Outcomes of Older Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-Negative Metastatic Breast Cancer Treated With a CDK4/6 Inhibitor and an Aromatase Inhibitor: An FDA Pooled Analysis.

PURPOSE: Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS: We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS: For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION: There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

Patient reported outcomes in anti-PD-1/PD-L1 inhibitor immunotherapy registration trials: FDA analysis of data submitted and future directions.

BACKGROUND: Patient-reported outcome measures can be used to capture the patient's experience with disease and treatment. Immunotherapy agents including the anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies have unique symptomatic side effects and patient-reported outcome data can help to characterize the benefits and burdens associated with therapy. METHODS: We reviewed registration trials in the Food and Drug Administration database for five anti-programmed death receptor-1/programmed death-ligand-1 inhibitor therapies to characterize trial design and patient-reported outcome assessment strategy (cutoff 31 December 2017). We evaluated the patient-reported outcome measurement coverage of eight key symptoms related to adverse events reported in immunotherapy agent product labels (fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritus, and fever). RESULTS: There were a total of 28 trials across seven disease types and one tumor agnostic indication reviewed, of which 17 were randomized and 25 were open label. Of the 28 trials, 21 contained patient-reported outcome measures and all 21 used >1 instrument. The most common instruments were the EuroQol five dimension (N = 19), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (N = 17). Disease-specific patient-reported outcome tools were included in nine trials (six lung, one head and neck, one melanoma and one renal cell). No trial used a patient-reported outcome strategy assessing all eight selected adverse events. CONCLUSION: Collection of patient-reported outcome data in anti-programmed death receptor-1/programmed death-ligand-1 inhibitor trials were variable and did not consistently assess important symptomatic adverse events. Use of a patient-reported outcome instrument with well-defined functional scales supplemented by item libraries to incorporate relevant symptomatic adverse events may allow for improved understanding of the patient experience while receiving therapy. These data, along with other clinical data such as hospitalizations and supportive care medication use can help inform the benefit-risk assessment for regulatory purposes.

FDA Approval Summary: Pertuzumab for Adjuvant Treatment of HER2-Positive Early Breast Cancer.

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4-month median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% (n = 171) in the pertuzumab arm and 8.7% (n = 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67-1.00; P = 0.047]. The proportion of IDFS events in patients with hormone receptor-negative disease was 8.2% (n = 71) and 10.6% (n = 91) in the pertuzumab and placebo arms, respectively (HR, 0.76; 95% CI, 0.56-1.04). The proportion of IDFS events for patients with node-positive disease was 9.2% (n = 139) and 12.1% (n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62-0.96). Adverse reactions in ≥30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence.

Blinding and Patient-Reported Outcome Completion Rates in US Food and Drug Administration Cancer Trial Submissions, 2007-2017.

BACKGROUND: Patient-reported outcomes (PROs) are commonly included in submissions to the United States Food and Drug Administration (FDA). Open-label designs are frequent in cancer trials. Between-arm differences in PRO missingness may affect results. We sought to compare PRO completion rates between study arms in randomized open-label and double-blind cancer trials. METHODS: Randomized, controlled trials for oncology and malignant hematology products submitted to the FDA in fiscal years 2007-2017 were identified using internal FDA databases. Applicant study reports were reviewed to assess PRO use and reporting of completion rates. Completion rates were collected for each PRO and compared between arms. Results were summarized using descriptive statistics. RESULTS: Ninety-six trials for anticancer products from 2007 to 2017 contained PROs. Fifty-one (53.1%) were randomized, controlled trials with useable information on PRO completion. The median completion rate for investigational arms was 89.7% (range = 33.7-100.0%) and 88.2% (range = 11.0-100.0%) for control arms. At six months, seven double-blind trials had gaps of at least 10% in at least one PRO between arms; in four trials, these gaps favored the control arm (median difference = 11.5%, range = 10.0-17.0%). For open-label trials, four trials had such gaps, all of which favored the investigational arm (median difference = 28.5%, range = 10.0-69.0%). CONCLUSIONS: Among trials that provided interpretable PRO completion information, completion rates were high. Most trials had comparable completion rates between arms. However, when large between-arm completion rate differences existed, differences favoring the experimental arm were more common in open-label trials compared with double-blind trials. Procedures must be put in place to improve reporting of PRO completion and reduce missingness, particularly in open-label trials.

Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype.

BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+ cells using immunohistochemistry (IHC) and quantified productive T-cell receptor ß (TCRß) rearrangements and TCRß clonality using next-generation sequencing (NGS) in 30 HER2+ breast cancer tissues treated with neoadjuvant H with or without P regimens. MATERIALS AND METHODS: Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRß was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. RESULTS: A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRß and TCRß clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+ and FoxP3+ cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). CONCLUSION: An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings.

FDA Approval Summary: Niraparib for the Maintenance Treatment of Patients with Recurrent Ovarian Cancer in Response to Platinum-Based Chemotherapy.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17-0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34-0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066-71. ©2018 AACRSee related commentary by Konstantinopoulos and Matulonis, p. 4062.

A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review.

Importance: Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening. Observations: This review describes all malignant hematology and oncology AAs from inception of the program on December 11, 1992, to May 31, 2017. During this period, the FDA granted AA to 64 malignant hematology and oncology products for 93 new indications. Of these AAs, 53 were for new molecular entities. Overall, the end point of response rate, including hematologic response rates, accounted for most AAs (81 [87%]), followed by time-to-event end points of progression-free survival or time to progression (8 [9%]) and disease-free survival or recurrence-free survival (4 [4%]). Single-arm trial designs provided the data for 67 (72%) of the initial AA indications. Of the 93 AAs, 51 (55%) have fulfilled their postmarketing requirement and verified benefit in a median of 3.4 years after their initial AA. Thirty-seven (40%) indications have not yet completed confirmatory trial(s) or verified benefit, and 5 indications receiving AA (5%) have been withdrawn from the market. Conclusions and Relevance: The use of the AA program during the past 25 years has increased over time, and only a small portion of indications under the AA program fail to verify clinical benefit. For patients with serious or life-threatening oncologic diseases, AA brings products to the market years before confirmatory trials are typically completed.

Neoadjuvant use of ipilimumab in locally advanced melanoma.

Recent advances in immune modulating therapies show great promise for patients with advanced melanoma, however optimal strategies for achieving long-term disease control in locally advanced melanoma are unclear. We present two cases of neoadjuvant ipilimumab, one case in combination with isolated limb infusion (ILI) followed by surgical resection and one followed by surgery alone. Both patients have had durable responses. These cases highlight the ongoing need for prospective trials in the neoadjuvant setting.

There is a mismatch between the medicare benefit package and the preferences of patients with cancer and their caregivers.

PURPOSE: To identify insured services that are most important to Medicare beneficiaries with cancer and their family caregivers when coverage is limited. METHODS: A total of 440 participants (patients, n = 246; caregivers, n = 194) were enrolled onto the CHAT (Choosing Health Plans All Together) study from August 2010 to March 2013. The exercise elicited preferences about what benefits Medicare should cover for patients with cancer in their last 6 months of life. Facilitated sessions lasted 2.5 hours, included 8 to 10 participants, and focused on choices about Medicare health benefits within the context of a resource-constrained environment. RESULTS: Six of 15 benefit categories were selected by > 80% of participants: cancer care, prescription drugs, primary care, home care, palliative care, and nursing home coverage. Only 12% of participants chose the maximum level of cancer benefits, a level of care commonly financed in the Medicare program. Between 40% and 50% of participants chose benefits not currently covered by Medicare: unrestricted cash, concurrent palliative care, and home-based long-term care. Nearly one in five participants picked some level of each of these three benefit categories and allocated on average 30% of their resources toward them. CONCLUSION: The mismatch between covered benefits and participant preferences shows that addressing quality of life and the financial burden of care is a priority for a substantial subset of patients with cancer in the Medicare program. Patient and caregiver preferences can be elicited, and the choices they express could suggest potential for Medicare benefit package reform and flexibility.

The ethics of clinical trials for cancer therapy.

Cancer clinical trials are intended to evaluate novel interventions and to improve outcomes. Such research depends on the participation of patients seeking the best options for care. The design, conduct, and analysis of trials must therefore be grounded in an ethical framework that respects and protects the interests of clinical trial participants.

To stent or not to stent: an evidence-based approach to palliative procedures at the end of life.

Patients near the end of life often undergo invasive procedures, such as biliary stenting for obstructive jaundice, with the intent of relieving symptoms. We describe a case in which the medical team and a patient and family are considering a second palliative biliary stent despite the patient's limited life expectancy. We review available evidence to inform the decision, focusing on the specific question of whether the benefits of palliative biliary stents in patients with advanced cancer outweigh the risks. We then apply the evidence to the issue of how the primary and/or palliative care team and the interventionist communicate with patients and their families about the risks and benefits of palliative procedures. Review of the evidence found several prospective case series without control groups that measured patient-centered outcomes. Studies had high attrition rates, results for improvements in symptoms and quality of life were mixed, and rates of complications and short-term mortality were high. In conclusion, the limited evidence does not support that the benefits of palliative biliary stents in this population outweigh the risks. We propose that primary care teams consider and discuss the larger picture of the goals of care with patients and families when considering offering these procedures, as well as benefits and potential harms, and consider involving palliative care services early, before consultation with an interventionist.