Use Of Subsequent Therapy Research Articles

Overall survival with darolutamide vs placebo in combination with androgen-deprivation therapy (ADT) and docetaxel: A sensitivity analysis from ARASENS accounting for subsequent therapy.

166 Background: Darolutamide (DARO) + ADT + docetaxel (DOC) is approved for metastatic hormone-sensitive prostate cancer (mHSPC) based on the phase 3 ARASENS study (NCT02799602). To address the impact of informative intercurrent events (eg, use of subsequent therapy) in censored patients (pts), as defined by the European Medicines Agency, we performed a post hoc sensitivity analysis of OS. Methods: Pts with mHSPC were randomized 1:1 to oral DARO 600 mg twice daily or placebo (PBO) + ADT + DOC. The primary endpoint was OS using a log-rank test, with HR (95% CI) calculated by Cox model, stratified by extent of disease (EoD; nonregional lymph node vs bone ± lymph node vs visceral ± lymph node/bone metastases) and alkaline phosphatase (< vs ≥ upper limit of normal). Pts with no documented death were censored at last known alive or data cut-off date, whichever was earlier. The post hoc sensitivity analysis counted initiation of subsequent systemic antineoplastic therapy as an event in censored pts still alive at end of follow-up. In addition planned sensitivity analyses used an unstratified log-rank test/Cox model, a log-rank test/Cox model with stratification factors from electronic case report forms, and a log-rank test/Cox model with EoD stratification factors from central imaging review. Results: In the primary analysis DARO + ADT + DOC significantly improved OS ( P<0.0001; Table), despite a high percentage of pts who entered follow-up in the PBO group receiving subsequent life-prolonging systemic therapies (374/495, 76%). Time to first subsequent systemic antineoplastic therapy (a key secondary endpoint) was significantly longer with DARO + ADT + DOC vs PBO + ADT + DOC (HR 0.39, 95% CI 0.33–0.46, P<0.001). Findings from the post hoc sensitivity analysis counting initiation of subsequent systemic antineoplastic therapy as an event in censored pts (pts with events: DARO 300/651, 46.1%; PBO 476/654, 72.8%) and the planned sensitivity analyses were consistent and supported the primary OS analysis (Table). Treatment-emergent adverse events (TEAEs) were similar between groups. TEAEs led to DARO/PBO discontinuation in 13.5%/10.6% of pts. Conclusions: The results of the post hoc and planned sensitivity analyses were consistent with and supportive of the ARASENS primary OS analysis. These data reinforce DARO + ADT + DOC as an effective and well tolerated new standard of care for early treatment intensification in pts with mHSPC. Clinical trial information: NCT02799602 . [Table: see text]

An Investigation into the Relationship Between Choice of Model Structure and How to Adjust for Subsequent Therapies Using a Case Study in Oncology.

A common challenge in health technology assessments (HTAs) of cancer treatments is how subsequent therapy use within the trial follow-up may influence cost-effectiveness model outcomes. Although overall survival (OS) is often a key driver of model results, there are no guidelines to advise how to adjust for this potential confounding, with different approaches available dependent on the model structure. We compared a partitioned survival analysis (PartSA) with a semi-Markov multi-state model (MSM) structure, with and without attempts to adjust for the impact of subsequent therapies on OS using a case study describing outcomes for people with relapsed/refractory multiple myeloma. Both model structures included three health states: pre-progression, progressed disease and death. Three traditional crossover methods were considered within the context of the PartSA, whereas for the MSM, the probability of post-progression death was pooled across arms. Impacts on the model incremental cost-effectiveness ratio (ICER) were recorded. The unadjusted PartSA produced an ICER of £623,563, and after adjustment yielded an ICER range of £381,340-£386,907. The unadjusted MSM produced an ICER of £1,283,780. Adjusting OS in the MSM resulted in an ICER of £345,486. The simplicity of the PartSA is lost when the decision problem becomes more complex (for example, when OS data are confounded by subsequent therapies). In this setting, the MSM structure may be considered more flexible, with fewer and less restrictive assumptions required versus the PartSA. Researchers should consider important study design features that may influence the generalisability of data when undertaking model conceptualisation.

P009: Improved Overall Survival with First-Line Brentuximab Vedotin plus Chemotherapy in Patients with Advanced Stage III/IV Classical Hodgkin Lymphoma: An Updated Analysis of ECHELON-1

Figure 1: Overall Survival in the Intent-to-Treat Population. New first-line treatment strategies for classical Hodgkin lymphoma (cHL) have not improved overall survival (OS) compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Five-year data from ECHELON-1 (NCT01712490) supported long-term progression-free survival (PFS) with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) in patients (pts) with previously untreated stage III/IV cHL vs ABVD, with a manageable long-term safety profile. We report an OS analysis from ECHELON-1 after a median of 6 years of follow-up (data cutoff June 1, 2021). Randomized pts (1:1) received ≤6 cycles of A+AVD (n=664) or ABVD (n=670) on days 1 and 15, every 28 days. The key secondary end point was OS (event-driven, type-1 error controlled) in the intent-to-treat population. Analysis of OS in prespecified subgroups was exploratory and not adjusted for multiplicity. PFS per investigator was reported for long-term follow-up. Deaths during follow-up, including reported causes of death per investigator, were summarized. We observed 39 OS events in the A+AVD arm vs 64 with ABVD, favoring A+AVD (hazard ratio [HR] 0.59; 95% confidence interval [CI] 0.40–0.88; p=0.009; median follow-up 73 months; Figure). OS was examined in prespecified subgroups; in a multivariable analysis adjusting for baseline demographic and disease factors, OS benefit was preserved (HR 0.53; 95% CI 0.34–0.83). PFS favored A+AVD (HR 0.68; 95% CI 0.53–0.86), consistent with prior reports. Subsequent therapy use was less frequent with A+AVD vs ABVD (135 [20%] vs 157 [24%]) including fewer autologous (44 [7%] vs 59 [9%]) and allogeneic stem cell transplants (4 [<1%] vs 12 [2%]) while use of radiation was similar (55 [8%] vs 58 [9%]), suggesting that the OS benefit was not due to undertreatment of pts in the ABVD arm. Fewer second malignancies (23 vs 32) and fewer deaths related to cHL or treatment complications (32 vs 45) or to second malignancies (1 vs 11) were reported with A+AVD vs ABVD, respectively; treatment-related deaths were comparable (8 vs 7). While fertility was not formally assessed, a total of 191 pregnancies were reported among pts and their partners (A+AVD 113; ABVD 78). More pts had peripheral neuropathy with A+AVD (443 [67%]) vs ABVD (286 [43%]), but most improved or resolved at last follow-up (379 [86%] vs 249 [87%]). To conclude, A+AVD significantly reduced risk of death vs ABVD by 41%. The long-term safety profile was manageable, consistent with prior reports.

Impact of ixazomib-lenalidomide-dexamethasone therapy on overall survival in multiple myeloma patients: Analysis of the emerging-markets subgroup of the TOURMALINE-MM1 trial.

Ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) showed clinical efficacy over placebo-Rd in patients with relapsed/refractory multiple myeloma (MM) in the TOURMALINE-MM1 trial. Over a median follow-up of ∼85months, as patients showed disease progression, they received subsequent novel therapies that confounded the overall survival (OS) benefit. Here, we conducted a post hoc analysis in 148 patients from seven countries defined as emerging markets, with limited access to novel therapies for MM during the trial period, to describe the impact of these therapies on OS. Patients were randomised to ixazomib-Rd (n = 71) or placebo-Rd (n = 77). The median progression-free survival (PFS) was 18.7 versus 10.2months, with ixazomib-Rd versus placebo-Rd (hazard ratio [HR], 0.504; p = 0.008) demonstrating a statistically significant improvement as observed in the primary trial. The median OS improved by 32.6months with ixazomib-Rd over placebo-Rd (63.5 vs. 30.9months; HR, 0.794; p = 0.261); however, the statistically significant benefit seen in PFS was not observed for OS. Improvement with ixazomib-Rd over placebo-Rd was observed in overall response (81.7% vs. 64.9%; odds ratio [OR], 2.38; p = 0.019) and complete response (22.5% vs. 3.9%; OR, 7.57; p < 0.001). Patient-reported quality of life and use of subsequent therapies were similar across treatment groups. No new safety concerns were identified. Compared with the main cohort, median OS was 10months longer with ixazomib-Rd and 21months shorter with placebo-Rd in this subgroup, indicating a clinically meaningful survival benefit of ixazomib-Rd treatment in this patient population with limited access to subsequent novel therapies.

Association of progression-free survival and overall response rate with overall survival in first-line randomized trials of immune checkpoint inhibitor–based regimens for metastatic non–small cell lung cancer (NSCLC): An FDA pooled analysis.

9029 Background: Overall Survival (OS) has represented the endpoint of choice to support approvals of Immune Checkpoint Inhibitors (ICIs) in first-line metastatic NSCLC. Despite continued interest in the use of earlier clinical endpoints as true surrogates for OS in this setting, the correlation of Progression-Free Survival (PFS) and Overall Response Rate (ORR) with OS remain an area of active investigation. We conducted a patient-level and trial-level pooled analysis of first-line randomized trials of ICI-based regimens to assess correlations of early clinical endpoints of PFS and ORR with OS in first-line metastatic NSCLC. Methods: The analysis included randomized trials comparing ICI-based regimens (anti-PD-(L)1 with or without anti-CTLA4 antibodies, with or without platinum-based chemotherapy) to platinum-based chemotherapy alone for the first-line treatment of patients with metastatic NSCLC that were submitted to the U.S. Food and Drug Administration between July 2016 to March 2021 to support a marketing application. Patient-level associations were estimated using Spearman (rs) correlation coefficients for PFS and OS, and Cox Proportional Hazards models in RECIST response-based subgroups for ORR and OS. At the trial level, associations were estimated using R2 coefficients from weighted linear regression models, using the log of hazard-ratio (HRs) for PFS and OS and log-odds ratio for ORR. Results: The pooled analysis included 13 trials enrolling 9,285 patients total. Seven trials compared ICIs combined with chemotherapy vs chemotherapy; 6 trials compared ICIs alone vs chemotherapy. Among all patients, the distribution of PD-L1 expression was 31%, 66%, and 32% for PD-L1 &lt;1%, ≥1%, and ≥50%, respectively. The table shows the correlation coefficients for PFS and OS, and ORR and OS at the patient and trial levels. At the patient level, the OS HR comparing ICI-based regimens to chemotherapy was 0.54 (95% CI: 0.48, 0.61) for RECIST responders and 0.96 (95% CI: 0.90, 1.02) for non-responders. Conclusions: This pooled analysis did not indicate a strong correlation between endpoints of PFS and ORR with OS at the patient and trial levels in first-line randomized trials of ICI-based regimens for metastatic NSCLC, potentially because of use of subsequent therapies, cross-over to ICIs, and continuation of ICIs beyond progression. Future research will explore the correlation of alternative endpoints with OS, such as time to treatment discontinuation. Our analysis supports the continued importance of OS as an endpoint for first-line NSCLC trials of ICI-based regimens.[Table: see text]

Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial.

115 Background: In ARCHES (NCT02677896), ENZA + ADT improved radiographic progression-free survival, OS, and other key secondary endpoints vs placebo (PBO) + ADT for pts with mHSPC (also known as metastatic castration-sensitive prostate cancer). Final OS results confirmed a long-term survival benefit with ENZA + ADT (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.53, 0.81; p&lt;0.0001). We present post hoc analyses of OS by disease volume and progression to M1 HSPC after initial diagnosis with localized disease (M0) or presentation of de novo mHSPC at initial diagnosis (M1). Methods: Pts with mHSPC (N=1150) were randomized 1:1 to ENZA (160 mg/day) + ADT (n=574) or PBO + ADT (n=576), stratified by disease volume and prior docetaxel use. After unblinding, 180 (31.3%) PBO + ADT-treated pts crossed over to open-label ENZA + ADT. High disease volume was defined per CHAARTED criteria. Medical profiles of pts assessed as MX/unknown metastasis at initial diagnosis (n=213) were further reviewed centrally and adjudicated as having either M0 or M1 disease. Median OS and HRs were estimated by Kaplan-Meier methods and Cox proportional hazards, respectively. Results: Median treatment duration was 40.2 months (mo) for ENZA + ADT and 13.8 mo for PBO + ADT. Inclusive of crossover, 401 (69.6%) PBO + ADT pts had subsequent life-prolonging therapy. OS benefits with ENZA + ADT were seen in all disease volume and M0/M1 populations at a similar magnitude to the overall population (Table). Median OS was not reached in most populations except PBO + ADT pts with high disease volume (45.9 mo; 95% CI 40.1, not estimable [NE]) or high disease volume and M1 disease (43.4 mo; 95% CI 36.4, 49.7) and ENZA + ADT pts with high disease volume and M0 disease (54.2 mo; 95% CI 54.2, NE). Conclusions: Our post hoc analysis demonstrates consistent long-term survival benefit with ENZA + ADT vs PBO + ADT across pts with mHSPC with high and low disease volumes and M0 or M1 disease at initial diagnosis, despite substantial treatment crossover and subsequent therapy use in PBO + ADT pts.[Table: see text]

The AIM-HN Study: A pivotal study evaluating the efficacy of tipifarnib in patients with recurrent or metastatic head and neck squamous cell carcinoma with HRAS mutations.

TPS6087 Background: Head and neck squamous cell carcinoma (HNSCC) accounts for more than 830,000 new cancer cases each year worldwide. The prognosis for recurrent and/or metastatic (R/M) HNSCC patients remains poor with an estimated median overall survival (mOS) of 7-15 months in the first line setting and 5-8 months in the second line setting and beyond. Approximately 4-8% of HNSCC tumors are driven by gain-of-function mutations in the HRAS (m HRAS) proto-oncogene. Tipifarnib is a potent and selective farnesyltransferase inhibitor that disrupts HRAS function by blocking required protein membrane localization, and subsequent cellular growth and survival. Data from a prior phase 2 study (RUN-HN; NCT02383927) of tipifarnib in R/M m HRAS HNSCC patients in the second line plus setting demonstrated encouraging efficacy, with an objective response rate (ORR) of 55% and mOS of 15.4 months for patients with mHRAS variant allele frequency (VAF) ≥ 20%, providing support for pursuing a pivotal trial in this patient population. Methods: AIM-HN (NCT03719690) is a global, open-label single-arm pivotal study evaluating the efficacy and tolerability of tipifarnib in second line plus R/M m HRAS HNSCC patients. The primary objective is to determine the ORR in patients with a m HRAS VAF ≥ 20% (High VAF population), as assessed using RECIST v1.1 by Independent Review Facility. Key secondary objectives include the ORR for patients of all VAF levels, and the duration of responses for both VAF≥ 20% and all VAF levels. Key inclusion criteria include: histologically confirmed head and neck cancer of squamous histology not amenable to local therapy with curative intent; known tumor missense HRAS mutation (with VAF determined and available) detected by Next Generation Sequencing; ECOG performance status of 0-1; measurable disease by RECIST v1.1; and adequate organ function. Key exclusion criteria include: salivary gland, thyroid, (primary) cutaneous squamous or non-squamous histologies; intolerable Grade 2 or ≥ Grade 3 neuropathy or unstable neurological symptoms within 4 weeks of Cycle 1 Day 1; or active, uncontrolled infections requiring systemic therapy. Tipifarnib is administered at a dose of 600 mg, orally with a meal twice a day for 7 days in alternating weeks (Days 1-7 and 15-21) of 28-day cycles until discontinuation criteria are met. All patients are being followed for safety through the End of Treatment visit, roughly 30 days after treatment discontinuation or immediately before the administration of another anticancer treatment, whichever occurs first. Upon therapy discontinuation, all patients are being followed approximately every 12 weeks for survival status, and the use of subsequent therapy. The IDMB last reviewed data in October 2020 and recommended the trial continue as planned. AIM-HN is continuing to enroll patients globally. Ho et al, JCO, accepted. Clinical trial information: NCT03719690.

PROSPER subgroup analysis by age and region: Overall survival and safety in men with nonmetastatic castration-resistant prostate cancer receiving androgen deprivation therapy plus enzalutamide.

84 Background: Previous reports on the PROSPER trial have shown that enzalutamide (ENZA) plus androgen deprivation therapy (ADT) significantly improves metastasis-free survival and overall survival (OS) over placebo (PBO) in men with nonmetastatic castration-resistant prostate cancer (nmCRPC) and rapidly rising prostate-specific antigen (PSA) levels. (Hussain et al. N Engl J Med. 2018;378:2465-2474/Sternberg et al. N Engl J Med. 2020;382:2197-2206). To inform decision-making for specific patients, we report here a post hoc analysis of OS and safety in subgroups of PROSPER by age and region. Methods: PROSPER included men with nmCRPC and a PSA doubling time ≤ 10 months. Enrolled men continued ADT and were randomized 2:1 to ENZA 160 mg once daily vs PBO. We performed a multivariable analysis for OS, including age (≤ 70 yrs and &gt; 70 yrs), geographic region, and other variables and further examined exposure-adjusted adverse events (AEs) by age and region. Results: Based on this post hoc analysis, OS benefit with ENZA treatment was similar across geographic regions (table) and for patients aged ≥ 70 yrs (hazard ratio [HR] 0.73; 95% CI 0.58-0.9) and those aged &lt; 70 yrs (HR 0.72, 95% CI 0.5-1.04). In our multivariate analysis, 3 factors emerged as significantly impacting estimated OS: Eastern Cooperative Oncology Group (ECOG) performance status (1 vs 0; HR 1.7; 95% CI 1.4-2.1), log of PSA (HR 1.2; 95% CI 1.1-1.3), and use of subsequent therapy (yes vs no; HR 2.5; 95% CI 2.1-3.1). Overall safety was consistent between age groups and across geographic regions. The proportion of patients reporting any grade treatment-emergent AEs (TEAEs) related to ENZA use was similar between age groups but decreased with increasing age. Conclusions: In men with nmCRPC and rapidly rising PSA, ENZA plus ADT treatment reduced the risk of death, regardless of age or geographic location. Patients reported any grade TEAEs at a similar proportion in both arms. Variables impacting OS included ECOG status, log PSA, and subsequent therapy. Clinical trial information: NCT02003924. [Table: see text]

PCN275 Network Meta-Analysis Design Considerations in a Complex and Rapidly Evolving Landscape: A Case Study in First-LINE (1L) Advanced NON-SMALL Cell LUNG Cancer (ANSCLC)

In 1L aNSCLC, the therapeutic landscape is complex and rapidly evolving. While the introduction of different immunotherapy-based treatments reflects advances in treatment efficacy and a shift toward more personalized medicine, it poses challenges in generating unbiased relative effect estimates via network meta-analysis (NMA). Our objective was to illustrate NMA design considerations in the 1L aNSCLC setting. A comprehensive set of NMA checklists was used for presenting NMA design choices in 1L aNSCLC. Using a systematically identified evidence base of 125 randomized controlled trials (RCTs), the following were identified as key design features: 1) proportional hazards assumption violations and differing lengths of follow-up; 2) effect modification, 3) lumping vs. splitting treatment nodes, and 4) study design heterogeneity including differences in blinding, chemotherapy arms, cross-over, and use of subsequent therapies. Methodological approaches to address the identified features were presented. Proportional hazards violations and differing lengths of follow-up were evident in RCTs comparing immunotherapies against chemotherapies. Several approaches were considered, including: constant hazard ratios for trials of similar follow-up; fractional polynomial/parametric NMAs; piecewise hazard ratios; restricted mean survival time; and survival at pre-defined times. Programmed death-ligand 1 expression level and histology were key effect modifying factors for some but not all comparisons in the network. Meta-regression was considered but was infeasible; instead, stratified networks were constructed. The choice to lump/split treatment nodes was endpoint-specific, with some chemotherapy combinations showing similar efficacy yet different safety profiles. Nine RCTs involved investigator’s choice control arms, adding complexity to defining treatment nodes. The cross-over design and use of subsequent therapy evolved over time and was evaluated alongside design heterogeneity using a study-by-study assessment of the potential impact on treatment effect size. We identified and presented approaches for handling multiple NMA design issues in 1L aNSCLC. These issues can be extrapolated and applied to other therapeutic settings.

Early relapse after high-dose melphalan autologous stem cell transplant predicts inferior survival and is associated with high disease burden and genetically high-risk disease in multiple myeloma.

Predicting patient outcome in multiple myeloma remains challenging despite the availability of standard prognostic biomarkers. We investigated outcome for patients relapsing early from intensive therapy on NCRI Myeloma XI. Relapse within 12months of autologous stem cell transplant was associated with markedly worse median progression-free survival 2 (PFS2) of 18months and overall survival (OS) of 26months, compared to median PFS2 of 85months and OS of 91months for later relapsing patients despite equal access to and use of subsequent therapies, highlighting the urgent need for improved outcome prediction and early intervention strategies for myeloma patients.

Cost effectiveness (CE) of blinatumomab (BLIN) versus inotuzumab ozogamicin (INO) in adult patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) with no more than one prior salvage therapy (S0/S1) from a United Kingdom health care perspective.

e18359 Background: To estimate Incremental CE Ratio (ICER) of BLIN vs INO in adults with R/R S0/S1 ALL based on matching-adjusted indirect comparison (MAIC) of TOWER and INO-VATE trials from a UK healthcare perspective. Methods: CE was estimated by a partitioned-survival model with outcomes based on published aggregate data from INO-VATE (cutoff: 01/05/2017) and individual patient data from TOWER weighted to match patients in INO-VATE using MAIC. Five analyses were conducted based on alternative approach for the MAIC (anchored through Standard of Care [SOC] vs unanchored), proportional hazard (PH) assumptions, and reference overall survival (OS) distributions. Rates of complete remission and HSCT, utilities, duration of therapy, and use of subsequent therapies also were MAIC adjusted. Due to inconsistent definitions of event-free survival (EFS) between the trials, EFS was assumed to be equal for BLIN and INO complete responders. Costs were estimated from published sources and included those of medicine and administration, key adverse events, HSCT, salvage therapy, and terminal care. Utilities were based on EORTC-8D values derived from EORTC QLQ-C30 assessments in TOWER. A 50-year time horizon was used. Results: In all analyses, BLIN was more costly and more effective than INO. The ICER for BLIN vs INO ranged from £4,014 to £13,371 per QALY. Conclusions: For various approaches for conducting MAIC of BLIN vs INO, BLIN was highly cost effective vs INO in R/R ALL adults with S0/S1 from a UK healthcare perspective. [Table: see text]

A within-trial cost-effectiveness analysis of panitumumab compared with bevacizumab in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer in the US

Aims: This analysis investigated the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) compared with bevacizumab plus mFOLFOX6 in the first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC).Materials and methods: The cost-effectiveness analysis was developed from a third-party payer perspective in the US and was implemented using a partitioned survival model with health states for first-line treatment (progression-free), disease progression with and without subsequent active treatment, and death. Survival analyses of patients with wild-type RAS mCRC from the PEAK head-to-head clinical trial of panitumumab vs bevacizumab were performed to estimate time in the model health states. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and US public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second-, and third-line settings. A life-time perspective was taken with future costs and outcomes discounted at 3% per annum. Scenario, one-way, and probabilistic sensitivity analyses were performed.Results: Compared with bevacizumab, the use of panitumumab resulted in an incremental cost of US $60,286, and an incremental quality-adjusted life-year (QALY) of 0.445, translating into a cost per QALY gained of US $135,391 in favor of panitumumab. Results were sensitive to wastage and dose rounding assumptions modeled.Limitations: Progression-free and overall survival were extrapolated beyond the follow-up of the primary analysis using fitted parametric curves. Costs and quality of life were estimated from multiple and different data sources.Conclusions: The efficacy of panitumumab in extending progression-free and overall survival and improving quality of life makes it a cost-effective option for first-line treatment of patients with wild-type RAS mCRC compared with bevacizumab.

Abstract 3639: Matching-adjusted indirect comparison of nivolumab + ipilimumab and BRAF+MEK inhibitors for the treatment of BRAF-mutant treatment-naive advanced melanoma

Abstract OBJECTIVES: Assess the relative overall survival (OS) and progression-free survival (PFS) of nivolumab + ipilimumab (NIVO+IPI) versus dabrafenib + trametinib (DAB+TRAM) and vemurafenib + cobimetinib (VEM+COBI) in treatment-naive patients with BRAF-mutant advanced melanoma. METHODS: In the absence of a direct head-to-head comparison, matching-adjusted indirect treatment comparisons (MAIC) were conducted using patient-level data for NIVO+IPI patients with BRAF-mutant tumors from the CheckMate 067 and 069 trials and published summary level results from BRAF+MEK pivotal trials (COMBI-d, COMBI-v, and coBRIM). NIVO+IPI baseline characteristics were matched to the DAB+TRAM or VEM+COBI patient characteristics by reweighting the NIVO+IPI patients by their odds of enrollment in the studies. Additional potential biases such as use of subsequent therapy were not controlled for. Cox proportional hazard models were fit to the weighted OS and PFS data for NIVO+IPI and virtual event and censor times derived from the published DAB+TRAM or VEM+COBI curves. To capture the non-proportionality observed in the OS and PFS curves, Cox models with separate hazard ratios (HRs) for &amp;lt;12 months and ≥12 months were also fit. RESULTS: The effective sample size of the NIVO+IPI patients was 106 after matching to DAB+TRAM and 59 after matching to VEM+COBI. The overall OS Cox models showed that NIVO+IPI had superior OS with HRs (95% confidence intervals) of 0.64 (0.46, 0.89) versus DAB+TRAM and 0.56 (0.36, 0.89) versus VEM+COBI. This benefit emerged with longer follow-up. At 12 months, the OS HRs were similar for NIVO+IPI versus DAB+TRAM (1.0; 0.67, 1.49) and VEM+COBI (1.01; 0.57, 1.80). However, beyond 12 months, NIVO+IPI had a significantly greater OS benefit versus DAB+TRAM (0.33; 0.18, 0.60) and versus VEM+COBI (0.29; 0.14, 0.63). PFS results were similar with insignificant differences observed at 12 months and superior PFS for NIVO+IPI beyond 12 months; HRs for ≥12 months were 0.29 (0.14, 0.62) for NIVO+IPI versus DAB+TRAM and 0.15 (0.04, 0.54) for NIVO+IPI versus VEM+COBI. CONCLUSION: After adjusting for patient population differences, NIVO+IPI had a significant OS benefit over DAB+TRAM and VEM+COBI. For both OS and PFS, the NIVO+IPI benefit emerges after 12 months of treatment. In the future, these results can be validated by ongoing randomized trials directly comparing sequential combination approaches. Disclosure: This research was funded by Bristol-Myers Squibb. Citation Format: Michael B. Atkins, David McDermott, Ahmad Tarhini, Michael Rael, Komal Gupte-Singh, Elliot O'Brien, Corey Ritchings, Sumati Rao. Matching-adjusted indirect comparison of nivolumab + ipilimumab and BRAF+MEK inhibitors for the treatment of BRAF-mutant treatment-naive advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3639.

Cost-effectiveness analysis in the Spanish setting of the PEAK trial of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer

Objective: To assess the cost-effectiveness of panitumumab in combination with mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) vs bevacizumab in combination with mFOLFOX6 as first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC) in Spain.Methods: A semi-Markov model was developed including the following health states: Progression free; Progressive disease: Treat with best supportive care; Progressive disease: Treat with subsequent active therapy; Attempted resection of metastases; Disease free after metastases resection; Progressive disease: after resection and relapse; and Death. Parametric survival analyses of patient-level progression free survival and overall survival data from the PEAK Phase II clinical trial were used to estimate health state transitions. Additional data from the PEAK trial were considered for the dose and duration of therapy, the use of subsequent therapy, the occurrence of adverse events, and the incidence and probability of time to metastasis resection. Utility weightings were calculated from patient-level data from panitumumab trials evaluating first-, second-, and third-line treatments. The study was performed from the Spanish National Health System (NHS) perspective including only direct costs. A life-time horizon was applied. Probabilistic sensitivity analyses and scenario sensitivity analyses were performed to assess the robustness of the model.Results: Based on the PEAK trial, which demonstrated greater efficacy of panitumumab vs bevacizumab, both in combination with mFOLFOX6 first-line in wild-type RAS mCRC patients, the estimated incremental cost per life-year gained was €16,567 and the estimated incremental cost per quality-adjusted life year gained was €22,794. The sensitivity analyses showed the model was robust to alternative parameters and assumptions.Limitations: The analysis was based on a simulation model and, therefore, the results should be interpreted cautiously.Conclusions: Based on the PEAK Phase II clinical trial and taking into account Spanish costs, the results of the analysis showed that first-line treatment of mCRC with panitumumab + mFOLFOX6 could be considered a cost-effective option compared with bevacizumab + mFOLFOX6 for the Spanish NHS.

Prescribing Patterns of Oral Antineoplastic Therapies Observed in the Treatment of Patients With Advanced Prostate Cancer Between 2012 and 2014: Results of an Oncology EMR Analysis

PurposeThe purpose of this study was to examine, using a US electronic medical records (EMR) database, the clinical characteristics and real-world treatment sequences in men with advanced prostate cancer who initiated treatment with abiraterone acetate or enzalutamide. MethodsThis retrospective, observational study evaluated adult male patients with a diagnosis of prostate cancer (International Classification of Diseases, Ninth Revision, Clinical Modification code 185) in the EMR database between July 1, 2011, and March 31, 2014, who had initiated first-line treatment with abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014. The first record for a patient initiating abiraterone acetate or enzalutamide was the index date. Patients had 6 months of pre-index medical record history and a variable length follow-up period, extending from the index date to the end of medical record data availability or date of the end of the study (March 31, 2014). The sequence of first- and second-line therapies for advanced prostate cancer therapy was reported. FindingsA total of 809 patients met study inclusion and exclusion criteria. This study found that the majority of patients who initiated treatment with either abiraterone acetate or enzalutamide between September 1, 2012, and March 31, 2014, received a single line of therapy (72%); abiraterone acetate was the most common first-line treatment (74% of first-line patients). A subset of patients treated first-line with either abiraterone acetate or enzalutamide were transitioned to an oral second-line agent (17% of first-line abiraterone acetate–treated patients transitioned to second-line enzalutamide, and 16% of first-line enzalutamide-treated patients transitioned to second-line abiraterone acetate). Chemotherapy with docetaxel was also a commonly observed second-line treatment selection, occurring in 8% of first-line abiraterone acetate–treated patients and in 7% of first-line enzalutamide-treated patients. ImplicationsThis EMR study is among the first to present evidence of US physician practice prescribing patterns regarding initiation of oral antineoplastic agents and use of subsequent therapies in patients with advanced prostate cancer.

Phase III study of nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem alone in patients (pts) with metastatic pancreatic adenocarcinoma (mPC): Subgroup analysis of Canadian pts from the MPACT trial.

439 Background: Weekly nab-P + Gem is a new option for first-line treatment (Tx) of mPC. In the MPACT trial, nab-P/Gem demonstrated superior overall survival (OS; primary endpoint) vs Gem alone as first-line Tx of mPC (Table). Here we report a subgroup analyses evaluating the efficacy and safety outcomes with nab-P + Gem vs Gem alone from the Canadian cohort of the MPACT trial. Methods: Previously untreated pts (N = 861) with mPC were randomized 1:1 (stratified by Karnofsky Performance Status [KPS], region, and the presence of liver metastases) to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle or Gem 1000 mg/m2 weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 of each 28-day cycle (cycle ≥ 2). Results: 63 pts from Canada enrolled in the MPACT trial. Baseline pt characteristics were well balanced. Median age was 61 years and KPS was similar for both groups and comparable to the intent-to-treat (ITT) populations. Primary lesion in the pancreatic head was more common among pts in the nab-P + Gem vs Gem arm (55% vs 30%); use of biliary stent was similar (33% nab-P + Gem; 27% Gem). Median OS and progression-free survival (PFS) were longer with nab-P + Gem vs Gem (Table). Median Tx duration was 4.2 mo with nab-P + Gem vs 3.2 mo with Gem. Use of subsequent therapy was 30% in the nab-P + Gem arm vs 43% in the Gem arm. The median relative dose intensity for Gem was similar in each arm (81% nab-P + Gem vs 85% Gem). The most common grade ≥ 3 AEs for nab-P + Gem vs Gem were neutropenia (22% vs 10%), fatigue (34% vs 33%), and neuropathy (25% vs 0%). Conclusions: Canadian pts participating in MPACT were similar to the ITT population and nab-P + Gem was well tolerated and showed improved median OS, PFS, and ORR vs Gem alone, although not statistically significant (likely due to the small number of pts). Clinical trial information: NCT00844649. [Table: see text]

Cost-effectiveness analysis of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer

ObjectiveTo investigate the cost-effectiveness of panitumumab plus mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) compared with bevacizumab plus mFOLFOX6 in first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC). DesignA semi-Markov model was constructed from a French health collective perspective, with health states related to first-line treatment (progression-free), disease progression with and without subsequent active treatment, resection of metastases, disease-free after successful resection and death. MethodsParametric survival analyses of patient-level progression-free and overall survival data from the only head-to-head clinical trial of panitumumab and bevacizumab (PEAK) were performed to estimate transitions to disease progression and death. Additional data from PEAK informed the amount of each drug consumed, duration of therapy, subsequent therapy use, and toxicities related to mCRC treatment. Literature and French public data sources were used to estimate unit costs associated with treatment and duration of subsequent active therapies. Utility weights were calculated from patient-level data from panitumumab trials in the first-, second- and third-line settings. A life-time perspective was applied. Scenario, one-way, and probabilistic sensitivity analyses were performed. ResultsBased on a head-to-head clinical trial that demonstrates better efficacy outcomes for patients with wild-type RAS mCRC who receive panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6, the incremental cost per life-year gained was estimated to be €26,918, and the incremental cost per quality-adjusted life year (QALY) gained was estimated to be €36,577. Sensitivity analyses indicate the model is robust to alternative parameters and assumptions. ConclusionsThe incremental cost per QALY gained indicates that panitumumab plus mFOLFOX6 represents good value for money in comparison to bevacizumab plus mFOLFOX6 and, with a willingness-to-pay ranging from €40,000 to €60,000, can be considered cost-effective in first-line treatment of patients with wild-type RAS mCRC.

Editorial: Biopsy of diffuse intrinsic pontine gliomas?

The authors have performed an important study in which 7 patients with diffuse intrinsic pontine gliomas (DIPGs) underwent biopsy at their institution. These cases were selected from a total of 54 involving patients with pontine tumors who presented to their institution since 2004. The cases in which biopsy was performed were deemed “atypical” in terms of neuroimaging findings. Of these, 2 were shown by neuropathological examination and hierarchical cluster analysis to be cases of pontine primitive neuroectodermal tumors (PNETs), which were treated in a different manner from DIPGs—with aggressive chemotherapy and tandem autologous stem cell transplant in conjunction with radiation therapy. In 2006, Zagzag et al.2 reported on 7 cases of brainstem tumors that were proven to be PNETs on the basis of biopsy. In their series, the brainstem PNETs occurred in younger children and were primarily focal lesions in contrast to the DIPGs. However, this report raised the specter that not all intrinsic brainstem lesions in children are DIPGs, and that biopsy in select circumstances would be warranted. In the current report, Sufit et al.1 have used the Affymetrix U133 Plus 2.0 GeneChip microarray to examine the 7 brainstem cases in which biopsy specimens were obtained, and have compared these results against those for other pediatric brain tumors, including medulloblastoma, atypical teratoid/rhabdoid tumor, ependymoma, and ganglioglioma to name a few. Their cluster analysis shows that pontine PNETs have a similar genetic profile to supratentorial PNETs, but a different profile, for the most part, from DIPGs. It should be noted that some of the histologically confirmed DIPGs clustered closely to the pontine PNETs. Why is this study important? It is important because we are approaching an era in which molecular studies of biopsy specimens from brain tumors can be used to help select or validate the use of subsequent therapies, as was shown in the 2 cases of pontine PNETs in which biopsy was performed here. The issue of whether biopsy specimens should be obtained in pontine lesions with atypical DPIG neuroimaging characteristics is becoming less controversial. At our institution, children with pontine tumors undergo biopsy if they have atypical neuroimaging or clinical features. It would be reasonable to perform biopsies of typical DIPGs within the context of a welldefined and structured clinical trial in which molecular analyses are being performed to advance our working knowledge of the genetic origins of these tumors. Biopsy can be performed, as demonstrated in this case series, with acceptable morbidity. Future studies of brainstem biopsies may take advantage of the latest Affymetrix Gene 1.1 ST array, which “tiles” across the entire transcript, as opposed to the U133 Plus 2.0 GeneChip array, in which the probes were designed to hybridize to the 3′ end of the transcript. These newly designed gene arrays may provide a more robust characterization of the genetic profile of brainstem tumors in children. (http://thejns.org/doi/abs/10.3171/2012.2.PEDS1237)

Continued Overall Survival Benefit After 5 Years' Follow-up with Bortezomib-Melphalan-Prednisone (VMP) Versus Melphalan-Prednisone (MP) in Patients with Previously Untreated Multiple Myeloma, and No Increased Risk of Second Primary Malignancies: Final Results of the Phase 3 VISTA Trial

Abstract 476▪FN2▪This icon denotes a clinically relevant abstract Background:Data from the initial report of the international, multicenter, phase 3 VISTA trial demonstrated that VMP was superior to MP across all efficacy endpoints, including response rates, time to progression, and overall survival (OS), in previously untreated multiple myeloma (MM) patients ineligible for high-dose therapy. Following this report, centralized assessment of response/progression was stopped and, per protocol, patients were followed for up to 4.5 years post-last patient in date for survival and the use of subsequent anti-MM therapy only. An updated analysis, conducted after a median follow-up of 36.7 months, demonstrated a continued significant OS benefit with VMP. Here we report the final updated OS analysis of VISTA after 5 years of follow-up, including an exploratory analysis of the risk of second primary malignancies (SPMs), an important issue for MM patients receiving long-term therapy. Methods:Patients were randomized (1:1) to receive nine 6-week cycles of VMP (N=344; bortezomib 1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, and 32, cycles 1–4, days 1, 8, 22, and 29, cycles 5–9; melphalan 9 mg/m2 days 1–4, prednisone 60 mg/m2, days 1–4, all cycles) or MP (N=338) alone. Patients were followed at least every 12 weeks for survival and subsequent therapy use. Data on SPMs were collected during February 2011 by surveying all study sites to capture information for 655 (96%) patients. Results:After median follow-up of 60.1 months, with only 5% of patients lost to follow-up, median OS was 56.4 versus 43.1 months for patients randomized to VMP compared to MP (HR 0.695, p=0.0004), reflecting a 31% reduced risk of death with VMP (Figure); 5-year OS rates were 46.0% and 34.4%, respectively. This compares favorably with the 6.6-month increase in median OS in a meta-analysis of six phase 3 trials of MP-thalidomide vs MP (Fayers et al, Blood 2011). The OS benefit with VMP was seen across patient subgroups, including those aged ≥75 years (median 50.7 vs 32.9 months, HR 0.71), patients with ISS stage III MM (median 42.1 vs 30.5 months, HR 0.67), and those with creatinine clearance <60 mL/min (median 56.8 vs 36.7 months, HR 0.70), but no significant difference was observed in the small subgroup of patients with documented high-risk cytogenetics (n=46). At data cut-off (March 24, 2011), 63% of VMP and 73% of MP patients had received subsequent MM therapies; use of subsequent therapies was generally similar between arms, except for a higher proportion of MP patients receiving subsequent bortezomib (43% vs 22%). Time to next treatment (median 27.0 vs 19.2 months; HR 0.557, p<0.0001) and treatment-free interval (median 16.6 vs 8.3 months, HR 0.573, p<0.0001) were superior with VMP vs MP. Among all patients who had received subsequent therapies, OS was superior with VMP vs MP (median 55.7 vs 46.4 months; HR 0.745, p=0.0162). A 30-month landmark OS analysis demonstrated superior survival from landmark among all VMP patients (median not reached) and among VMP patients who had received any subsequent therapy (median 28.2 months) vs MP patients who had received subsequent bortezomib (median 23.0 months). Taking into account the longer observation period due to prolonged survival on the VMP arm, analyses of SPM risk (Table) showed no difference in incidence proportions or ‘exposure’-adjusted incidence rates between arms. Rates on both arms (VMP 0.0166, MP 0.013 per patient-year) were consistent with background incidence rate in the general population aged 65–74 years (0.019, SEER database). Conclusions:VMP resulted in a substantial long-term OS benefit vs MP (13.3-month increase in median), which was seen across patient subgroups and regardless of extensive subsequent therapy. There was no increased risk of SPMs identified with VMP vs expected background rates. [Display omitted] SPMs: relative risk (RR)VMPMPRR (95% CI)*Incidence proportionPatients with data collected, N327328Hematologic**, n (%)3 (1)3 (1)1.003 (0.204, 4.933)Fatal2 (1)3 (1)0.669 (0.113, 3.976)Non-hematologic, n (%)16 (5)10 (3)1.605 (0.739, 3.484)Fatal6 (2)6 (2)1.003 (0.327, 3.078)Incidence ratePatient-years for which data collected, N11671004Hematologic, n per patient-year0.00260.0030.862 (0.174, 4.269)Fatal0.00170.0030.574 (0.096, 3.436)Non-hematologic, n per patient-year0.01400.0101.389 (0.630, 3.061)Fatal0.00520.0060.859 (0.277, 2.664)*RR <1 favors VMP;**Acute leukemia, n=2 both arms, 1 MDS (VMP), 1 B-cell lymphoma (MP) Disclosures:San Miguel:Janssen-Cilag: Consultancy; Celgene: Consultancy; Millennium Pharmaceuticals, Inc: Consultancy. Dimopoulos:Millennium Pharmaceuticals, Inc.: Honoraria; Ortho Biotech: Consultancy, Honoraria. Kropff:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Spicka:Janssen-Cilag: Honoraria; Celgene: Honoraria. Petrucci:Janssen-Cilag: Honoraria; Celgene: Honoraria. Palumbo:Janssen-Cilag: Honoraria; Celgene: Honoraria. Dmoszynska:Janssen-Cilag: Research Funding. Delforge:Janssen-Cilag: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Mateos:Janssen-Cilag: Honoraria; Celgene: Honoraria. Anderson:Celgene: Consultancy, Honoraria; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Esseltine:Millennium Pharmaceuticals, Inc.: Employment; Johnson & Johnson: Equity Ownership. Liu:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Deraedt:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Cakana:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Richardson:Celgene: Consultancy; Janssen Research & Development: Consultancy; Millennium Pharmaceuticals, Inc.: Consultancy.

Post-study therapy as a source of confounding in survival analysis of first-line studies in patients with advanced non-small-cell lung cancer.

Clinical trials exploring the long-term effects of first-line therapy in patients with advanced non-small-cell lung cancer generally disregard subsequent treatment although most patients receive second and third-line therapies. The choice of further therapy depends on critical intermediate events such as disease progression and it is usually left at the physician's discretion. Time-dependent confounding may then arise with standard survival analyses producing biased effect estimates, even in randomized trials. Herein we describe the concept of time-dependent confounding in detail and discuss whether the response to first-line treatment may be a potential time-dependent confounding factor for survival in the context of subsequent therapy. A prospective observational study of 406 patients with advanced non-small-cell lung cancer served as an example base. There is evidence that time-dependent confounding may occur in multivariate survival analysis after first-line therapy when disregarding subsequent treatment. In the light of this important but underestimated aspect some of the large and meaningful recent clinical first-line lung cancer studies are discussed, focussing on subsequent treatment and its potential impact on the survival of the study patients. No recently performed lung cancer trial applied adequate statistical analyses despite the frequent use of subsequent therapies. In conclusion, effect estimates from standard survival analysis may be biased even in randomized controlled trials because of time-dependent confounding. To adequately assess treatment effects on long-term outcomes appropriate statistical analyses need to take subsequent treatment into account.