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Background: Next-generation sequencing (NGS) for tumor molecular profiling is used in Oncology to identify ‘actionable alterations’ for clinical trials or on/ off-label therapy. ...Tumor NGS can also reveal potentially heritable germline mutations. The frequency of such incidental germline mutations has been estimated to be 4-15%. The 2015 ASCO Statement supports communication of medically relevant incidental germline findings from somatic mutation profiling to patients (PTS). The impact of tumor NGS testing on hereditary cancer risk assessment programs in the context of a wider population management strategy is unknown. We sought to evaluate this within our Kaiser Permanente Northern California (KPNC) population with ready access to tumor NGS and an ongoing hereditary cancer risk assessment program. Methods: Kaiser Permanente Northern California (KPNC) is part of a large, integrated health care system. NGS at KPNC is performed in collaboration with STRATA Oncology, a precision oncology partnership. All NGS results are reviewed by a multidisciplinary KPNC Genomic Oncology Committee (GOC)which also includes genetic counselors and pathologists. We examined all NGS reports between November 2017 through December 2019 to determine the types of cancers tested, number with a possible germline mutation and number referred for genetic counseling and testing (GCT). Results: 4,825 PTS with advanced cancer underwent STRATA NGS testing. A total of 207 PTS (4.3%) were identified as potential germline mutation carriers, all 207 were recommended for GCT referral. Of these, 92 (45.0%) separately met 2020 NCCN Criteria for Genetic/Familial High-Risk Assessment (2020NG/FA), prior to tumor NGS; 115 (53.6%) did not and 3 (1.4%) had insufficient information. The cancers most frequently meeting NCCN criteria were pancreatic, breast and colon. Of the 92 PTS who met 2020NG/FA, 60 (65%) underwent GCT and 34 (57%) were confirmed to have a germline mutation. Of the 115 PTS that did not meet 2020NG/FA, 47 (41%) underwent GCT and 19 (40%) were confirmed to have a germline mutation. Overall germline mutations were confirmed in 16.5% of patients who did not meet 2020NG/FA and 37% who did. Conclusions: In our community-based integrated healthcare system, systematic review of next-generation sequencing results by an expert GOC led to more robust identification of germline mutation carriers and navigated them to appropriate GCT. Ongoing work will clarify data on cascade testing. We are currently developing automated workflows for GCT.
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Background: We assessed whether or not adjuvant pembrolizumab given over 1 year would improve OS and RFS in comparison to high dose ipilimumab (ipi10) or HDI - the two FDA-approved ...adjuvant treatments for high risk resected melanoma at the time of study design. Methods: Patients age 18 or greater with resected stages IIIA(N2), B, C and IV were eligible. Patients with CNS metastasis were excluded. At entry, patients must have had complete staging and adequate surgery to render them free of melanoma including completion lymph node dissection for those with sentinel node positive disease. Prior therapy with PD-1 blockade, ipilimumab or interferon was not allowed. Two treatment arms were assigned based on stratification by stage, PD-L1 status (positive vs. negative vs. unknown), and intended control arm (HDI vs. Ipi10). Patients enrolled between 10/2015 and 8/2017 were randomized 1:1 to either the control arm (1) interferon alfa-2b 20 MU/m2 IV days 1-5, weeks 1-4, followed by 10 MU/m2/d SC days 1, 3, and 5, weeks 5-52 (n=190), or (2) ipilimumab 10 mg/kg IV q3w for 4 doses, then q12w for up to 3 years (n=465), or the experimental arm pembrolizumab 200 mg IV q3w for 52 weeks (n=648). The study had three primary comparisons: 1) RFS among all patients, 2) OS among all patients, 3) OS among patients with PD-L1+ baseline biopsies. Results: 1,426 patients were screened and 1,345 patients were randomized with 11%, 49%, 34%, and 6% AJCC7 stage IIIA(N2), IIIB, IIIC and IV, respectively. This final analysis was performed per-protocol 3.5 years from the date the last patient was randomized, with 512 RFS and 199 OS events. The pembrolizumab group had a statistically significant improvement in RFS compared to the control group (pooled HDI and ipi10) with HR 0.740 (99.618% CI, 0.571 to 0.958). There was no statistically signifcant improvement in OS in the 1,303 eligible randomized overall patient population with HR 0.837 (96.3% CI, 0.622 to 1.297), or among the 1,070 (82%) patients with PD-L1 positive baseline biopsies with HR 0.883 (97.8% CI, 0.604 to 1.291). Gr 3/4/5 event rates were as follows: HDI 69/9/0%, ipi10 43/5/0.5% and pembrolizumab 17/2/0.3%. Conclusions: Pembrolizumab improves RFS but not OS compared to HDI or ipi10 in the adjuvant treatment of patients with high-risk resected melanoma. Pembrolizumab is a better tolerated adjuvant treatment regimen than HDI or Ipi10. Support: NIH/NCI NCTN grants CA180888, CA180819, CA180820, CA180863; and in part by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Editorial Acknowledgement: With special thanks to Elad Sharon, MD, MPH, and Larissa Korde, MD, MPH. National Cancer Institute, Investigational Drug Branch, for their contributions to this trial, as well as Nageatte Ibrahim, MD, and Sama Ahsan, MD Merck. Clinical trial information: NCT02506153.
A diagnosis of melanoma requires multidisciplinary specialized care across all stages of disease. Although many important advances have been made for the treatment of melanoma for local and advanced ...disease, barriers to optimal care remain for many patients who live in areas without ready access to the expertise of a specialized melanoma center. In this article, we review some of the recent advances in the treatment of melanoma and the persistent challenges around the world that prevent the delivery of the best standard of care to patients living in the community. With the therapeutic landscape continuing to evolve and newer more complex drug therapies soon to be approved, it is important to recognize the many challenges that patients face and attempt to identify tools and policies that will help to improve treatment outcomes for their melanoma.
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Background: Four immune checkpoint inhibitors have been FDA approved from 2011 to 2016. Immune checkpoint inhibitors function differently from chemotherapy and have different ...benchmarks for response as well as different side effect profiles. This report examines how oncologists in two large medical groups have introduced these new treatments into their practices. Kaiser Permanente is a large HMO which insures 8.5 million members in the state of California and has an exclusive contract with 2 large medical groups to care for its members. There are over 200 medical oncologists caring for KP members practice at over 35 medical centers. The care of the KP members has been documented in an EPIC based medical record systems since 2006. Methods: The Pharmacy Research Outcomes Group has conducted a retrospective cohort study looking at patients who initiated Checkpoint inhibitors between March 2011 and September 2016 for this review and followed the patients till December 2016. Electronically available data collected for this review includes patient characteristics such as but not exclusive to: cancer diagnosis, previous therapies, current therapies, age, sex, ethnicity, immune related adverse events (IRAEs) proxy by diagnosis code, duration of immunotherapy, use of systemic steroids, Charlson Co-morbity Index and survival. Results: We reviewed a total of 1760 users of Checkpoint Inhibitors. We show the uptake of this class of medications aligns with approved checkpoint inhibitors and the new indications of these agents. We were able to electronically pull medical information and define IRAEs. Our data closely matches the expected incidence of IRAEs as reported in clinical trials. We were also able to monitor the use of steroids in response to these events. Conclusions: The ability to collect and track this information has allowed the group to better understand patient selection practices as well as management practices in the community practice setting.
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Background: Checkpoint inhibitors (CI) are rapidly changing the treatment (Tx) landscape across multiple cancers. They have brought with them a new set of immune-related toxicities ...and complications . Currently, our knowledge of irAEs has been largely informed by clinical trials enrolling younger and fitter pts. In this study, we report the experience of our large community practice, where many elderly pts of diverse backgrounds received PDIs. Methods: We conducted a retrospective cohort study, including pts who were ≥65 years old (yo) and had received PDIs between FDA approval in 2014 and September 2016, with follow-up through December 2016. Through data-mining of our electronic medical record, we evaluated the incidence of irAE and Tx outcomes, stratified by age, ethnicity, gender, co-morbidity index, and tumor subtype. Results: There were 776 pts included in the analysis. 58% were male and 29% were non-Caucasian. 83% were ages 65 to 79 yo and 17% were ≥80 yo (range 80-94 yo). 28 % of pts had a CCI > 5. Over 55% received PDIs for non-small cell lung cancer (NSCLC), followed by 12% for melanoma. 65-79 yo pts experienced similar incidence of irAE compared to pts ≥80 yo (14% vs 18%, p = 0.26). Notably, incidence was similar for gastrointestinal, pulmonary, and endocrine toxicity, though pts ≥80 yo experienced higher incidence of dermatologic toxicity (p = 0.01). Pts 65-79 yo received PDIs for median 3.3 months (mos), while pts ≥80 yo were on Tx for median 2.8 mos.The rate of irAE that resulted in health care utilization were noted in 15% of pts. Time to onset of irAE was similar between the 2 age groups (p = 0.40). Unadjusted hazard ratio (HR) for survival at the end of study was similar for pts 65-79 yo and ≥80 yo who had melanoma (HR = 0.99, p = 0.97) or NSCLC (HR = 1.32, p = 0.12). Conclusions: This is the first report of Tx outcomes with PDI use in elderly pts in a real-world setting. We found irAE rates and Tx outcomes to be similar for pts age 65-79 yo and those ≥ 80 yo. With rising cancer incidence among an ageing population, it is important for the oncology community to understand how CI therapy affects older pt groups to improve their cancer outcomes.
Abstract
Background: BRAF and MEK inhibitors yield objective responses in the majority of BRAFV600E/K mutant melanoma patients, but acquired resistance limits response durations. Preclinical data ...suggests that intermittent dosing of these agents may delay acquired resistance by deselecting tumor cells that grow optimally in the presence of these agents. S1320 is a randomized phase 2 clinical trial designed to determine whether intermittent versus continuous dosing of dabrafenib and trametinib improves progression-free survival (PFS) in patients with advanced BRAFV600E/K melanoma.
Methods: All patients received continuous dabrafenib and trametinib for 8-weeks after which non-progressing patients were randomized to receive either continuous treatment or intermittent dosing of both drugs on a 3-week-off, 5-week-on schedule. Unscheduled treatment interruptions of both drugs for > 14 days were not permitted. Responses were assessed using RECIST v1.1 at 8-week intervals scheduled to coincide with on-treatment periods for patients on the intermittent dosing arm. Adverse events were assessed using CTCAE v4 monthly. The design assumed exponential PFS with a median of 9.4 months using continuous dosing, 206 eligible patients and 156 PFS events. It had 90% power with a two-sided α = 0.2 to detect a change to a median with an a priori hypothesis that intermittent dosing would improve the median PFS to 14.1 months using a Cox model stratified by the randomization stratification factors.
Results: 242 patients were treated and 206 patients without disease progression after 8 weeks were randomized, 105 to continuous and 101 to intermittent treatment. 70% of patients had not previously received immune checkpoint inhibitors. There were no significant differences between groups in terms of baseline patient characteristics. The median PFS was statistically significantly longer, 9.0 months from randomization, with continuous dosing vs. 5.5 months from randomization with intermittent dosing (p = 0.064). There was no difference in overall survival between groups (median OS = 29.2 months in both arms p = 0.93) at a median follow up of 2 years. 77% of patient treated continuously discontinued treatment due to disease progression vs. 84% treated intermittently (p = 0.34).
Conclusions: Continuous dosing with the BRAF and MEK inhibitors dabrafenib and trametinib yields superior PFS compared with intermittent dosing.
Support: NIH/NCI grants CA180888, CA180819, CA180820
Citation Format: Alain Algazi, Megan Othus, Adil Daud, Roger Lo, Janice Mehnert, Thach-Giao Truong, Robert Conry, Kari Kendra, Gary Doolittle, Joseph I. Clark, Michael Messino, Dennis F. Moore, Christopher Lao, Bryan A. Faller, Rangaswamy Govindarajan, Amy Harker-Murray, Luke Dreisbach, James Moon, Kenneth Grossman, Antoni Ribas. SWOG S1320: Improved progression-free survival with continuous compared to intermittent dosing with dabrafenib and trametinib in patients with BRAF mutated melanoma abstract. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT013.
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Background: S1320 is a phase 2 randomized clinical trial presented at the 2020 AACR Annual Meeting in April demonstrating that continuous dosing of dabrafenib and trametinib ...yields longer PFS than intermittent dosing of these agents in patients with BRAF
V600E/K
melanoma. Here we look at the association between prior exposure to ICB and PFS in patients randomized to either intermittent or continuous dosing on S1320. Methods: Patients without disease progression after 8 weeks of dabrafenib and trametinib were randomized 1:1 to proceed with intermittent therapy (3-week-off, 5-week-on) or to stay on the continuous daily dosing schedule. The design called for 206 randomized patients with the primary outcome of PFS. Response assessments were made using RECIST v1.1 at 8-week intervals. A post-hoc analysis assessed differences in PFS in the pool of all randomized patients based on prior exposure to anti-PD1 antibodies, a randomization stratification factor. Kaplan-Meier estimates and multivariable Cox regression models (controlling for pre-randomization age, Zubrod performance status, LDH, unknown primary, M-Stage) were used to evaluate the association between this stratification factor and PFS. Results: Of 242 patients treated on study, 105 were randomized to continuous dosing, 101 to intermittent dosing, and 36 were not randomized due to disease progression at 8 weeks or other factors. 37% of the 242 enrolled and 37% of the 206 randomized patients had previously been treated with ICB. Among all randomized patients, there were no differences in baseline characteristics comparing patients with and without prior immune checkpoint inhibitor exposure: age median 62 vs 59, LDH elevation 37% vs 39%,, stage IVB/C 73% vs 64%, Zubrod performance status 0, 57% vs 58%. PFS was longer in patients with prior ICB exposure (hazard ratio = 0.60, 95% confidence interval 0.41,-0.98, median = 6 vs 9 months from randomization, 8 vs 11 months from starting treatment). There was no difference in the association between prior ICB exposure and PFS between arms (interaction p-value = 0.62). Conclusions: In patients without early progression on dabrafenib and trametinib, PFS was longer with prior to exposure to ICB . Although the groups had similar baseline characteristics and rates of randomization, these results could still be influenced by non-controlled factors influencing clinicians’ decisions to start a patient on immune versus targeted therapy. Clinical trial information: NCT02196181.
Abstract
Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and c-KIT approved for use in renal cell carcinoma (RCC). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models ...suggest that HDACi-mediated epigenetic modulation of VEGF expression prevents PAZ resistance and potentiates efficacy. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors with an expansion cohort in RCC.
Methods: The primary endpoint was the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary endpoints included pharmacokinetics (PK) and efficacy. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) with at a starting dose of 400 mg/day and 45 mg/m2 orally twice daily respectively. An alternate ABX dosing schedule days 1-4, 8-11, and 15-18 was investigated (schedule B) due to toxicity of Schedule A.
Results: 52 patients (pts) (RCC; N = 23) with advanced solid tumors were enrolled (N = 22 schedule A; N = 30 schedule B). There were six dose-limiting toxicities including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ? 3 related adverse events observed were fatigue (13%), thrombocytopenia (12%), and diarrhea (10%). The MTD was PAZ 800 mg/day + ABX 45 mg/m2 BID on schedule B. 8 evaluable pts (19%) (N = 6 RCC; 2 thyroid; median number of prior lines of therapy = 3) achieved partial tumor response (PR), with median duration of response of 9.2 months (1-33.2+). 7/9 (78%) of pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 15 out of 48 evaluable pts (31%) experienced stable disease or better for ? 6 months, and two previously PAZ-refractory pts with PRs remain on study for > 20 and 37 mos respectively. PK analyses did not reveal drug-drug interaction. Degree of histone acetylation and metabolomic profile are being evaluated.
Conclusion: The combination of PAZ + ABX was well tolerated and durable tumor control (> 3 yrs) was observed in RCC and thyroid cancer. Tumor regressions observed in majority of PAZ-refractory tumors preliminarily support the potential of ABX to reverse therapeutic resistance. A randomized phase 2 study with cross-over design is planned to further evaluate the combination of PAZ + HDACi.
Citation Format: Rahul Aggarwal, Scott Thomas, Jennifer Grabowsky, Armand Harb, Jim Leng, Anne Reinert, Ilaria Mastroserio, Thach-Giao Truong, Pamela N. Munster. Abexinostat (ABX) as a means to reverse pazopanib (PAZ) resistance: a phase I study in advanced solid tumor malignancies. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT016.
We conducted a randomized phase 3 trial to evaluate whether adjuvant pembrolizumab for one year (648 patients) improved recurrence-free survival (RFS) or overall survival (OS) in comparison to ...high-dose interferon alfa-2b for one year or ipilimumab for up to three years (655 patients), the approved standard-of-care adjuvant immunotherapies at the time of enrollment for patients with high-risk resected melanoma. At a median follow-up of 47.5 months, pembrolizumab was associated with significantly longer RFS than prior standard-of-care adjuvant immunotherapies (hazard ratio HR 0.77; 99.62% confidence interval CI 0.59–0.99; P=0.002). There was no statistically significant association with OS among all patients (HR, 0.82; 96.3% CI 0.61–1.09; P=0.15). Proportions of treatment-related adverse events of grades 3 to 5 were 19.5% with pembrolizumab, 71.2% with interferon alfa-2b, and 49.2% with ipilimumab. Therefore, adjuvant pembrolizumab significantly improved RFS but not OS compared to the prior standard-of-care immunotherapies for patients with high-risk resected melanoma.
Abstract Introduction: BCC is a common form of skin cancer that shares treatment-related aspects with the more well-studied skin malignancy, melanoma, including sensitivity to anti-PD-1/PD-L1 ...immunotherapy. However, despite major advances in peri-operative immunotherapy for melanoma, little is known regarding these strategies in BCC. This phase 1B, single-arm study evaluated neoadjuvant-adjuvant treatment with pembrolizumab (PEMBRO) together with standard of care (SOC) resection in advanced BCC of the head and neck. Methods: Eligible patients had resectable, locally advanced BCC of the head and neck, defined by at least one of the following high-risk characteristics: a measurement of ≥ 20 mm, indication for post-operative radiation, or perineural invasion (PNI) in multiple nerves. Patients were naive to hedgehog inhibitors (HHI) and had an ECOG of 0 or 1. All patients received IV PEMBRO at a dose of 200 mg every 3 weeks for a total of 4 cycles, then within 4 weeks underwent a SOC resection followed by adjuvant PEMBRO until a total of 17 cycles was completed. After the 30-day post treatment safety follow-up visit, patients were followed for up to 5 years post-operatively. The primary endpoint was pathological response rate. Secondary endpoints included RECIST response by radiographic or physical exam, adverse events (AE), and recurrence-free survival (RFS). Results: 13 patients were enrolled in the trial from July 2020 to May 2023, and received at least one dose of PEMBRO. Two patients withdrew from the trial after one dose of PEMBRO, one following treatment-related G3 hepatitis and a second due to an unrelated medical complication (cholecystitis). Out of 11 patients undergoing surgical resection, 10 patients received 4 out of 4 and 1 patient received 3 out of 4 planned cycles of neoadjuvant PEMBRO (investigator preference without new related AE). Pathological complete response (pCR) was observed in 3 patients (23%). For those with RECIST measurable disease, 2 patients demonstrated a complete response (CR), 1 patient a partial response (PR), and 5 patients showed stable disease (SD). Two patients had progressive disease (PD). One patient with a complete pathologic response had a discordant RECIST response with PD noted radiographically. All 13 patients experienced at least one AE of G1 or 2. The highest grade of related AEs were noted in 2 patients with grade 3 hepatitis and pruritus respectively that resolved with supportive therapy. As of November 2023, the median follow-up time is 17.6 months with no recurrences noted. Conclusions: Neoadjuvant-adjuvant PEMBRO shows promising efficacy and an acceptable safety profile in resectable advanced BCC of the head and neck. Given these positive results and the healthcare burden BCC accounts for, these findings warrant further study. Citation Format: Grace M. Jones, James Isaacs, Lucy Boyce Kennedy, Jennifer Ko, Allison Vidimos, Alok Vij, Christine Poblete-Lopez, Jennifer Lucas, Yee Peng Phoon, Melissa McEnery-Stonelake, Jon Meine, Thach-Giao Truong, Pauline Funchain, Brian Gastman. Neoadjuvant-adjuvant pembrolizumab in resectable advanced basal cell carcinoma of the head and neck: An open-label, single-arm, phase 1b trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7518.
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