platinum sensitivity in tumor cells. The sequence effect, by which intercalation of trabectedin + PLD between platinum regimens may enhance the activity of next platinum and improve survival, is currently under investigation in the Phase III prospective INternational OVArian cancer patients Trial with YONdelis.

Update on relapsed ovarian cancer treatment: from new consensus to daily clinical practice.

The outcome of the 5th Ovarian Cancer Consensus Conference (OCCC) held in November 2015 in Tokyo, Japan, was the development of new and revised consensus statements to guide clinical investigations in ovarian cancer. The OCCC statements may also have direct application to daily clinical practice. This review examines the consensus statements for recurrent ovarian cancer and their impact on treatment paradigms. Importantly, patients are no longer to be categorized by the platinum-free interval (with its arbitrary 6-month cut-off points) but according to the question: 'is platinum still an option for the patient?' Another important change since the 4th OCCC in 2010 is the inclusion of BRCA mutation status when defining patient subgroups for entry into clinical trials.

Prognostic factors for patients with brain metastasis from gynecological cancer: a significance of treatment-free interval of more than 6 months.

OBJECTIVE: Treatment-free interval has been confirmed as a significant prognostic factor in recurrent gynecological cancers. However, treatment-free interval has not been evaluated in previous studies investigating brain metastasis from gynecological malignancies. The aim of the study was to establish a predictive model of survival period after brain metastasis from gynecological cancer. METHODS: Of a total of 2848 patients with gynecological cancer, patients with brain metastasis were included in the study. Data at the time of brain metastasis diagnosis, which included primary origin, presence of extracranial metastasis, the Eastern Cooperative Oncology Group (ECOG) performance status, the number of brain metastases, brain-metastasis free-interval, treatment-free interval and treatment for brain metastasis were collected. Survival data were analyzed using Kaplan-Meier methods and Cox proportional hazards models. RESULTS: Incidences of brain metastasis were 1.7% (47/2848). Median survival period after diagnosis of brain metastasis was 20 weeks (4-5 months). The 6-, 12- and 24-month survival rates after brain metastasis were 44.0%, 22.0% and 16.5%, respectively. Cox regression analysis showed that extracranial metastasis (hazard ratio [HR], 5.2; 95% confidence interval [CI]: 1.04-26.3), ECOG performance status of 3-4 (HR, 3.1; 95% CI: 1.20-7.91), treatment-free interval of <6 months (HR, 3.8; 95% CI: 1.09-13.1), and no anti-cancer treatment for brain metastasis (HR, 3.6; 95% CI: 1.34-9.41) were significantly and independently related to poor survival. CONCLUSION: Treatment-free interval should be assessed in a future study to verify prognostic predictors of brain metastasis from gynecological cancer.

Prognostic factors modifying the treatment-free interval in recurrent ovarian cancer.

OBJECTIVES: While primary treatment for high-grade serous ovarian cancer tends to be uniform - maximal debulking and platinum/taxane adjuvant chemotherapy - there is little standardization of treatment in the recurrent setting beyond the exhaustive use of platinum therapies. Using secondary data from multiple centers participating in the Cancer Genome Atlas study (TCGA), we seek to characterize clinical features, timing and serial response data to provide empirical evidence for treatment expectations in the recurrent setting. METHODS: We conducted a retrospective survival analysis of TCGA study primary and secondary patient chemotherapy regimens by characterizing the dynamics of 1119 lines of therapy comprising the treatment of 461 high-grade serous ovarian cancer patients. All patients with post-surgical drug therapy information from the TCGA database were included in this study. RESULTS: A complete response to adjuvant therapy led to longer overall survival, but did not affect treatment free intervals (TFIs) after relapse of disease. A strong predictor of the TFI on the next treatment regimen was the previous TFI with a decaying effect. The number of previous treatments, of platinum treatments, and the length of time from surgery all have an exponentially decreasing effect on TFI. Re-treatment times appear to cluster at predictable times following surgery. CONCLUSIONS: While patients experience a consistent reduction in TFI with increasing re-treatment, the initial adjuvant interval is unrelated to later interval lengths. Platinum re-treatment remained an effective option in patients typically thought to be platinum resistant and the timing of monitoring visits may drive overall re-treatment patterns.

Considerations for selecting second-line treatment in patients with progressive small cell lung cancer and the use of Lurbinectedin in this setting.

Small cell lung cancer (SCLC) is characterized by high initial responses to platinum-based chemotherapy plus immune checkpoint inhibitors; however, most patients quickly relapse and require subsequent treatment. Second-line treatment options in SCLC remain limited, and treatment algorithms are not completely consistent across the available guidelines in this setting. This review highlights key considerations regarding selection of second-line treatment for patients with relapsed SCLC. In particular, the role of lurbinectedin, which was first approved in 2020, representing the first significant addition to treatment algorithms in this setting for decades, is summarized. Future directions, including the identification of SCLC subtypes and the need for predictive biomarkers to guide patient selection and targeted therapy, are also discussed.

Treatment-Free Interval: A Novel Approach to Assessing Real-World Treatment Effectiveness and Economic Impact Among Patients with Irritable Bowel Syndrome with Diarrhea.

INTRODUCTION: Objective assessment of treatment effectiveness using real-world claims data is challenging. This study assessed treatment-free intervals (TFI) as a proxy for treatment effectiveness, and all-cause healthcare costs among adult patients with irritable bowel syndrome with diarrhea (IBS-D) treated with rifaximin or eluxadoline in the USA. METHODS: Adult patients (18-64 years) with IBS-D and ≥ 1 rifaximin or eluxadoline prescription were identified in the IQVIA PharMetrics® Plus database (10/01/2015-12/31/2021) and classified into two mutually exclusive cohorts (i.e., rifaximin and eluxadoline). Index date was the date of rifaximin or eluxadoline initiation. Entropy-balanced baseline characteristics, TFI (periods of ≥ 30 consecutive days without IBS-D treatment), and healthcare costs were reported. Healthcare costs were compared between cohorts using mean cost differences. RESULTS: There were 7094 and 2161 patients in the rifaximin and eluxadoline cohorts, respectively. After balancing, baseline characteristics (mean age 44.1 years; female 72.4%) were similar between cohorts. A higher proportion of patients treated with rifaximin achieved a TFI of ≥ 30 days (76.2% vs. 66.7%), ≥ 60 days (67.0% vs. 47.0%), ≥ 90 days (61.0% vs. 38.7%), ≥ 180 days (51.7% vs. 31.0%), and ≥ 240 days (47.7% vs. 27.9%) compared to eluxadoline. Among patients with a TFI ≥ 30 days, mean TFI durations were 8.3 and 6.0 months for the rifaximin and eluxadoline cohorts. Mean all-cause healthcare costs were lower for rifaximin vs. eluxadoline ($18,316 vs. $23,437; p = 0.008), primarily driven by pharmacy costs ($7348 vs. $10,250; p < 0.001). In a simulated health plan of one million commercially insured lives, initiating 50% of patients on rifaximin instead of eluxadoline resulted in total cost savings of $2.1 million per year or $0.18 per-member-per-month. CONCLUSIONS: This real-world study suggests that TFI is a meaningful surrogate measure of treatment effectiveness in IBS-D. Patients treated with rifaximin had longer treatment-free periods and lower healthcare costs than patients treated with eluxadoline.

Phase II Trial of Intermittent Therapy in Patients with Metastatic Renal Cell Carcinoma Treated with Front-line Ipilimumab and Nivolumab.

INTRODUCTION: The combination of ipilimumab/nivolumab is approved for patients with treatment-naïve, intermediate-, and poor-risk metastatic renal cell carcinoma (mRCC), but duration of therapy and safety/efficacy of reinduction at progression is unknown. A phase II trial of intermittent ipilimumab/nivolumab with reinduction at progression was conducted (NCT03126331). PATIENTS AND METHODS: Patients with treatment-naïve mRCC were treated with induction ipilimumab/nivolumab followed by up to 24 weeks of maintenance nivolumab. Patients who achieved a complete response (CR) or partial response (PR) were eligible for inclusion and entered a treatment-free observation period. Patients were restaged every 12 weeks. Patients with no disease progression (PD) remained off therapy. Upon PD, patients were re-challenged with 2 doses of ipilimumab/nivolumab every 3 weeks. Study objectives were to estimate success rate of observation in patients who achieve a CR/PR, and to assess toxicity in patients undergoing reinduction. The study accrued slower than expected and was closed prior to the anticipated accrual goal of 20 patients. RESULTS: Nine patients were included; 89% male, median age 57, 67% clear-cell histology, and 78% intermediate-risk by IMDC criteria. Response to ipilimumab/nivolumab followed by nivolumab maintenance prior to enrollment was 33% CR and 67% PR. Most (78%) patients have remained off therapy, with a median treatment-free interval (TFI) of 34.3 months (range, 8.7-41.8). Two patients had PD off therapy and received 2 cycles of reinduction ipilimumab and nivolumab. No grade 3 or greater toxicities occurred with reinduction. Both patients developed PD at their first scans after reinduction. CONCLUSION: This prospective study demonstrates that patients with a radiographic response to ipilimumab/nivolumab can have prolonged treatment-free intervals. Further studies of de-escalation strategies are warranted. TRIAL REGISTRATION: NCT03126331 [Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331].

Multiple myeloma: Unveiling the survival data with different lines of treatments.

Purpose: The incidence of multiple myeloma (MM) is rising and there are fewer Indian studies; a comprehensive research of MM patients' survival data in a real-world population is needed. This study aims to analyze the survival status of MM patients with different treatment regimens along with its correlation to other parameters such as treatment-free interval (TFI) and time-to-next treatment (TTNT). Materials and Methods: This was a retrospective observational study, done in the department of oncology, at a tertiary care hospital in Kerala, from August 2019 to July 2020, to analyze the survival data in patients diagnosed with MM from 2015 to 2019. The effectiveness endpoints include time-to-event analyses such as TTNT and TFI. After receiving various therapy regimens, the survival rates were analyzed; the Kaplan-Meier estimator was used to determine the cumulative survival. The correlations between overall survival (OS) and duration of therapy, TFI, TTNT, and other parameters were calculated using the Karl Pearson's correlation coefficient. Results: 72 (82.80%) of the patients survived to the end of the study (OS), with a mean survival time of 4.02 ± 2.81 years. 52 (59.80%) patients had progression-free survival (PFS), while the remaining 35 (40.22%) had no significant disease prognosis. Both OS and PFS showed a significant positive correlation (P > 0.05) with TTNT and TFI. Conclusions: Completely adherent chemotherapy for 1 year can promise a survival time not <2 years. Longer TFI resulted in better OS and PFS. Extending the duration of the second LOT correlated with the better OS and PFS.

A Treatment-free Interval Allowed by Ponatinib as Fourth-line Therapy.

Background: The third-generation tyrosine kinase inhibitor ponatinib has demonstrated high clinical efficacy in the setting of patients with resistant chronic phase chronic myeloid leukemia (CML), also inducing deep molecular responses. However, ponatinib-related cardiovascular toxicities make management challenging, especially of those patients with CML with previous cardiovascular comorbidities. Case Report: We report on the efficacy of ponatinib treatment used as fourth-line therapy in a 55-year-old woman affected by significant comorbidities (mainly cardiovascular) present before the diagnosis of CML. Ponatinib therapy induced a rapid and excellent clinical response, with the achievement of a durable deep molecular response that allowed us to propose a strategy of treatment discontinuation in order to reduce drug-related toxicities. Conclusion: A strategy of a treatment-free interval might represent a useful clinical tool in those patients with CML who achieve a durable deep molecular response but are also affected by significant comorbidities in order to minimize the risk of ponatinib-related toxicities.

Systemic Treatment Initiation in Classical and Endemic Kaposi's Sarcoma: Risk Factors and Global Multi-State Modelling in a Monocentric Cohort Study.

BACKGROUND: Although several studies described the clinical course of epidemic and post-transplant Kaposi's Sarcoma (KS), the lack of large cohorts of classic/endemic KS, precluded such characterization. METHODS: We used multi-state modelling in a retrospective monocentric study to evaluate global disease evolution and identify risk factors for systemic treatment (ST) initiation. 160 classic/endemic KS patients consecutively diagnosed between 1990 and 2013 were included. RESULTS: 41.2% of classic/endemic KS patients required ST. Cumulative incidence of ST after 2 years of follow-up was 28.4% [95% CI: 20.5; 35.5]. Multivariate analysis identified six risk factors for ST initiation: time between first symptoms and diagnosis ≥1 year, endemic KS, total number of lesions ≥10, visceral, head or neck localization and presence of edema. Type of ST, type of KS, age and time between diagnosis and ST were not associated with response. Mean treatment-free time during the first 5 years following ST was 44 months for interferon and 44.6 months for chemotherapy treated patients (Mean difference: -0.5 months [95% CI: -9.5; 4.9]). CONCLUSIONS: Our study reveals ST risk factors in classic/endemic KS and highlights the clinical aggressiveness of the endemic KS subtype. No efficacy difference was observed between standard of care treatments, enabling treatment choice based on patient's fitness.

Neoadjuvant Chemotherapy Reduces the Treatment-free Interval After First-line Treatment in Patients With Advanced Ovarian Cancer.

BACKGROUND/AIM: The aim of the study was to compare platinum resistance and treatment-free interval (TFI) following treatment with neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS) in women with advanced epithelial ovarian cancer (EOC). PATIENTS AND METHODS: The study included patients diagnosed with primary EOC, stage IIIC or IV, between 2005 and 2013. Patients were grouped according to first-line treatment (PDS vs. NACT-IDS). Date of second-line treatment initiation was used to evaluate platinum sensitivity. RESULTS: The study population included 521 patients, of which 371 (71%) and 150 (29%) underwent PDS and NACT-IDS, respectively. We found no difference in platinum resistance between groups. Platinum-sensitive patients treated with NACT-IDS had a shorter median TFI (372 vs. 497 days, p=0.042). Similarly, patients with no residual tumor after IDS had a shorter median TFI (280 vs. 302 days, p=0.005). CONCLUSION: NACT-IDS may shorten the TFI after first-line platinum-based chemotherapy.

Clinical and economic outcomes of treatment sequences for intermediate- to poor-risk advanced renal cell carcinoma.

Aim: To assess the cost-effectiveness of treatment sequences for patients with intermediate- to poor-risk advanced renal cell carcinoma. Patients & methods: A discrete event simulation model was developed to estimate patients' lifetime costs and survival. Efficacy inputs were derived from the CheckMate 214 and CheckMate 025 studies and network meta-analyses. Safety and cost data were obtained from the published literature. Results: The estimated average quality-adjusted life-years (QALYs) gained was the highest on nivolumab + ipilimumab-initiated sequences (3.6-5.3 QALYs) versus tyrosine kinase inhibitor (TKI)-initiated sequences (2.1-3.7 QALYs). Incremental cost per QALY gained for nivolumab + ipilimumab-initiated sequences was below the willingness-to-pay threshold of $150,000 versus other sequences. Conclusion: Immuno-oncology combination therapy followed by TKIs is cost-effective versus TKI sequences followed by immuno-oncology or sequencing TKIs.

A phase II trial of intermittent nivolumab in patients with metastatic renal cell carcinoma (mRCC) who have received prior anti-angiogenic therapy.

BACKGROUND: Nivolumab is approved for mRCC patients who have received prior anti-angiogenic therapy but the duration of therapy required for sustained clinical benefit is unknown. A phase II clinical trial to investigate the feasibility of intermittent nivolumab dosing was conducted. METHODS: Patients ≥18 years of age with mRCC who were previously treated with at least one antiangiogenic therapy were eligible. Patients were treated with nivolumab for twelve weeks. Patients who had RECIST PD were removed from the trial. Patients who did not initially achieve ≥10% reduction in tumor burden (TB) continued nivolumab per standard of care. Patients with ≥10% TB reduction entered a treatment-free observation phase with re-imaging every 12 weeks. Nivolumab was restarted in patients with a ≥ 10% TB increase and again held with TB reduction ≥10%. This intermittent nivolumab dosing continued until RECIST PD while on nivolumab. The primary objective was feasibility of intermittent nivolumab, defined as the proportion of patients eligible for intermittent therapy who elect to receive intermittent nivolumab. Intermittent nivolumab would be considered "feasible" if the acceptance rate was ≥80%. Forty patients provides > 95% power with 0.05 type I error, assuming a null acceptance rate of 50%. With the approval of the combination of ipilimumab/nivolumab (April 2018) in front-line mRCC, this cohort was closed prior to completed pre-planned approval. RESULTS: Of the 14 patients enrolled, 13 (93%) were male with a median age 65. All had a prior nephrectomy and 12 (86%) were intermediate-risk by IMDC criteria. Five patients (36%) met the criteria for the intermittent phase of the trial (median TB decrease 46%) and all agreed to intermittent therapy. With a median follow-up of 48 weeks, only one patient restarted therapy. The four remaining patients have a sustained response for a median of 34 weeks (range, 16-53) off therapy. No patients developed RECIST PD while off therapy. CONCLUSIONS: This prospective experience of intermittent nivolumab dosing in mRCC supports further investigation of intermittent immunotherapy dosing strategies in RCC. TRIAL REGISTRATION: NCT03126331 (Intermittent Nivolumab in Metastatic Renal Cell Carcinoma Patients; Date of registration 4/27/2017; https://clinicaltrials.gov/ct2/show/NCT03126331 ).