Neoadjuvant-Adjuvant or Adjuvant-Only Pembrolizumab in Advanced Melanoma.

BACKGROUND: Whether pembrolizumab given both before surgery (neoadjuvant therapy) and after surgery (adjuvant therapy), as compared with pembrolizumab given as adjuvant therapy alone, would increase event-free survival among patients with resectable stage III or IV melanoma is unknown. METHODS: In a phase 2 trial, we randomly assigned patients with clinically detectable, measurable stage IIIB to IVC melanoma that was amenable to surgical resection to three doses of neoadjuvant pembrolizumab, surgery, and 15 doses of adjuvant pembrolizumab (neoadjuvant-adjuvant group) or to surgery followed by pembrolizumab (200 mg intravenously every 3 weeks for a total of 18 doses) for approximately 1 year or until disease recurred or unacceptable toxic effects developed (adjuvant-only group). The primary end point was event-free survival in the intention-to-treat population. Events were defined as disease progression or toxic effects that precluded surgery; the inability to resect all gross disease; disease progression, surgical complications, or toxic effects of treatment that precluded the initiation of adjuvant therapy within 84 days after surgery; recurrence of melanoma after surgery; or death from any cause. Safety was also evaluated. RESULTS: At a median follow-up of 14.7 months, the neoadjuvant-adjuvant group (154 patients) had significantly longer event-free survival than the adjuvant-only group (159 patients) (P = 0.004 by the log-rank test). In a landmark analysis, event-free survival at 2 years was 72% (95% confidence interval [CI], 64 to 80) in the neoadjuvant-adjuvant group and 49% (95% CI, 41 to 59) in the adjuvant-only group. The percentage of patients with treatment-related adverse events of grades 3 or higher during therapy was 12% in the neoadjuvant-adjuvant group and 14% in the adjuvant-only group. CONCLUSIONS: Among patients with resectable stage III or IV melanoma, event-free survival was significantly longer among those who received pembrolizumab both before and after surgery than among those who received adjuvant pembrolizumab alone. No new toxic effects were identified. (Funded by the National Cancer Institute and Merck Sharp and Dohme; S1801 ClinicalTrials.gov number, NCT03698019.).

Barriers to Clinical Trial Participation: Comparative Study Between Rural and Urban Participants.

BACKGROUND: The National Clinical Trials Network program conducts phase 2 or phase 3 treatment trials across all National Cancer Institute's designated cancer centers. Participant accrual across these clinical trials is a critical factor in deciding their success. Cancer centers that cater to rural populations, such as The University of Kansas Cancer Center, have an additional responsibility to ensure rural residents have access and are well represented across these studies. OBJECTIVE: There are scant data available regarding the factors that act as barriers to the accrual of rural residents in these clinical trials. This study aims to use electronic screening logs that were used to gather patient data at several participating sites in The Kansas University of Cancer Center's Catchment area. METHODS: Screening log data were used to assess what clinical trial participation barriers are faced by these patients. Additionally, the differences in clinical trial participation barriers were compared between rural and urban participating sites. RESULTS: Analysis revealed that the hospital location rural urban category, defined as whether the hospital was in an urban or rural setting, had a medium effect on enrolment of patients in breast cancer and lung cancer trials (Cohen d=0.7). Additionally, the hospital location category had a medium effect on the proportion of recurrent lung cancer cases at the time of screening (d=0.6). CONCLUSIONS: In consideration of the financially hostile nature of cancer treatment as well as geographical and transportation barriers, clinical trials extended to rural communities are uniquely positioned to alleviate the burden of nonmedical costs in trial participation. However, these options can be far less feasible for patients in rural settings. Since the number of patients with cancer who are eligible for a clinical trial is already limited by the stringent eligibility criteria required of such a complex disease, improving accessibility for rural patients should be a greater focus in health policy.

Evaluation of the Durability of the Immune Humoral Response to COVID-19 Vaccines in Patients With Cancer Undergoing Treatment or Who Received a Stem Cell Transplant.

Importance: The durability of the antibody response to COVID-19 vaccines in patients with cancer undergoing treatment or who received a stem cell transplant is unknown and may be associated with infection outcomes. Objective: To evaluate anti-SARS-CoV-2 spike protein receptor binding domain (anti-RBD) and neutralizing antibody (nAb) responses to COVID-19 vaccines longitudinally over 6 months in patients with cancer undergoing treatment or who received a stem cell transplant (SCT). Design, Setting, and Participants: In this prospective, observational, longitudinal cross-sectional study of 453 patients with cancer undergoing treatment or who received an SCT at the University of Kansas Cancer Center in Kansas City, blood samples were obtained before 433 patients received a messenger RNA (mRNA) vaccine (BNT162b2 or mRNA-1273), after the first dose of the mRNA vaccine, and 1 month, 3 months, and 6 months after the second dose. Blood samples were also obtained 2, 4, and 7 months after 17 patients received the JNJ-78436735 vaccine. For patients receiving a third dose of an mRNA vaccine, blood samples were obtained 30 days after the third dose. Interventions: Blood samples and BNT162b2, mRNA-1273, or JNJ-78436735 vaccines. Main Outcomes and Measures: Geometric mean titers (GMTs) of the anti-RBD; the ratio of GMTs for analysis of demographic, disease, and treatment variables; the percentage of neutralization of anti-RBD antibodies; and the correlation between anti-RBD and nAb responses to the COVID-19 vaccines. Results: This study enrolled 453 patients (mean [SD] age, 60.4 [13,1] years; 253 [56%] were female). Of 450 patients, 273 (61%) received the BNT162b2 vaccine (Pfizer), 160 (36%) received the mRNA-1273 vaccine (Moderna), and 17 (4%) received the JNJ-7846735 vaccine (Johnson & Johnson). The GMTs of the anti-RBD for all patients were 1.70 (95% CI, 1.04-2.85) before vaccination, 18.65 (95% CI, 10.19-34.11) after the first dose, 470.38 (95% CI, 322.07-686.99) at 1 month after the second dose, 425.80 (95% CI, 322.24-562.64) at 3 months after the second dose, 447.23 (95% CI, 258.53-773.66) at 6 months after the second dose, and 9224.85 (95% CI, 2423.92-35107.55) after the third dose. The rate of threshold neutralization (≥30%) was observed in 203 of 252 patients (80%) 1 month after the second dose and in 135 of 166 patients (81%) 3 months after the second dose. Anti-RBD and nAb were highly correlated (Spearman correlation coefficient, 0.93 [0.92-0.94]; P < .001). Three months after the second dose, anti-RBD titers were lower in male vs female patients (ratio of GMTs, 0.52 [95% CI, 0.34-0.81]), patients older than 65 years vs patients 50 years or younger (ratio of GMTs, 0.38 [95% CI, 0.25-0.57]), and patients with hematologic malignant tumors vs solid tumors (ratio of GMTs, 0.40 [95% CI, 0.20-0.81]). Conclusions and Relevance: In this cross-sectional study, after 2 doses of an mRNA vaccine, anti-RBD titers peaked at 1 month and remained stable over the next 6 months. Patients older than 65 years of age, male patients, and patients with a hematologic malignant tumor had low antibody titers. Compared with the primary vaccine course, a 20-fold increase in titers from a third dose suggests a brisk B-cell anamnestic response in patients with cancer.

An Open-Label, Randomized, Multi-Center Study Comparing the Sequence of High Dose Aldesleukin (Interleukin-2) and Ipilimumab (Yervoy) in Patients with Metastatic Melanoma.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.

Incidence of Intracranial Melanoma Progression in the Setting of Positive Extracranial Response to Targeted Therapy and Immunotherapy: An Indication for More Frequent Screening in This Population?

Background and objective The incidence of intracranial metastases from melanoma is on the rise. In this study, we aimed to determine the incidence of intracranial disease progression in patients on BRAF/MEK targeted therapy and immunotherapy in the setting of controlled or improving extracranial disease. Methods This was a single-center, retrospective review that involved patients who underwent stereotactic radiosurgery (SRS) for intracranial metastatic melanoma between January 1, 2014, and December 31, 2018. We focused on BRAF/MEK mutation status and dates of treatment with BRAF/MEK targeted therapy, immunotherapy [ipilimumab (Yervoy), nivolumab (Opdivo), or pembrolizumab (Keytruda)], and combination targeted and immunotherapy. Results A total of 51 patients were enrolled: 36 males and 15 females. The average age of the patients was 58.6 years, and 26 among them were BRAF mutation-positive. Seventeen had prior surgery with SRS as adjuvant therapy. The other 34 had SRS as primary treatment. Forty-two patients had extracranial disease present at the time of SRS. There were 34 patients treated with targeted and immune therapy. Overall, 16 patients (47.1%) demonstrated controlled or improving extracranial disease, and 18 (52.9%) demonstrated progressing extracranial disease at the time of SRS. In the subgroup analysis, patients treated with BRAF/MEK targeted therapy demonstrated a 75% rate of extracranial disease control. The extracranial disease was controlled in 43.75% of patients on immunotherapy with intracranial progression, while it was controlled in 30% of patients on both BRAF/MEK targeted therapy and immunotherapy with intracranial progression. Sixteen patients (47.1%) developed intracranial metastasis in our study while having a stable systemic disease with BRAF/MEK targeted therapy, immunotherapy, or a combination of the two. Conclusion Based on our findings, a systemic response to targeted therapy and immunotherapy does not necessarily parallel intracranial protection.

Economics of Using Telemedicine to Supplement Hospice Care in Rural Areas.

Background: Hospice care in rural areas is often characterized by provider shortages and vast geographical service areas to cover, making access to quality end-of-life care challenging. Telemedicine, broadly, is the utilization of interactive televideo (ITV) technology to provide health services over a distance. For over 25 years, telemedicine has been proposed as a solution to address access issues. In 2015, the University of Kansas Medical Center (Kansas City, Kansas) partnered with Hospice Services, Inc. (HSI) (Phillipsburg, Kansas), to augment traditional, face-to-face (FTF) hospice care with hospice care delivered through mobile tablets. Objective: This work examines the costs of TeleHospice (TH) (telemedicine use in hospice care) when compared with the costs of FTF hospice services. Design: Detailed administrative data from July 1, 2018, to December 31, 2018, were analyzed to estimate the costs of service after TH use was inculcated into routine practice. Results: his, which averages a daily census of 34 patients, conducted 257 calls, averaging 28 hours a month. The average time for a TH call was 18 and 17 minutes for nursing and medical director calls, respectively. Through various hospice functions, including administrative, patient, and nonpatient-related connections, HSI saved over $115,000 in staff travel time and mileage reimbursement. Administratively, by hosting their weekly 15-member interdisciplinary meeting through ITV, HSI saved $29,869 of staff travel time and mileage reimbursement. Conclusions: Our estimates indicate substantial cost saving potential with the use of TH services. Further research is needed to assess the effects of TH utilization on the experiences and subsequent cost of hospice care.

Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma.

Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNα gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing. SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone.This article is highlighted in the In This Issue feature, p. 1861.

Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial.

Preclinical modeling suggests that intermittent BRAF inhibitor therapy may delay acquired resistance when blocking oncogenic BRAFV600 in melanoma1,2. We conducted S1320, a randomized, open-label, phase 2 clinical trial (NCT02196181) evaluating whether intermittent dosing of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib improves progression-free survival in patients with metastatic and unresectable BRAFV600 melanoma. Patients were enrolled at 68 academic and community sites nationally. All patients received continuous dabrafenib and trametinib during an 8-week lead-in period, after which patients with non-progressing tumors were randomized to either continuous or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. The trial has completed accrual and 206 patients with similar baseline characteristics were randomized 1:1 to the two study arms (105 to continuous dosing, 101 to intermittent dosing). Continuous dosing yielded a statistically significant improvement in post-randomization progression-free survival compared with intermittent dosing (median 9.0 months versus 5.5 months, P = 0.064, pre-specified two-sided α = 0.2). Therefore, contrary to the initial hypothesis, intermittent dosing did not improve progression-free survival in patients. There were no differences in the secondary outcomes, including overall survival and the overall incidence of treatment-associated toxicity, between the two groups.

Vision loss with pembrolizumab treatment: A report of two cases.

BACKGROUND: Vision loss and other ocular toxicities are rare, but detrimental, side effects of immune checkpoint inhibitors. Herein, we report two patients who developed vision loss while on pembrolizumab treatment. CASES PRESENTATION: Case 1 - A 58-year-old man was started on pembrolizumab for advanced melanoma. He was tolerating the treatment well. After receiving 14 cycles of pembrolizumab, he developed acute bilateral vision loss and occipital headaches. An emergent ophthalmologic evaluation revealed bilateral shallow choroidal effusion with bilateral focal exudative retinal detachment. After excluding other possible etiologies, inflammatory process secondary to pembrolizumab was suspected. Pembrolizumab was stopped, and the patient was started on a course of systemic and topical steroids. His vision improved within days and he recovered completely within two months. Calculated Naranjo Nomogram score was 7 indicating a "probable" correlation; Case 2 - A 57-year-old man with stage IIIC melanoma was started on adjuvant pembrolizumab. After a few weeks of treatments, he reported minor bilateral vision changes that progressively worsened over a period of six months. An ophthalmologic evaluation revealed bilateral posterior uveitis with right optic disc edema. Pembrolizumab-related inflammatory changes were suspected, and he was started on systemic and topical steroids. His symptoms improved within a few weeks and steroids were tapered. He was re-challenged with pembrolizumab and his symptoms quickly re-occurred. Pembrolizumab was stopped indefinitely and the patient again treated with systemic and topical steroids. His symptoms resolved and his vision returned to baseline within two months. The Naranjo Nomogram score was 9 indicating a "definite" correlation. CONCLUSIONS: Vision loss is a serious complication that may occur at any point during treatment with PD-1 inhibitors. Vision loss is very distressing to the patients and their families. It is prudent for practitioners to recognize early vision abnormalities in patients receiving PD-1 antagonists to prevent permanent vision loss.

TeleHospice: A Community-Engaged Model for Utilizing Mobile Tablets to Enhance Rural Hospice Care.

BACKGROUND: In rural communities, providing hospice care can be a challenge. Hospice personnel sometimes travel great distances to reach patients, resulting in difficulty maintaining access, quality, cost-effectiveness, and safety. In 1998, the University of Kansas Medical Center piloted the country's first TeleHospice (TH) service. At that time, challenges with broad adoption due to cost and attitudes regarding technology were noted. A second TH project was launched in early 2017 using newer technology; this article updates that ongoing implementation. METHODS: The Organizational Change Manager was followed for the guided selection of the hospice partner. The University of Kansas Medical Center partnered with Hospice Services, Inc. (HSI), a leader in rural hospice care, providing services to 16 Kansas counties. Along with mobile tablets, a secure cloud-based videoconferencing solution was chosen for ease of use. RESULTS: From August 2017 through January 2018, 218 TH videoconferencing encounters including 917 attendees occurred. Calls were made for direct patient care, family support, and administrative purposes. These TH calls have been shown to save HSI money, and initial reports suggest they may strengthen the communication and relationships between staff, patients, and the patient's family. CONCLUSION: Finding innovative, cost-effective, and community-driven approaches such as TH are needed to continually advance hospice care. TeleHospice's potential to supplement and improve hospice services while reducing costs is significant, but continued research is needed to understand best fit within frontier hospices, to inform future urban applications, and to address reimbursement.

Nivolumab-induced new-onset seronegative rheumatoid arthritis in a patient with advanced metastatic melanoma: A case report and literature review.

Immune-related adverse events have been reported in patients treated with anti-programmed death-1 receptor drugs such as nivolumab. We present a case of a new-onset seronegative rheumatoid arthritis in a patient with metastatic melanoma treated with nivolumab.

Expanding Local Cancer Clinical Trial Options: Analysis of the Economic Impact of the Midwest Cancer Alliance in Kansas.

PURPOSE: Patients benefit from receiving cancer treatment closer to home when possible and at high-volume regional centers when specialized care is required. The purpose of this analysis was to estimate the economic impact of retaining more patients in-state for cancer clinical trials and care, which might offset some of the costs of establishing broader cancer trial and treatment networks. METHOD: Kansas Cancer Registry data were used to estimate the number of patients retained in-state for cancer care following the expansion of local cancer clinical trial options through the Midwest Cancer Alliance based at the University of Kansas Medical Center. The 2014 economic impact of this enhanced local clinical trial network was estimated in four parts: Medical spending was estimated on the basis of National Cancer Institute cost-of-care estimates. Household travel cost savings were estimated as the difference between in-state and out-of-state travel costs. Trial-related grant income was calculated from administrative records. Indirect and induced economic benefits to the state were estimated using an economic impact model. RESULTS: The authors estimated that the enhanced local cancer clinical trial network resulted in approximately $6.9 million in additional economic activity in the state in 2014, or $362,000 per patient retained in-state. This estimate includes $3.6 million in direct spending and $3.3 million in indirect economic activity. The enhanced trial network also resulted in 45 additional jobs. CONCLUSIONS: Retaining patients in-state for cancer care and clinical trial participation allows patients to remain closer to home for care and enhances the state economy.

Searching for cures: Inner-city and rural patients' awareness and perceptions of cancer clinical trials.

Fewer than 5% of cancer patients participate in clinical trials, making it challenging to test new therapies or interventions for cancer. Even within that small number, patients living in inner-city and rural areas are underrepresented in clinical trials. This study explores cancer patients' awareness and perceptions of cancer clinical trials, as well as their perceptions of patient-provider interactions related to discussing cancer clinical trials in order to improve accrual in cancer clinical trials. Interviews with 66 former and current in inner-city and rural cancer patients revealed a lack of awareness and understanding about clinical trials, as well as misconceptions about what clinical trials entail. Findings also revealed that commercials and television shows play a prominent role in forming inner-city and rural patients' attitudes and/or misconceptions about clinical trials. However, rural patients were more likely to hold unfavorable views about clinical trials than inner-city patients. Patient-provider discussions emerged as being crucial for increasing awareness of clinical trials among patients and recruiting them to trials. Findings from this study will inform communication strategies to enhance recruitment to cancer clinical trials by increasing awareness and countering misconceptions about clinical trials.

Economic Costs Avoided by Diagnosing Melanoma Six Months Earlier Justify >100 Benign Biopsies.

New melanoma drugs bring enormous benefits but do so at significant costs. Because melanoma grows deeper and deadlier over time, deeper lesions are costlier due to increased sentinel lymph node biopsy, chemotherapy, and disease-associated income loss. Prior studies have justified pigmented lesion biopsies on a "value per life" basis; by contrast we sought to assess how many biopsies are justified per melanoma found on a purely economic basis. We modeled how melanomas in the United States would behave if diagnosis were delayed by 6 months, eg, not biopsied, only observed until the next surveillance visit. Economic loss from delayed biopsy is the obverse of economic benefit of performing biopsy earlier. Growth rates were based on Liu et al. The results of this study can be applied to all patients presenting to dermatologists with pigmented skin lesions suspicious for melanoma. In-situ melanomas were excluded because no studies to date have modeled growth rates analogous to those for invasive melanoma. We assume conservatively that all melanomas not biopsied initially will be biopsied and treated 6 months later. Major modeled costs are (1) increased sentinel lymph node biopsy, (2) increased chemotherapy for metastatic lesions using increased 5-yr death as metastasis marker, and (3) income loss per melanoma death at $413,370 as previously published. Costs avoided by diagnosing melanoma earlier justify 170 biopsies per melanoma found. Efforts to penalize "unnecessary" biopsies may be economically counterproductive.

J Drugs Dermatol. 2016;15(5):527-532.