Try a new search

Format these results:

Searched for:

person:pavlia01

Total Results:

277


Germline immunomodulatory expression quantitative trait loci (ieQTLs) associated with immune-related toxicity from checkpoint inhibition

Ferguson, Robert; Chat, Vylyny; Morales, Leah; Simpson, Danny; Monson, Kelsey R; Cohen, Elisheva; Zusin, Sarah; Madonna, Gabriele; Capone, Mariaelena; Simeone, Ester; Pavlick, Anna; Luke, Jason J; Gajewski, Thomas F; Osman, Iman; Ascierto, Paolo; Weber, Jeffrey; Kirchhoff, Tomas
BACKGROUND:Immune checkpoint inhibition (ICI) has improved clinical outcomes for metastatic melanoma patients; however, 65-80% of patients treated with ICI experience immune-related adverse events (irAEs). Given the plausible link of irAEs with underlying host immunity, we explored whether germline genetic variants controlling the expression of 42 immunomodulatory genes were associated with the risk of irAEs in melanoma patients treated with the single-agent anti-CTLA-4 antibody ipilimumab (IPI). METHODS:We identified 42 immunomodulatory expression quantitative trait loci (ieQTLs) most significantly associated with the expression of 382 immune-related genes. These germline variants were genotyped in IPI-treated melanoma patients, collected as part of a multi-institutional collaboration. We tested the association of ieQTLs with irAEs in a discovery cohort of 95 patients, followed by validation in an additional 97 patients. RESULTS:We found that the alternate allele of rs7036417, a variant linked to increased expression of SYK, was strongly associated with an increased risk of grade 3-4 toxicity [odds ratio (OR) = 7.46; 95% confidence interval (CI) = 2.65-21.03; p = 1.43E-04]. This variant was not associated with response (OR = 0.90; 95% CI = 0.37-2.21; p = 0.82). CONCLUSION/CONCLUSIONS:We report that rs7036417 is associated with increased risk of severe irAEs, independent of IPI efficacy. SYK plays an important role in B-cell/T-cell expansion, and increased pSYK has been reported in patients with autoimmune disease. The association between rs7036417 and IPI irAEs in our data suggests a role of SYK overexpression in irAE development. These findings support the hypothesis that inherited variation in immune-related pathways modulates ICI toxicity and suggests SYK as a possible future target for therapies to reduce irAEs.
PMID: 37301715
ISSN: 1879-0852
CID: 5535092

Phase 1 study of the pan-RAF inhibitor tovorafenib in patients with advanced solid tumors followed by dose expansion in patients with metastatic melanoma

Rasco, Drew W; Medina, Theresa; Corrie, Pippa; Pavlick, Anna C; Middleton, Mark R; Lorigan, Paul; Hebert, Chris; Plummer, Ruth; Larkin, James; Agarwala, Sanjiv S; Daud, Adil I; Qiu, Jiaheng; Bozon, Viviana; Kneissl, Michelle; Barry, Elly; Olszanski, Anthony J
PURPOSE/OBJECTIVE:Genomic alterations of BRAF and NRAS are oncogenic drivers in malignant melanoma and other solid tumors. Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan‑RAF inhibitor. This first-in-human phase 1 study explored the safety and antitumor activity of tovorafenib. METHODS:This two-part study in adult patients with relapsed or refractory advanced solid tumors included a dose escalation phase and a dose expansion phase including molecularly defined cohorts of patients with melanoma. Primary objectives were to evaluate the safety of tovorafenib administered once every other day (Q2D) or once weekly (QW), and to determine the maximum-tolerated and recommended phase 2 dose (RP2D) on these schedules. Secondary objectives included evaluation of antitumor activity and tovorafenib pharmacokinetics. RESULTS:Tovorafenib was administered to 149 patients (Q2D n = 110, QW n = 39). The RP2D of tovorafenib was defined as 200 mg Q2D or 600 mg QW. In the dose expansion phase, 58 (73%) of 80 patients in Q2D cohorts and 9 (47%) of 19 in the QW cohort had grade ≥ 3 adverse events. The most common of these overall were anemia (14 patients, 14%) and maculo-papular rash (8 patients, 8%). Responses were seen in 10 (15%) of 68 evaluable patients in the Q2D expansion phase, including in 8 of 16 (50%) patients with BRAF mutation-positive melanoma naïve to RAF and MEK inhibitors. In the QW dose expansion phase, there were no responses in 17 evaluable patients with NRAS mutation-positive melanoma naïve to RAF and MEK inhibitors; 9 patients (53%) had a best response of stable disease. QW dose administration was associated with minimal accumulation of tovorafenib in systemic circulation in the dose range of 400-800 mg. CONCLUSIONS:The safety profile of both schedules was acceptable, with QW dosing at the RP2D of 600 mg QW preferred for future clinical studies. Antitumor activity of tovorafenib in BRAF-mutated melanoma was promising and justifies continued clinical development across multiple settings. GOV IDENTIFIER/UNASSIGNED:NCT01425008.
PMCID:10261210
PMID: 37219686
ISSN: 1432-0843
CID: 5508322

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A.; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S.; Rahma, Osama E.; Suarez-Almazor, Maria E.; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35"“3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95"“5.66), P =.054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P =.53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
SCOPUS:85175548637
ISSN: 2162-4011
CID: 5616442

Overall survival (OS) in patients treated with adjuvant nivolumab (NIVO): Comparison of data from the phase 3 randomized Checkmate 238 (CM238) trial with real world (RW) data [Meeting Abstract]

Moser, J; Bhatia, S; Amin, A; Pavlick, A C; Betts, K; Du, E; Poretta, T; Moshyk, A; Sakkal, L A; Palaia, J; Lobo, M; Benito, M P; Kadakia, R; Chen, Y; Xu, C; Yin, L; Sundar, M; Weber, J
In CM238, 76% of patients (pts) with high-risk resected melanoma (MEL) treated with adjuvant NIVO were alive at 5 years, but there is limited RW data to validate these findings in a similar patient population. This study compared the OS of pts treated with adjuvant NIVO in CM238 vs. RW pts. Pts with stage III resected MEL (AJCC 8th edition) who received adjuvant NIVO were selected from CM238 and the nationwide Flatiron Health electronic health record-derived de-identified database (the RW cohort). Pts in the RW cohort were required to meet the eligibility criteria in CM238 where possible. OS/real-world OS (rwOS) were evaluated using Kaplan-Meier methods and compared using Cox proportional hazards models after adjusting for key prognostic baseline variables (age, sex, race, disease stage, time from surgical resection to index date, ECOG, and comorbidities) between the two cohorts. In the RW cohort, 492 pts with resected stage III MEL received adjuvant NIVO and 320 pts met the eligibility criteria of CM238. Compared with pts in the CM238 cohort, pts in the RW cohort were older (median: 64 vs. 56 years), heavier (91 vs. 82 kg), had a higher proportion of diabetes (9% vs. 6%) and ECOG PS 1 (17% vs. 10%), and had slightly more stage IIIA (4% vs. 1%), less stage IIIB (29% vs. 32%), and similar stage IIIC (63% vs. 63%) and stage IIID (4% vs. 5%). Before adjustment, pts in the RW cohort had a higher risk of mortality compared with pts in the CM238 cohort (HR: 1.46; 95% CI, 1.00 to 2.13; p < 0.05). After adjusting for differences in key patient characteristics, OS was similar between the two cohorts (HR: 1.12; 95% CI, 0.68 to 1.84, p = 0.66). In conclusion, pts with stage III resected MEL treated with adjuvant NIVO in the RW setting had OS similar to those in CM238 after adjusting for key prognostic factors
EMBASE:640045833
ISSN: 1755-148x
CID: 5511232

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases

Reid, Pankti; Sandigursky, Sabina; Song, Juhee; Lopez-Olivo, Maria A; Safa, Houssein; Cytryn, Samuel; Efuni, Elizaveta; Buni, Maryam; Pavlick, Anna; Krogsgaard, Michelle; Abu-Shawer, Osama; Altan, Mehmet; Weber, Jeffrey S; Rahma, Osama E; Suarez-Almazor, Maria E; Diab, Adi; Abdel-Wahab, Noha
Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.
PMCID:10732692
PMID: 38126033
ISSN: 2162-402x
CID: 5626492

Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma

Khushalani, Nikhil I; Vassallo, Melinda; Goldberg, Judith D; Eroglu, Zeynep; Kim, Younchul; Cao, Biwei; Ferguson, Robert; Monson, Kelsey R; Kirchhoff, Tomas; Amato, Carol M; Burke, Paulo; Strange, Ann; Monk, Emily; Gibney, Geoffrey Thomas; Kudchadkar, Ragini; Markowitz, Joseph; Brohl, Andrew S; Pavlick, Anna; Richards, Alison; Woods, David M; Weber, Jeffrey
BACKGROUND:Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS:Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS:High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS:Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER:NCT01176474 and NCT02970981.
PMCID:9717375
PMID: 36450385
ISSN: 2051-1426
CID: 5374052

Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma

Weber, Jeffrey S; Levinson, Benjamin A; Laino, Andressa S; Pavlick, Anna C; Woods, David M
Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction. The endpoints of the trial were safety, definition of a recommended phase 2 dose, preliminary assessment of response, and correlative marker determination. Patient PBMC and serum samples collected at baseline and on-treatment were assessed by flow cytometry and Luminex assays for immune correlates. Ten patients were treated: nine with 70-mg and one with 50-mg mocetinostat. In the 70-mg cohort, eight patients had objective responses. The patient in the 50-mg cohort had an early progression of disease. All patients had grade 2 or higher toxicities, and six had grades 3 and 4 toxicities. Patient PBMC showed significant decreases in myeloid-derived suppressor cells and trends towards reduced anti-inflammatory monocyte phenotypes. Patient serum showed significant upregulation of granzyme A and TNF and trends towards increased granzyme B and IFNγ. Collectively, combining CPI and mocetinostat had favorable response rates but with high levels of toxicity. Assessment of immune correlates supports a shift away from immunosuppressive phenotypes towards enhanced immune responses.
PMID: 35678233
ISSN: 1473-5636
CID: 5248472

Safety and Effectiveness of Immune Checkpoint Inhibitors Combination versus Single Agent Therapy in Patients with Pre-existing Autoimmune Diseases [Meeting Abstract]

Reid, P; Sandigursky, S; Lopez-Olivo, M A; Song, J; Safa, H; Cytryn, S; Buni, M; Pavlick, A; Krogsgaard, M; Abu-Shawer, O; Altan, M; Weber, J; Suarez-Almazor, M; Diab, A; Abdel-Wahab, N
Background/Purpose: Treatment with a combination of immune checkpoint inhibitors (ICI) has promising outcomes in many tumor types but carries higher adverse event risk than ICI monotherapy. Also, patients with pre-existing autoimmune disease (AID) have largely been excluded from ICI clinical trials due to concern for pre-existing AID flare or immune-related adverse events (irAEs). This is the first study to analyze safety and effectiveness of ICI combination versus monotherapy for this at-risk population.
Method(s): We conducted a multi-center retrospective study in patients with pre-existing AIDs receiving ICIs (i.e., antiprogrammed cell death protein 1 (PD-1) single-agent (monotherapy) or ICI combination). Primary endpoints included the time to occurrence of any-type ICI AE (irAE or AID flare), time to irAEs and time to AID flares in the presence of the competing risk of death with progression free survival (PFS, time to progression or death) and overall survival (OS) as secondary endpoints. We used Fine-Gray models and Cox regression models to investigate the factors associated with these endpoints.
Result(s): 133 patients with pre-existing AID who received ICIs were identified: 69 (52%) monotherapy and 64 (48%) combination (Table 1). About half the patients had melanoma (44%) and 25% had lung cancer. Rheumatic (34%) or dermatologic (22%) pre-existing AIDs were the most common. Most patients (95%) had controlled autoimmune disease at ICI start. Six of 7 patients with active AID at baseline experienced some AE. Patients receiving baseline DMARD(s) were more likely to experience an AE (95%CI 1.079-2.996, p=0.024). The cumulative incidence of irAEs was higher for ICI combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.28, 95%CI 1.36-3.84), adjusting for age at malignancy, but there was no significant difference between rate of high-grade toxicity for patients treated with ICI combination versus monotherapy (See Figure 1). On subgroup analysis for patients with melanoma or lung cancer, the cumulative incidence of irAEs or AID flares were not statistically different between treatment groups. PFS was longer (but not statistically significant) for combination therapy for any tumor type compared to single agent (median 12.3mo, 95%CI 5.0-23.2 versus 7.3mo, 95%CI 5.2-11.3, p=0.116). Similar trend was noted for PFS for melanoma (median 23.2mo combination vs. 14.0mo monotherapy, p=0.4237), while the opposite relation was noted for lung cancer subgroup (4.4mo combination vs. 7.1mo monotherapy, p=0.2933).
Conclusion(s): Efficacy of ICI combination versus monotherapy was not statistically significant and so still remains unclear in this patient population, but there was no significant difference in rates of high-grade toxicity between the two cohorts. Our data supports the notion that patients with pre-existing AIDs should not be indiscriminately precluded from getting ICI combination. Our results provide guidance for future prospective clinical trials studying combination therapy for subgroups of this at-risk population. No statistically significant difference appreciated in high grade adverse events between patients with pre-existing autoimmune disease treated with ICI combination versus monotherapy. Grading determined by the Common Terminology Criteria for Adverse Events rubric with grade 3 or higher considered "high grade."
EMBASE:639967125
ISSN: 2326-5205
CID: 5512972

Significant survival improvements for patients with melanoma brain metastases: can we reach cure in the current era?

Berger, Assaf; Bernstein, Kenneth; Alzate, Juan Diego; Mullen, Reed; Silverman, Joshua S; Sulman, Erik P; Donahue, Bernadine R; Pavlick, Anna C; Gurewitz, Jason; Mureb, Monica; Mehnert, Janice; Madden, Kathleen; Palermo, Amy; Weber, Jeffrey S; Golfinos, John G; Kondziolka, Douglas
PURPOSE/OBJECTIVE:New therapies for melanoma have been associated with increasing survival expectations, as opposed to the dismal outcomes of only a decade ago. Using a prospective registry, we aimed to define current survival goals for melanoma patients with brain metastases (BM), based on state-of-the-art multimodality care. METHODS:We reviewed 171 melanoma patients with BM receiving stereotactic radiosurgery (SRS) who were followed with point-of-care data collection between 2012 and 2020. Clinical, molecular and imaging data were collected, including systemic treatment and radiosurgical parameters. RESULTS:SRS were predictors of long-term survival ([Formula: see text] 5 years) from initial SRS (p = 0.023 and p = 0.018, respectively). Five patients (16%) of the long-term survivors required no active treatment for [Formula: see text] 5 years. CONCLUSION/CONCLUSIONS:Long-term survival in patients with melanoma BM is achievable in the current era of SRS combined with immunotherapies. For those alive [Formula: see text] 5 years after first SRS, 16% had been also off systemic or local brain therapy for over 5 years. Given late recurrences of melanoma, caution is warranted, however prolonged survival off active treatment in a subset of our patients raises the potential for cure.
PMID: 35665462
ISSN: 1573-7373
CID: 5248172

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of nonmelanoma skin cancer

Silk, Ann W; Barker, Christopher A; Bhatia, Shailender; Bollin, Kathryn B; Chandra, Sunandana; Eroglu, Zeynep; Gastman, Brian R; Kendra, Kari L; Kluger, Harriet; Lipson, Evan J; Madden, Kathleen; Miller, David M; Nghiem, Paul; Pavlick, Anna C; Puzanov, Igor; Rabinowits, Guilherme; Ruiz, Emily S; Sondak, Vernon K; Tavss, Edward A; Tetzlaff, Michael T; Brownell, Isaac
Nonmelanoma skin cancers (NMSCs) are some of the most commonly diagnosed malignancies. In general, early-stage NMSCs have favorable outcomes; however, a small subset of patients develop resistant, advanced, or metastatic disease, or aggressive subtypes that are more challenging to treat successfully. Recently, immune checkpoint inhibitors (ICIs) have been approved by the US Food and Drug Administration (FDA) for the treatment of Merkel cell carcinoma (MCC), cutaneous squamous cell carcinoma (CSCC), and basal cell carcinoma (BCC). Although ICIs have demonstrated activity against NMSCs, the routine clinical use of these agents may be more challenging due to a number of factors including the lack of predictive biomarkers, the need to consider special patient populations, the management of toxicity, and the assessment of atypical responses. With the goal of improving patient care by providing expert guidance to the oncology community, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). The expert panel drew on the published literature as well as their own clinical experience to develop recommendations for healthcare professionals on important aspects of immunotherapeutic treatment for NMSCs, including staging, biomarker testing, patient selection, therapy selection, post-treatment response evaluation and surveillance, and patient quality of life (QOL) considerations, among others. The evidence- and consensus-based recommendations in this CPG are intended to provide guidance to cancer care professionals treating patients with NMSCs.
PMID: 35902131
ISSN: 2051-1426
CID: 5276872