Effectiveness and Safety of Retreatment with 177Lu-DOTATATE in Patients with Progressive Neuroendocrine Tumors: A Retrospective Real-World Study in the United States.

Advanced neuroendocrine tumors (NETs) are associated with a poor prognosis. A regimen of 4 cycles of 177Lu-DOTATATE has been shown to improve both progression-free survival (PFS) and overall survival (OS) in patients with advanced NETs. To the best of our knowledge, this is the first study in the United States to evaluate the effectiveness and safety of additional cycles of 177Lu-DOTATATE therapy in patients with progressive NETs. Methods: This was a retrospective chart review of adults with advanced NETs. The patients had undergone initial treatment with up to 4 cycles of 177Lu-DOTATATE and, after disease progression and a period of at least 6 mo since the end of the initial treatment, were retreated with at least 1 additional cycle at a single center (2010-2020). Patient characteristics, treatment patterns, and clinical outcomes were evaluated descriptively. Response was evaluated according to RECIST 1.1; toxicity was defined using criteria from Common Terminology Criteria for Adverse Events, version 5.0. Kaplan-Meier plots were used to evaluate PFS and OS. Results: Of the 31 patients who received 177Lu-DOTATATE retreatment, 61% were male and 94% were White. Overall, patients received a median of 6 cycles (4 initial cycles and 2 retreatment cycles), and the mean administered activity was 41.9 GBq. Two patients also went on to receive additional retreatment (1 and 2 cycles, individually) after a second period of at least 6 mo and progression after retreatment. Best responses of partial response and stable disease were observed in 35% and 65% of patients after the initial treatment and 23% and 45% of patients after retreatment, respectively. The median PFS after the initial treatment was 20.2 mo and after retreatment was 9.6 mo. The median OS after the initial treatment was 42.6 mo and after retreatment was 12.6 mo. Hematologic parameters decreased significantly during both the initial treatment and retreatment but recovered such that there was little difference between the values before the initial treatment and before the retreatment. Clinically significant hematotoxicity occurred in 1 and 3 patients after the initial treatment and retreatment, respectively. No grade 3 or 4 nephrotoxicity was observed. Conclusion: Retreatment with 177Lu-DOTATATE after progression appeared to be well tolerated and offered disease control in patients with progressive NETs after initial 177Lu-DOTATATE treatment.

Real-world outcomes of different lines and sequences of treatment in BRAF-positive advanced melanoma patients.

The objective of this study is to compare efficacy with different treatment sequences and lines of treatment among BRAF V600 mutated (BRAF+) advanced melanoma patients with immunotherapies (IO) and targeted therapies (TT) using real-world data. This was a retrospective cohort study using the Novartis BRAF+ meLanoma patients ObsErvational database, the harmonized customized data from Flatiron and ConcertAI. The study included BRAF+ advanced unresectable melanoma patients treated with first-line (1L) IO or TT between 1 January 2014 and 31 May 2020. Patient characteristics and treatment patterns were described. Kaplan-Meier curves and propensity score-adjusted Cox models were used for analyzing progression-free survival (PFS) and overall survival (OS). A total of 1961 patients were included, of which, 57.2% received IO and 42.8% received TT on 1L therapy. Overall, 603 patients initiated a 2L therapy: 56.2% IO and 43.8% TT. Regardless of treatment sequence, patients progressed at a relatively similar rate with no significant difference between groups (median PFS: 12.9 months for 1L TT/2L IO and 13.1 months for 1L IO/2L TT; HR, 0.84; P = 0.137). The 2-year OS rate was also similar with 1L TT/2L IO and 1L IO/2L TT (78% vs. 80%; HR, 1.09; P = 0.730). PFS was worse on 2L therapy compared with 1L (median 4.7 vs. 6.5 months). Efficacy on 2L therapy was poor compared with 1L. Among patients who received 2L therapy, regardless of treatment sequences, outcomes were comparable between 1L TT/2L IO and 1L IO/2L TT in this study that reflects real-world experiences beyond clinical trial selective eligibility criteria.

Risk tolerance in adjuvant and metastatic melanoma settings: a patient perspective study using the threshold technique.

Background: Adverse events (e.g., pyrexia) may affect treatment patterns and adherence. This study explored pyrexia risk tolerance among melanoma patients when treatment benefit is unknown versus known. Materials & methods: US respondents with stage III (n = 100) or stage III unresectable/stage IV melanoma (n = 125) chose between hypothetical melanoma treatments, defined by reoccurrence/progression-free survival and pyrexia risk, one resembling standard-of-care and one resembling dabrafenib + trametinib. Respondents chose first when efficacy was unknown and then when efficacy was known; pyrexia risk was varied systematically to define maximum acceptable risk. Results: Maximum acceptable risk of pyrexia was statistically significantly higher when efficacy was known versus unknown in stage III patients (85 vs 34%) and stage III unresectable/stage IV patients (66 vs 57%). Conclusion: Patients accepted higher levels of pyrexia risk when they understood treatment benefit.

Stage III melanoma incidence and impact of transitioning to the 8th AJCC staging system: a US population-based study.

AIM: To estimate incidence of stage III melanoma using the American Joint Committee on Cancer (AJCC) staging, 7th and 8th edition. PATIENTS & METHODS: The SEER US cancer registry was analyzed (2010-2014). AJCC7 stages were recorded in the data; AJCC8 stages were inferred. RESULTS: Of 106,195 melanoma patients, 7669 and 7342 had stage III melanoma by AJCC7 and AJCC8, respectively (95% overlap). Nearly 30% of patients with AJCC7 stage III melanoma were reclassified in a higher stage III group by AJCC8 versus 7% in lower stage group. Regardless of the AJCC edition, incidence of stage III melanoma has increased from 2010 to 2014 both overall and within each stage III group. CONCLUSION: Providing appropriate management to this growing population of high-risk patients is a priority.

Patterns of treatment and BRAF testing with immune checkpoint inhibitors and targeted therapy in patients with metastatic melanoma presumed to be BRAF positive.

Patients with BRAF V600 (BRAF) mutated metastatic melanoma are eligible for therapy with both immune checkpoint inhibitors and targeted therapies, making treatment choice a complex decision. The present study aimed to describe patterns of treatment with immunotherapy and targeted therapy and BRAF testing in patients with metastatic melanoma presumed to have BRAF mutations (BRAF+) in the years following the approval of the newer generation of immune checkpoint inhibitors and targeted therapies (2014-2016). Two large US commercial claims databases [Truven Health Analytics MarketScan and IQVIA Real-World Data Adjudicated Claims - USA (IQVIA RWD Adjudicated Claims - USA)] were used. Patients were presumed BRAF+ if they received at least 2 lines of therapy of which at least 1 included targeted therapy. Sequence of lines of therapy and regimens used in first (1L), second (2L), and third (3L), as well as timing of BRAF testing by sequence of therapy were described. In the Truven sample (n=162), targeted therapy was used by 66% in 1L and by 54% in 2L, and 62% had a BRAF test; in the IQVIA RWD Adjudicated Claims - USA sample (n=247), targeted therapy was used by 62% in 1L and by 50% in 2L, and 68% had a BRAF test. Among those with a claim for a BRAF test prior to 1L, over two-thirds were initiated on targeted therapy. These findings suggest that the rate of BRAF testing remained low in the years following the approval of BRAF-targeted regimens for metastatic disease. Given the recently approved adjuvant treatment options for stage III melanoma, improving the rates of BRAF testing becomes increasingly important.

Postsurgical treatment landscape and economic burden of locoregional and distant recurrence in patients with operable nonmetastatic melanoma.

Surgery is the mainstay treatment for operable nonmetastatic melanoma, but recurrences are common and limit patients' survival. This study aimed to describe real-world patterns of treatment and recurrence in patients with melanoma and to quantify healthcare resource utilization (HRU) and costs associated with episodes of locoregional/distant recurrences. Adults with nonmetastatic melanoma who underwent melanoma lymph node surgery were identified from the Truven Health MarketScan database (1 January 2008 to 31 July 2017). Locoregional and distant recurrence(s) were identified on the basis of postsurgery recurrence indicators (i.e. initiation of new melanoma pharmacotherapy, new radiotherapy, or new surgery; secondary malignancy diagnoses). Of 6400 eligible patients, 219 (3.4%) initiated adjuvant therapy within 3 months of surgery, mostly with interferon α-2b (n=206/219, 94.1%). A total of 1191/6400 (18.6%) patients developed recurrence(s) over a median follow-up of 23.1 months (102/6400, 1.6% distant recurrences). Among the 219 patients initiated on adjuvant therapy, 73 (33.3%) experienced recurrences (distant recurrences: 13/219, 5.9%). The mean total all-cause healthcare cost was $2645 per patient per month (PPPM) during locoregional recurrence episodes and $12 940 PPPM during distant recurrence episodes. In the year after recurrence, HRU was particularly higher in patients with distant recurrence versus recurrence-free matched controls: by 9.2 inpatient admissions, 54.4 inpatient days, 8.8 emergency department admissions, and 185.9 outpatient visits (per 100 person-months), whereas all-cause healthcare costs were higher by $14 953 PPPM. It remains to be determined whether the new generation of adjuvant therapies, such as immune checkpoint inhibitors and targeted agents, will increase the use of adjuvant therapies, and reduce the risk of recurrences and associated HRU/cost.

Healthcare resource utilization in patients with metastatic melanoma receiving first-line therapy with dabrafenib + trametinib versus nivolumab or pembrolizumab monotherapy.

OBJECTIVE: To compare healthcare resource utilization (HRU) between patients with metastatic melanoma (MM) initiated on first-line (1L) combination therapy with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib (D + T; oral) and those initiated on 1 L monotherapy with the anti-PD1 monoclonal antibodies nivolumab or pembrolizumab (N/P; intravenous). METHODS: Patients with melanoma initiated on D + T or N/P from Q1/2014 to Q2/2016 (defined as 1 L treatment for MM) were identified in the Truven MarketScan database. Entropy balancing was used to reweight the N/P cohort in order to make it comparable to the D + T cohort with respect to the mean and variance of baseline covariates. HRU outcomes during 1 L therapy, reported per patient-year (PPY), were described and compared between the two cohorts post-weighting (i.e. independently of baseline covariates). RESULTS: Of the 445 patients included, 202 and 243 were initiated on D + T and N/P, respectively. After weighting, patients initiated on N/P had more outpatient visits for drug administration during 1 L therapy than those initiated on D + T (difference = 18.6 visits PPY [95% CI = 16.0-21.1]). Patients initiated on N/P also had more outpatient office visits for reasons other than drug administration (difference = 8.1 visits PPY [95% CI = 1.9-13.7]). No significant differences were observed for other HRU parameters (i.e. inpatient admissions, inpatient days, and emergency department visits during 1 L therapy). CONCLUSIONS: HRU during 1 L therapy was generally similar between patients initiated on D + T and N/P. Nonetheless, patients initiated on N/P had more outpatient visits, including more outpatient visits for reasons unrelated to drug administration.

Economic Burden of Adverse Events Associated with Immunotherapy and Targeted Therapy for Metastatic Melanoma in the Elderly.

BACKGROUND: Immunotherapies and targeted therapies have drastically improved survival in metastatic melanoma, but they can cause a range of adverse events (AEs). Understanding the costs of these events would facilitate an accurate comparison of melanoma treatments. OBJECTIVE: To compare the costs and frequency of AEs associated with immunotherapy and with targeted therapy in elderly patients with metastatic melanoma. METHODS: We conducted a retrospective cohort study using Medicare claims data from 2011 to 2014. Patients included had to have ≥1 diagnoses of metastatic melanoma and ≥1 claims for an immunotherapy or targeted therapy. We compared the 30-day expenditures of patients with and without each AE using a generalized linear model to determine the incremental cost per AE in patients who received immunotherapy or targeted therapy. The baseline demographic and clinical differences were adjusted for using propensity score with inverse probability of treatment. We also compared the mean costs of AEs associated with immunotherapy and targeted therapy. RESULTS: A total of 844 patients were included in the study (mean age, 75 years; standard deviation, 14 years). The mean baseline Charlson Comorbidity Index score was 8.4, and 65% of the patients were male. The mean cost for AEs was highest for respiratory events (ie, $24,150). Gastrointestinal, respiratory, and hematologic AEs were more common in patients who received immunotherapy, whereas general and administration-site AEs and other AEs (eg, fatigue, infections, muscular weakness) were more frequent in patients who received targeted therapy. AE-related costs with immunotherapy were highest for gastrointestinal, respiratory, and pain-related AEs; AEs with targeted therapy were highest for cardiovascular and general and administration-site events. CONCLUSION: These findings suggest that incremental costs associated with treatment-related AEs among elderly patients with metastatic melanoma were substantial, but the risks for and costs of the various types of AEs differed by therapy. Understanding the risks for and costs of AEs associated with the various therapeutic options can inform treatment decision-making in elderly patients with metastatic melanoma.

Carboplatin in the treatment of Ewing sarcoma: Results of the first Brazilian collaborative study group for Ewing sarcoma family tumors-EWING1.

BACKGROUND: Large cooperative group studies have shown the efficacy of risk-adapted treatment for Ewing sarcoma. However, validation and local adaptation by National cooperative groups is needed. A multicenter protocol to determine the efficacy and safety of a risk-adapted intensive regimen was developed by the Brazilian cooperative group. PROCEDURE: Patients <30 years old with Ewing sarcoma were eligible. Induction chemotherapy consisted of two cycles of ICE (ifosfamide, carboplatin, and etoposide) followed by two cycles of VDC (vincristine, doxorubicin, and cyclophosphamide), followed by local control. Patients with low risk (LR) disease (localized resectable with normal LDH) received 10 additional alternating courses of IE with VDC. For patients with high-risk (HR) disease (unresectable, pelvic, metastatic, or high LDH), two additional cycles of ICE were given. RESULTS: One-hundred seventy five patients (39% metastatic) were enrolled. Fifty-two patients (29.7%) were LR and 123 (70.3%) were HR. Overall response rate at end of induction was 27.4%. Five-year event-free survival (EFS) and overall survival (OS) estimates were 51.4% and 54.4%, respectively. Patients with localized disease had better outcomes than patients with metastases (5-year EFS 67.9% vs. 25.5%, and 5-year OS 70.3% vs. 29.1%, respectively). On multivariate analysis, the presence of metastatic disease was the only prognostic factor (P < 0.01). CONCLUSION: The VDC/ICE protocol was feasible, and considering the high tumor burden in our population, resulted in comparable results to those reported by cooperative groups in high-income countries. Further adaptation to maximize efficacy and minimize toxicity will be required.