Communicating Healthcare Economic and Pre-approval Information With Healthcare Decision-Makers: Opportunities Following the 21st Century Cures Act and FDA Guidance

With rising US healthcare costs, population health decision-makers have expressed interest in receiving pre-approval information to help with the budgeting and forecasting needed to accommodate pharmaceutical and medical device launches. Additionally, there has been a strong emphasis placed on the economics and quality of new products. Manufacturers have historically been reluctant to share pre-approval or healthcare economic information (HCEI) due to unclear regulatory guidance for these types of communications. The 21st Century Cures Act, as well as the June 2018 FDA guidance on payor communications have more clearly defined guardrails to communicate this information. This paper provides insights on how to optimize this new guidance and facilitate robust and compliant conversations with decision-makers

Maleimide Self-Reaction in Furan/Maleimide-Based Reversibly Crosslinked Polyketones:Processing Limitation or Potential Advantage?

Polymers crosslinked via furan/maleimide thermo-reversible chemistry have been extensively explored as reprocessable and self-healing thermosets and elastomers. For such applications, it is important that the thermo-reversible features are reproducible after many reprocessing and healing cycles. Therefore, side reactions are undesirable. However, we have noticed irreversible changes in the mechanical properties of such materials when exposing them to temperatures around 150 °C. In this work, we study whether these changes are due to the self-reaction of maleimide moieties that may take place at this rather low temperature. In order to do so, we prepared a furan-grafted polyketone crosslinked with the commonly used aromatic bismaleimide (1,1′-(methylenedi-4,1-phenylene)bismaleimide), and exposed it to isothermal treatments at 150 °C. The changes in the chemistry and thermo-mechanical properties were mainly studied by infrared spectroscopy, 1H-NMR, and rheology. Our results indicate that maleimide self-reaction does take place in the studied polymer system. This finding comes along with limitations over the reprocessing and self-healing procedures for furan/maleimide-based reversibly crosslinked polymers that present their softening (decrosslinking) point at relatively high temperatures. On the other hand, the side reaction can also be used to tune the properties of such polymer products via in situ thermal treatments

Clinical characteristics, treatment patterns, and outcomes in adult patients with germline BRCA1/2-mutated, HER2-negative advanced breast cancer: a retrospective medical record review in the United States

AimTo examine clinical characteristics, real-world treatment patterns, and health outcomes among patients with germline BRCA1/2-mutated, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer (ABC).MethodsA retrospective analysis was conducted using medical records from patients with HER2-negative ABC with BRCA1/2 mutation who received cytotoxic chemotherapy. Data were stratified into groups with triple-negative breast cancer (TNBC) or hormone receptor–positive (HR+)/HER2-negative diagnoses. Time-to-event outcomes (i.e., real-world progression-free survival [rwPFS] and overall survival [OS]) were calculated to summarize health outcomes.ResultsWhen diagnosed with ABC, most patients were younger than 60 years (mean age = 57.3 years), were white (76.4%), and had a family history of BRCA-related cancer (71.5%). A total of 305 patient records were examined; 194 patients (63.6%) had advanced TNBC, and 111 patients (36.4%) had HR+/HER2-negative ABC. Chemotherapy was primarily used as first-line treatment for both subgroups, but the TNBC subgroup received poly (ADP-ribose) polymerase (PARP) inhibitors at triple the rate as a second-line treatment and double the rate as a third-line treatment compared with the HR+/HER2-negative subgroup. Two-year OS rates were similar between the TNBC (73.9%) and the HR+/HER2-negative subgroups (77.0%), and anemia, nausea, and neutropenia were the most commonly reported toxicities across all treatments.ConclusionClinicians should consider the use of targeted agents such as PARP inhibitors in earlier lines of therapy for ABC given the growing evidence that PARP inhibitors may improve PFS compared with chemotherapy while potentially offering a more manageable toxicity profile and improved quality of life

Neoadjuvant Talazoparib in Patients With Germline BRCA1/2 Mutation-Positive, Early-Stage Triple-Negative Breast Cancer: Results of a Phase II Study

BACKGROUND: The undetermined efficacy of the current standard-of-care neoadjuvant treatment, anthracycline/platinum-based chemotherapy, in patients with early-stage triple-negative breast cancer (TNBC) and germline BRCA mutations emphasizes the need for biomarker-targeted treatment, such as poly(ADP-ribose) polymerase inhibitors, in this setting. This phase II, single-arm, open-label study evaluated the efficacy and safety of neoadjuvant talazoparib in patients with germline BRCA1/2-mutated early-stage TNBC. PATIENTS AND METHODS: Patients with germline BRCA1/2-mutated early-stage TNBC received talazoparib 1 mg once daily for 24 weeks (0.75 mg for moderate renal impairment) followed by surgery. The primary endpoint was pathologic complete response (pCR) by independent central review (ICR). Secondary endpoints included residual cancer burden (RCB) by ICR. Safety and tolerability of talazoparib and patient-reported outcomes were assessed. RESULTS: Of 61 patients, 48 received ≥80% talazoparib doses, underwent surgery, and were assessed for pCR or progressed before pCR assessment and considered nonresponders. pCR rate was 45.8% (95% confidence interval [CI], 32.0%-60.6%) and 49.2% (95% CI, 36.7%-61.6%) in the evaluable and intent-to-treat (ITT) population, respectively. RCB 0/I rate was 45.8% (95% CI, 29.4%-63.2%) and 50.8% (95% CI, 35.5%-66.0%) in the evaluable and ITT population, respectively. Treatment-related adverse events (TRAE) were reported in 58 (95.1%) patients. Most common grade 3 and 4 TRAEs were anemia (39.3%) and neutropenia (9.8%). There was no clinically meaningful detriment in quality of life. No deaths occurred during the reporting period; 2 deaths due to progressive disease occurred during long-term follow-up (\u3e400 days after first dose). CONCLUSIONS: Neoadjuvant talazoparib monotherapy was active despite pCR rates not meeting the prespecified threshold; these rates were comparable to those observed with combination anthracycline- and taxane-based chemotherapy regimens. Talazoparib was generally well tolerated. CLINICALTRIALS.GOV IDENTIFIER: NCT03499353

<i>BRCA1/2</i> Mutation Testing in Patients with HER2-Negative Advanced Breast Cancer: Real-World Data from the United States, Europe, and Israel

Poly(adenosine diphosphate-ribose) polymerase inhibitors are approved to treat patients harboring a germline breast cancer susceptibility gene 1 or 2 mutation (BRCA1/2mut) with human epidermal growth factor receptor 2—negative (HER2−) advanced breast cancer (ABC). This study evaluated differences in patient demographics, clinical characteristics, and BRCA1/2mut testing within the United States (US), European Union 4 (EU4; France, Germany, Italy, and Spain), and Israel in a real-world population of patients with HER2− ABC. Oncologists provided chart data from eligible patients from October 2019 through March 2020. In the US, EU4, and Israel, 73%, 42%, and 99% of patients were tested for BRCA1/2mut, respectively. In the US and the EU4, patients who were not tested versus tested for BRCA1/2mut were more likely to have hormone receptor—positive (HR+)/HER2− ABC (US, 94% vs. 74%, p p BRCA1/2-related cancer (US, 6% vs. 19%, p = 0.002; EU4, 10% vs. 28%, p p p BRCA1/2 testing rates in the US and Europe

Abstract PS10-47: Physician and patient satisfaction with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy in adult patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study

Abstract Background: Within the past 3 years, PARPi have demonstrated improved progression-free survival and favorable PROs compared with chemotherapy in randomized clinical trials in patients with gBRCA1/2mut HER2- ABC. These agents are now available in multiple countries for the treatment of gBRCA1/2mut HER2- locally advanced and/or metastatic breast cancer. Limited information is available on physician/patient satisfaction with PARPi from the RW. We assessed RW physician/patient treatment satisfaction among adult patients with gBRCA1/2mut HER2- ABC in Germany, France, Italy, Spain (EU4), US, and Israel. Methods: Oncologist were recruited to abstract data from medical records (2019/2020) for patients with gBRCA1/2mut HER2- ABC. Physicians were asked to rank (1=very dissatisfied to 5=very satisfied) their satisfaction with their patient’s current ABC treatment. The scores were dichotomized to a 0/1 variable (0=very dissatisfied/ dissatisfied/moderately satisfied; 1=satisfied/very satisfied). A subset of patients completed the Cancer Treatment Satisfaction Questionnaire, a validated instrument that was used to measure patient’s satisfaction with their current therapy. The physician and patient sample were matched. Physician/patient satisfaction scores were compared between chemotherapy and PARPi monotherapy utilizing inverse probability weighted regression adjustment controlling for age at therapy initiation, Charlson Comorbidity Index at time of data collection, baseline symptoms, hormone receptor (HR) status, ECOG score at therapy initiation, stage of therapy initiation (locally advanced breast cancer or metastatic breast cancer) and number of lines of ABC treatment. Results: Overall 96 adult female patients participated; mean age was 51 years. Tumor characteristics were: 34.4% HR+/HER2-, 65.6% triple negative breast cancer. Chemotherapy (n=58) was received among 60.4% of pts [n=29 (50.0%) platinum based, n=29 (50.0%) non-platinum based], and PARPi monotherapy (n=38) was received among 39.6% of pts. Physicians were significantly more likely to be satisfied or very satisfied with PARPi in comparison with chemotherapy (95.4% vs. 40.8%, p<0.001). Mean patient satisfactions scores were numerically higher with PARPi vs. chemotherapy: expectation of therapy 81.3 vs. 72.0 (p=0.13), feelings about side effects 55.7 vs. 51.4 (p=0.30), satisfaction with therapy 74.0 vs. 68.5 (p=0.13). Conclusions: PARPi have demonstrated superior efficacy and favorable PROs vs. chemotherapy in randomized controlled trials. In this RW study, physicians reported significantly higher satisfaction with PARPi vs. chemotherapy; patients reported numerically higher satisfaction scores with PARPi vs. chemotherapy across all domains. These findings further support the value of PARPi in patients with gBRCA1/2mut HER2- ABC. Additional studies to validate these findings are planned. Funding: Pfizer Citation Format: Michael Patrick Lux, Alexander Niyazov, Katie Lewis, James Pike, Alex Rider, Bhakti Arondekar, Reshma Mahtani. Physician and patient satisfaction with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy in adult patients with germline BRCA1/2 mutated (gBRCA1/2mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-47

Abstract PS10-32: Patient reported outcomes (PROs) with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy (CTX) in patients (pts) with germline BRCA1/2 mutated ( gBRCA1/2 mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study

Abstract Background: In ABC, where treatment is palliative, an important goal is the maintenance or improvement of quality of life (QoL). In the past 3 years, PARPi have demonstrated improved progression-free survival and favorable PROs compared with CTX in randomized clinical trials (RCTs) in pts with ABC and a gBRCA1/2mut. These agents are now available in multiple countries for the treatment of gBRCA1/2mut HER2- locally advanced and/or metastatic breast cancer. Limited information is available on the PRO benefit of these agents in the RW setting. We assessed RW cancer-related and breast-cancer specific PROs among adult pts with gBRCA1/2mut HER2- ABC in Germany, France, Italy, Spain (EU4), US, and Israel. Methods: Oncologists were recruited to abstract data from medical records (2019/2020) for pts with gBRCA1/2mut HER2- ABC. A subset of pts completed the European Organisation for Research and Treatment of Cancer Quality of Life Core 30 (EORTC QLQ-C30) and the breast cancer module QLQ-BR23. PROs were compared between CTX and PARPi monotherapy utilizing inverse probability weighted regression adjustment (IPWRA) controlling for age at therapy initiation, Charlson Comorbidity Index at time of data collection, baseline symptoms, hormone receptor (HR) status, ECOG score at therapy initiation, stage of therapy initiation (locally advanced breast cancer or metastatic breast cancer) and number of lines of ABC treatment. Results: Overall 96 female pts participated; mean age was 51 years. Tumor characteristics were: 34.4% HR+/HER2-, 65.6% triple negative breast cancer. CTX (n=58) was received among 60.4% of pts [n=29 (50.0%) platinum based, n=29 (50.0%) non-platinum based], and PARPi monotherapy (n=38) was received among 39.6% of pts. Compared to pts receiving CTX, pts receiving PARPi reported significantly better scores in physical and social functioning (Table 1). Pts receiving PARPi reported significantly better symptoms scores vs. CTX in constipation, breast symptoms, arm symptoms and systemic therapy side effects (Table 1). Pts receiving PARPi reported significantly worse scores vs. CTX in nausea/vomiting (Table 1). Global health status (GHS)/QoL scores were numerically better among pts receiving PARPi vs. CTX (Table 1). Conclusions: PARPi have demonstrated superior efficacy and favorable PROs vs. CTX in RCTs in pts with gBRCA1/2mut HER2- ABC. In this RW study, the PRO benefits reported with PARPi were consistent with what has been observed in RCTs, further supporting the value of PARPi. Additional studies to validate these findings are planned. Funding: Pfizer EORTC QLQ-BR23 categories sexual enjoyment and upset by hair loss were excluded from the analysis due to low sample size Table 1. IPWRA Analysis for the EORTC QLQ-C30 and QLQ BR-23a scoresCTX (n=58)PARPi Monotherapy (n=38)P valueEORTC QLQ-C30 GHS/QoL and functional scalesGHS/QoL56.5665.240.10Physical71.9079.980.045Role64.5568.060.55Emotional61.2464.580.61Cognitive78.2078.840.89Social63.5781.950.01EORTC QLQ-BR23 Functional scalesSexual12.3717.230.31Future perspective46.6844.530.81Body Image53.2265.360.13EORTC QLQ-C30 Symptoms scalesFatigue40.6739.620.87Nausea/vomiting18.2834.510.005Pain34.2638.880.42Dyspnea22.1523.290.82Insomnia30.7832.400.82Appetite loss24.8531.990.29Constipation18.751.85<.001Diarrhea16.2614.570.81Financial difficulties16.2616.830.92EORTC QLQ-BR23 Symptoms ScalesBreast symptoms13.280.350.008Arm symptoms11.392.600.001Systemic therapy side effects29.3913.48<.001 Citation Format: Reshma Mahtani, Alexander Niyazov, Katie Lewis, James Pike, Alex Rider, Bhakti Arondekar, Michael Patrick Lux. Patient reported outcomes (PROs) with poly(ADP-ribose) polymerase inhibitors (PARPi) versus chemotherapy (CTX) in patients (pts) with germline BRCA1/2 mutated (gBRCA1/2mut) HER2- advanced breast cancer (ABC): Results from a multi-country real-world (RW) study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-32

Impact of race on biomarker testing among HER2- advanced breast cancer (ABC) patients (pts) in the United States: Results from a real-world study

10598 Background: African Americans (AA) have the highest breast cancer (BC) mortality rate. Access to treatment is a known contributing factor. In the past 4 years, several targeted therapies for HER2- BC have become available which require testing for specific biomarkers. This study assessed the impact of race on biomarker testing rates in HER2- ABC pts receiving treatment in the US. Methods: Oncologists were recruited to abstract data from medical charts for the next 8-10 pts receiving treatment with HER2- ABC during Sept 2019-Apr 2020. Pts records were stratified by race and categorized into 3 mutually exclusive cohorts [White/Caucasian (White), AA, Other]. The other race cohort was excluded from this analysis due to small sample size. Differences in pt demographics/clinical characteristics were analyzed via Fisher’s exact tests. Testing rates for actionable biomarkers (i.e. BRCA1/2, PIK3CA, PD-L1) were compared between White and AA pts utilizing logistic regressions controlling for age, known family history of a BRCA-related cancer, hormone receptor (HR) status and practice setting (academic vs. community). Further analyses by age will be presented. Results: This analysis included 378 pts records, provided by 40 oncologists. Mean age was 64 years; 77% had HR+/HER2- ABC; 20% had advanced triple negative breast cancer (TNBC), 3% had ABC with an unknown HR status. Compared to White pts, AA pts were significantly more likely to have advanced TNBC (27% vs. 18%, p<0.05). Compared to White pts, AA pts had significantly lower BRCA1/2 mutation (mut) testing rates (Table). Numerically lower rates of PIK3CAmut and PD-L1 testing were observed among AA pts (Table). BRCA1/2mut positivity rate (germline [g] and/or somatic [s]) was higher among AA vs. White pts (30% vs. 22%). Positivity rate for PIK3CAmut was lower for AA vs. White pts (8% vs. 11%). Conclusions: A higher than expected BRCA1/2mut positivity rate was observed than previously reported in the literature. This is likely because this analysis included s BRCA1/2mut and represented a high risk pt population. Across all biomarkers assessed, AA pts had lower testing rates than White pts. This suggests racial disparities in testing rates of actionable biomarkers. Consistent with guidelines, and with the increased availability of targeted therapies, focused efforts should be developed to increase biomarker testing in AA pts. Funding: Pfizer Biomarker Testing Rates by Race.[Table: see text

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1.

Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory-Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (-1.08 [-1.52, -0.65]) and the BRCA1/2 subset (-1.15 [-1.67, -0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib

Patient-reported Outcomes in Men with Metastatic Castration-resistant Prostate Cancer Harboring DNA Damage Response Alterations Treated with Talazoparib: Results from TALAPRO-1.

Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory-Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (-1.08 [-1.52, -0.65]) and the BRCA1/2 subset (-1.15 [-1.67, -0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib