Dose Of Pembrolizumab Research Articles

A case of chronic lymphocytic leukemia with a paraneoplastic neurologic syndrome and leptomeningeal disease

Abstract Purpose Chronic lymphocytic leukemia (CLL) is a hematologic malignancy characterized by overproduction of monoclonal B cells. Paraneoplastic neurologic syndrome (PNS) and leptomeningeal disease (LMD) associated with CLL are both rare entities. We present a unique case that is, to our knowledge, the second reported case of CLL associated with Kelch-like protein 11– (KLHL11-) PNS and the first case of CLL with both LMD and KLHL11-PNS. Methods/results The patient was a 68-year-old woman who developed abdominal pain, nausea, vomiting, and vertigo. Imaging revealed retroperitoneal lymphadenopathy. After further studies, including flow cytometry, she was diagnosed with CLL. She received one dose of pembrolizumab with ibrutinib, and months later received three doses of Obinutuzumab, which were discontinued due to their side effects. The patient reported excessive fatigue, temporal headache, nausea, vomiting, vertigo, tremor of the upper extremities, and head bobbing. Lumbar puncture was positive for CLL cells, and the CSF paraneoplastic panel was positive for KLHL11 antibodies, with a titer of 1:64. She received intravenous immunoglobulin, intravenous methylprednisolone, plasmapheresis, intravenous rituximab, and Zanubrutinib, with minimal response. She was then prescribed intrathecal rituximab, which caused slight clinical improvement. Complete response was noted via CSF cytology. About 4 months later, she underwent Ommaya placement and received intraventricular rituximab. Her symptoms persisted despite improvement in CSF cytology, likely due to persistent PNS that was difficult to treat. Conclusion KLHL11-PNS is a rare disease entity that often evolves clinically into treatment-refractory rhombencephalitis. Though PNS and LMD management strategies may overlap, their clinical outcomes may be discordant.

RTID-03. A MULTICENTER, RANDOMIZED, CONTROLLED TRIAL OF FOCUSED-ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER DISRUPTION PLUS SYSTEMIC PEMBROLIZUMAB FOR PATIENTS WITH NSCLC BRAIN METASTASES (LIMITLESS)

Abstract BACKGROUND Systemic therapy for brain metastases (BM) is hindered by blood-brain barrier (BBB). Low-intensity focused ultrasound (LIFU), combined with IV microbubble oscillators, leads to non-invasive BBB disruption, which could enhance intracranial delivery of systemic immune checkpoint inhibitors. This randomized controlled trial (RCT) aims to evaluate safety and efficacy of LIFU-mediated BBB disruption plus systemic pembrolizumab for NSCLC BM. METHODS LIMITLESS (NCT05317858) is an ongoing, multicenter, parallel-arm, open-label RCT that randomizes NSCLC BM patients on standard-of-care pembrolizumab monotherapy to LIFU plus pembrolizumab (arm 1) or pembrolizumab alone (arm 2) in a 2:1 ratio. Included patients have age ≥18 years, normal organ function, KPS ≥70, EGFR- and ALK-negative primary tumor, and ≤3 BM with ≥1 BM meeting RANO-BM measurable disease criteria. All patients receive standard-of-care therapy, while those on arm 1 undergo LIFU before each pembrolizumab dose (200mg IV q3weeks). Patients undergo pre-treatment brain MRI, followed by IV microbubbles for enhanced sonication effects. MR-guided BBB disruption is performed using transcranial 220kHz LIFU device with real-time acoustic-feedback-based power control for maintaining effective microbubble activation. Pembrolizumab is infused immediately after sonication, and repeat MRI is done 24-48 hours later to assess treatment effects. Primary study outcome is overall objective response rate (ORR) at 6 months as assessed using RANO-BM. Using Bayesian design for power analysis, a superior ORR of 60% is assumed for LIFU arm versus 30% for control arm for total sample size of N=96 (64 participants in LIFU and 32 in control arm), for 80% power using two-sided chi-square test with alpha=0.05. For upper-bound estimate, ORR of 45% in LIFU arm and 30% in control arm, the study needs N=369 participants (246 in LIFU arm and 123 in control arm). Secondary outcomes are best ORR and median time-to-response. Exploratory outcomes are median progression-free survival (PFS), overall survival (OS), median intracranial PFS, median extracranial PFS, and quality of life. Patient enrollment commenced in 2022 and remains ongoing.

Pembrolizumab Induced Recall Dermatitis Occurring 5 Years After Radiotherapy

Background and Clinical Significance: Radiation recall dermatitis (RRD) following immune checkpoint inhibitor (ICI) therapy has been infrequently reported. Case Presentation: We present a 47-year-old female patient who developed RRD of the breast following three doses of pembrolizumab administered as an adjuvant treatment post-nephrectomy for Stage III renal cell carcinoma (RCC). Notably, the affected breast had previously undergone external beam radiotherapy 247 weeks earlier for Stage IA invasive ductal carcinoma. She had received no prior chemotherapy at any point. RRD manifested as breast induration, erythema, and peau d’orange, and contraction of breast volume was noted following three cycles of pembrolizumab on week 17 (400 mg dose every 6 weeks). The dermatitis responded rapidly to systemic corticosteroids and no treatment interruption was needed. Conclusion: To date, this is the longest reported interval from completion of radiotherapy to RRD. A literature search underscores the variability in presentation and management of ICI-associated RRD.

Effect of alternative dosing strategies of pembrolizumab and nivolumab on health-care emissions in the Netherlands: a carbon footprint analysis

Hospitals contribute substantially to greenhouse gas emissions and face a moral obligation to prioritise emission reduction. Drugs constitute an important component of the greenhouse gas emissions of hospitals. Alternative dosing strategies (ADS) have been implemented to improve the cost-effectiveness of pembrolizumab and nivolumab. However, the impact of these ADS on greenhouse gas emissions remains unknown. Therefore, we aimed to analyse the effect of ADS implementation on the carbon emissions of treatment with pembrolizumab and nivolumab. We used a process-based lifecycle assessment to quantify the environmental impact of pembrolizumab and nivolumab, focused on equivalent carbon dioxide emissions (CO2e). Lifecycle inventory and impact data from Erasmus University Medical Center (Rotterdam, Netherlands) were used to calculate the CO2e for pembrolizumab and nivolumab, their dosing intervals, and the impact of ADS on CO2e. The functional unit of the study was the administration of a single dose of pembrolizumab or nivolumab. In 2022, the annual carbon emissions related to pembrolizumab and nivolumab treatment in the Erasmus University Medical Center were 445 tons of CO2e, averaging 94 kg of CO2e per dose. Pharmaceutical production was the main driver of treatment-related carbon emissions (mean 92·9% of total emissions). Applying ADS resulted in 21-26% and 9-11% CO2e reductions for pembrolizumab and nivolumab, respectively. This study shows the environmental impact of pembrolizumab and nivolumab treatment and calls for further implementation of ADS for pembrolizumab, nivolumab, and other anti-PD-(L)1 monoclonal antibodies, and more sustainable pharmaceutical production processes. Our findings create environmental awareness and contribute to the promotion and understanding of health-care practices with lower carbon emissions. None.

12459 Exceptional Response To A Single Dose Of Pembrolizumab As Salvage Therapy In A Patient With Metastatic Adrenocortical Carcinoma (ACC)

Abstract Disclosure: L. Branchaud-Croisetière: None. J. Castilloux: None. E. Turcotte: None. A. Bégin: None. M. St-Jean: Advisory Board Member; Self; GlaxoSmithKline, HRA Pharmaceuticals. Research Investigator; Self; AstraZeneca, Novo Nordisk, Spruce Biosciences. Speaker; Self; GlaxoSmithKline, Recordati Rare Diseases. In advanced ACC, limited effective treatment options are available beyond mitotane and cytotoxic chemotherapy. PD-L1 blockade has shown promising results in small numbers of advanced ACC. In ACC, the reported partial response rate to pembrolizumab is around 25%.[1] Only one case of a significant partial response to a single dose of Pembrolizumab as salvage therapy for metastatic ACC was previously published.[1] In April 2023, a 19-year-old woman presented with severe hypertension, hypokalemia and clinical signs of Cushing syndrome (CS). Thoraco-abdominal scan revealed a left-sided cluster of confluent adrenal masses (7.3 x 14.4 x 11.4 cm), a left cortical renal lesion (2.8x2x2.1cm), a right ovarian teratoma (7.9 x 7.8x7.9 cm) and at least 25 pulmonary micronodules. FDG-PET SCAN revealed a significant hypermetabolism of the left adrenal lesions (SUV 18.6), ovarian teratoma (SUV 5.5) and pulmonary micronodules (SUV 1.1-2). Cortisol and androgens secretion was confirmed biochemically. Initially, she was not candidate for a debulking surgery because the tumor was surrounding the aorta, and mesenteric arteries. Hypertension and hypokalemia were treated with spironolactone, amlodipine, amiloride and irbesartan. Cushing syndrome was treated with metyrapone. In April 2023, Etoposide-Doxorubicine-Cisplatin (EDP) was administered in combination with Mitotane (max: 8g/day). After 6 cycles of EDP-M the disease regressed slightly but was considered stable based on RECIST criteria. After 8 cycles, the follow-up imaging showed a progression of the adrenal lesion (9.2x18.2cm) but stable pulmonary micronodules. A biopsy of the adrenal lesion, for therapeutic purpose, revealed microsatellite stability (MSS). The patient refused germinal genetic testing. It was decided in multidisciplinary tumor board to try Pembrolizumab. In December 2023, she received one cycle of Pembrolizumab (140mg), but the treatment was complicated by grade 4 immune-mediated hepatitis. A few weeks following Pembrolizumab she completely normalized her blood pressure and hypokalemia despite cessation of all her anti-hypertensive drugs. Pembrolizumab and Mitotane were stopped and hepatitis completely resolved after two months of Mycophenolate Mofetil and ongoing decreasing dose of prednisone. In March 2024, CT scan showed a 60% regression of the adrenal mass (4.1 x 7.2 cm), stability of the renal lesion and ovarian teratoma and complete resolution of the pulmonary micronodules. We suspect an ongoing effect of immunotherapy and Mitotane, since Mitotane levels were still in the therapeutic range (15.1 mg/L) six weeks following cessation. Mitotane was resumed in March 2024. The patient will potentially have a resection of the left adrenal lesion in the next month. This is second published case of a significant response to Pembrolizumab as second-line therapy for advanced ACC. [1] Raj Net al. J Clin Oncol. 2020 Presentation: 6/1/2024

Successful use of therapeutic plasma exchange for the management of acute lung transplant rejection secondary to immune checkpoint inhibitor therapy

The use of immune checkpoint inhibitors (ICIs) in individuals with a history of solid organ transplantation is fraught with the emergence of solid organ transplantation rejection (SOTR). The current recommendations for the management of SOTRs secondary to ICI include the use of high-dose steroids along with the escalation of immunosuppressive therapy. Therapeutic Plasma Exchange (TPE) has been described to be effective in managing various immune-related toxicities, however, the data for using TPE in the setting of acute SOTRs induced by ICIs are limited. Herein, we describe the successful use of TPE in a patient with a history of bilateral lung transplantation who developed an episode of mixed acute cellular and antibody-mediated lung transplant rejection after a single dose of PD-1 inhibitor Pembrolizumab for the treatment of underlying melanoma.

1258MO Low dose versus standard dose pembrolizumab for treatment of stage IV stage non-small cell lung carcinoma: Results of the pre-planned interim analysis of the NVALT-30 clinical trial

1258MO Low dose versus standard dose pembrolizumab for treatment of stage IV stage non-small cell lung carcinoma: Results of the pre-planned interim analysis of the NVALT-30 clinical trial

Real-world overall survival after alternative dosing for pembrolizumab in the treatment of non-small cell lung cancer: A nationwide retrospective cohort study with a non-inferiority primary objective

BackgroundHigh and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. MethodsThis is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. ResultsDistribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48–8.04 mg/day) vs. 9.15 mg/day (IQR:8.33–9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69–1.003). ConclusionThis large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs.

Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC.

195 Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with the addition of targeted therapy to IO, an established first-line paradigm in some other cancer types (RCC), but historically challenging in NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640). Methods: Patients (pts) with advanced KRAS G12C mutant NSCLC (tissue or plasma) in any treatment line, including prior KRAS G12Ci and/or prior IO were eligible. Dose escalation of olomorasib plus pembrolizumab followed a mTPI-2 method. Safety was evaluated across all pts dosed with the combination. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Results: As of 30 October 2023, 50 pts with advanced NSCLC received 50-150 mg BID PO olomorasib plus 200 mg Q3W pembrolizumab. Median age was 66 yrs (range, 42-83), median number of prior systemic therapies was 2 (range, 0-8), and 34% had received a prior KRAS G12Ci. During escalation, 2 of 6 ptstreated at 150 mg BID developed grade ³3 LFTs, precluding further evaluation of this dose. In 44 pts treated at 50 or 100 mg BID, TRAEs ≥10% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%), fatigue (14%), nausea (14%) and pruritus (11%); grade 3 TRAEs in ≥10% of pts were diarrhea (16%); pneumonitis was seen in 3 pts (grades 2/3/4). TRAEs led to olomorasib dose reduction in 14% of pts, olomorasib dose hold in 27%, and pembrolizumab dose hold in 18%. Due to TRAEs, 9% of pts discontinued olomorasib or pembrolizumab and 9% discontinued both. 27 pts remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among the 30 efficacy evaluable KRAS G12Ci-naïve pts (60% IO pre-treated, 60% chemotherapy pre-treated), at a median follow-up of 6 months (95% CI, 4-7) ORR was 63% (15 PR, 4 unconfirmed PR pending/ongoing; 95% CI, 44-80) and DCR was 93% (28/30; 95% CI, 78-99); the median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 <50%/unknown (3 pts PD-L1 unavailable). In 9 first-line pts, ORR was 78% (6 PR, 1 unconfirmed PR pending/ongoing; 95% CI, 40-97) and DCR was 100%. Conclusions: Olomorasib (50 or 100 mg BID) in combination with pembrolizumab demonstrated favorable safety and antitumor activity in pts with KRAS G12C-mutant advanced NSCLC, supporting further development in first-line NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .

Ramucirumab in combination with pembrolizumab for recurrent or metastatic head and neck squamous cell carcinoma: a single-centre, phase 1/2 trial

VEGF, a key mediator of angiogenesis and resistance to immunotherapy, is overexpressed in head and neck squamous cell carcinoma (HNSCC). We aimed to determine the recommended phase 2 dose of ramucirumab, a selective VEGFR2 inhibitor, given with pembrolizumab and the objective response rate of this combination as first-line treatment for recurrent or metastatic HNSCC. In this single-centre, phase 1/2 trial, which was done at Washington University (St Louis, MO, USA), eligible patients were aged 18 years or older with incurable recurrent or metastatic HNSCC and an Eastern Cooperative Oncology Group performance status of 0-2. Patients in phase 2 were required to have had no previous systemic therapy for recurrent or metastatic disease. In a dose de-escalation phase 1 design, patients received ramucirumab (starting dose 10 mg/kg given intravenously) and pembrolizumab (200 mg intravenously) on day 1 of each 21-day cycle. The recommended phase 2 dose of ramucirumab was defined as the highest dose at which one or fewer of three patients had dose-limiting toxicity during cycle one (primary endpoint of phase 1). In a Simon's two-stage phase 2 design, patients received the recommended phase 2 dose of ramucirumab and pembrolizumab. Tumour response (primary endpoint of phase 2) was assessed by Response Evaluation Criteria in Solid Tumours (version 1.1). We hypothesised that there would be an objective response rate of 32% or higher (null ≤13%). Eight or more responses among 33 evaluable patients (those with at least one response assessment) was evidence for activity (80% power; one-sided α=0·05). Analyses were done per protocol. The trial is registered with ClinicalTrials.gov, NCT03650764, and is closed to enrolment. Between June 18, 2019, and Feb 11, 2021, three patients enrolled and were treated in phase 1 and 37 patients in phase 2. Median age of all patients was 64 years (IQR 59-72). 36 (90%) of 40 patients were men and four (10%) were women, and 36 (90%) patients were White, three (8%) were Black or African American, and one (3%) was Asian. In phase 1, no dose-limiting toxicity event occurred. The recommended phase 2 dose of ramucirumab was 10 mg/kg. Median follow-up for patients on phase 2 was 14·8 months (IQR 4·9-31·0). In phase 2, 18 (55%; 95% CI 38-70) of 33 evaluable patients had an objective response, including confirmed complete response in 11 patients, confirmed partial response in six patients, and unconfirmed partial response in one patient. The most common grade 3 or worse adverse events were dysphagia (14 [38%] of 37 patients), lung infection (11 [30%]), lymphocyte count decrease (ten [27%]), hypophosphataemia (nine [24%]), and hypertension (eight [22%]). No treatment-related deaths were recorded. Ramucirumab and pembrolizumab were safe to administer to patients with recurrent or metastatic HNSCC, and the objective response rate with this combination as first-line treatment for recurrent or metastatic HNSCC was favourable. Further studies of ramucirumab and pembrolizumab in patients with recurrent or metastatic HNSCC are warranted. Lilly and the Joseph Sanchez Foundation.

FDG-PET associations with pathological response and survival with neoadjuvant immunotherapy for melanoma.

9523 Background: This study sought to describe the changes seen with FDG-PET following neoadjuvant immunotherapy in melanoma patients (pts), and explore associations with pathological response and recurrence-free survival (RFS). Methods: Two prospective clinical trial cohorts of stage III pts with RECIST measurable nodal melanoma were included; 1) NeoTrio, 13 pts received 2 doses of preoperative pembrolizumab alone, and 2) NeoPele, 20 pts received 2 doses of pembrolizumab and 5 weeks of lenvatinib preoperatively. All pts underwent baseline and week 6 (preoperative) FDG-PET assessments and all had surgery. PET responses were evaluated based on the modified EORTC criteria. In addition to the standard categories Complete Metabolic Response (CMR), Partial Metabolic Response (PMR), Stable Metabolic Disease (SMD), and Progressive Metabolic Disease (PMD), a novel category was established, near-CMR, where the maximum standardized uptake value (SUVmax) decreased by more than 90%. PET responses were determined while blinded to the outcome data. Pathological response was determined as per INMC criteria. Results: 33 pts were included, 67% male, median age 65 years, 48% BRAF mutant. Pathological response, PET response and correlations are shown in the Table. All 8 (24%) pts achieving CMR or near-CMR obtained major pathologic response (MPR), while the 14 pts (42%) with PMR had variable pathological outcomes (57% MPR, 21% pPR, 21% pNR). For the 6 pts with PMD, 5 (83%) had pNR and the one pts who achieved pCR recurred with brain metastases. After a median 29.9 mo follow-up (95% CI 27.0-33.1), PET response associated with RFS; those with CMR/near CMR had 100% 24mo RFS (nil recurrences to date) while those with PMR or SMD had inferior survival (79% and 80% 24mo RFS), and those with PMD the worst outcomes (17% 24mo RFS, all pts except one have recurred) (p=0.0029). The predictive value of PET and pathology for RFS was assessed using the Cox Proportional Hazards model. 12- and 24-month RFS AUCs of PET and pathology response were similar at 81.5% (95% CI: 67.7-95.3) vs. 80.9% (95% CI: 67.8-93.9), and 83.3% (95% CI: 69.1-97.5%) vs. 80.8% (95% CI: 66.6-94.9), respectively. Conclusions: FDG-PET demonstrates utility in predicting pathological response and survival with neoadjuvant immunotherapy in melanoma. PET may identify pts who are not going to be pathological responders and who have the worst survival outcomes, enabling a potential switch of neoadjuvant systemic therapy. [Table: see text]

Different dosing strategies of pembrolizumab in the treatment of NSCLC: A real-world retrospective observational study.

e23264 Background: Immune checkpoint inhibitors lack a dose-response relationship, allowing optimisation of dosing strategies that may reduce drug use. Pembrolizumab received its initial regulatory approval for the treatment of non-small cell lung cancer (NSCLC) at weight-based dosing (2 mg/kg every 3 weeks (Q3W)), as employed in pivotal clinical trials demonstrating its efficacy and safety. This dosing regimen was later replaced by the currently approved flat-dosing (200 mg Q3W or 400 mg Q6W) in all indications, potentially increasing drug use. This retrospective observational study evaluates differences in pembrolizumab use for different dosing strategies in a real-world patient cohort. Methods: Overall, 124 advanced NSCLC patients, treated with first-line pembrolizumab monotherapy at a single institution, were included. During the observation period, pembrolizumab flat-dosing was employed, with possible extensions of treatment administrations. Patient and treatment data were obtained from medical records. Duration of treatment was calculated from day 1 of first cycle to last day of last cycle, excluding treatment delays due to adverse events. Pembrolizumab use was calculated for 3 dosing strategies: i) as actually received, ii) as flat-dosing, iii) as body-weight dosing, capped at 200 mg Q3W. It is presented as median dose Q3W and cummulative dose in the whole cohort. Results: Included patients had a median weight of 73 kg (IQR: 65-84) and received a total of 1600 mg of pembrolizumab (IQR: 800-3600) over 24 weeks (IQR: 12-60). The median pembrolizumab dose was i) 190 mg Q3W (IQR: 172-200) as actually received by patients, and would be ii) 200 mg Q3W (IQR: 200-200) in case of flat dosing, and iii) 146 mg Q3W (IQR: 130-168) in case of body-weight dosing. Overall, total pembrolizumab dose in the whole cohort was i) 283,600 mg actually used, and would be ii) 327,800 mg in flat-dosing, and iii) 251,200 mg body-weight dosing, resulting in a 23.4% reduction of drug use in weight-adjusted vs flat-based dosing. Conclusions: Pembrolizumab dosing adjusted to body weight, as initially approved, would reduce drug use vs the currently approved flat-dosing, reaching nearly a 25% reduction in our cohort of patients.

INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (<65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .

First-line pembrolizumab for lung cancer in a Spanish real-world study.

e23268 Background: KEYNOTE (KN) 024 trial showed that pembrolizumab significantly improves progression free survival (PFS) and overall survival (OS) in patients with previously untreated advanced non-small cell lung cancer (NSCLC) with a PD-L1 expression ≥ 50% without EGFR/ALK alterations. The main aim of this study is to report the outcomes (PFS and OS) of pembrolizumab in a real life setting. Methods: Multicenter retrospective study in 42 Spanish hospitals. Inclusion period: 01/2016 – 07/2020; cut-off date: 31/12/2021. Demographic, clinical and treatment-related data were retrospectively obtained from patients’ medical files. Statistical analysis was carried out using descriptive metrics and survival analysis techniques (Kaplan-Meier, log-rank test, Cox regression). Results: In our cohort of 1005 patients, 74.5% were males, mean age was 66.4 ± 9.7 and mean BMI 25.6 ± 4.6. The majority were current (35.6%) or former smokers (56.6%), with 11 % of patients with ECOG ≥ 2. Patients with a non squamous histology were 79.5% and 95.2% were classified as IV stage (30.3% had hepatic and/or brain metastases, 49.3% had ≥ 2 metastatic sites). Pembrolizumab dose was mainly fixed (83.1% of patients), while the number of treatment cycles was highly variable. 31.8% received concurrent radiotherapy, while previous corticoid (PCE), antibiotic and proton pump inhibitors (PPI) exposure were 18.2%, 7.7% and 40.7% respectively. With a median follow-up of 6.3 months, median OS and PFSwere 19 (95%CI: 16.2 – 21.3) and 8.7 (95%CI: 7.2 – 10.1) months. Several variables were associated with PFS and OS after univariate survival analysis. Age and previous antibiotic exposure were associated to worse OS but not to PFS. Multivariate analysis showed that ECOG ≥2 (HR 2.7 95%CI 2-3.5) and previous PPI exposure (HR 1.3 95%CI 1.1-1.6) were predictors of poor outcome. Conclusions: In our cohort, pembrolizumab showed lower OS and similar PFS than KN 024. Our results confirm that poor PS (ECOG) is a negative predictive factor for effectiveness. [Table: see text]

Intravesical local administration of pembrolizumab for treatment of bladder cancer: A novel strategy to minimize toxicity.

e14687 Background: A major hallmark of bladder cancer (BCa) is a higher treatment success rate than prostate cancer following stimulation of innate anti-tumor immune response either by intravesical BCG or to FDA approved intravenous anti-PD1 checkpoint antibody (pembrolizumab) approved for BCG resistant BCa since 2021. However, injected pembrolizumab is characterized by a markedly higher incidence (66%) of serious adverse events than the median duration of complete response of ~40% for non-muscle invasive BCa (NMIBC) and 15-20% for invasive BCa. Since the toxicity (fatigue, Pneumonitis and diarrhea) of injected pembrolizumab is linked to systemic breakdown of T-cell mediated immune surveillance we enquired whether analogous to BCG, pembrolizumab can be administered intravesically to safely induce a localized anti-tumor response in mouse model of BCa. Methods: Six weeks old female mice of B6D2F1 strain (n=10) were ad libitum fed carcinogen, N-butyl-N-4-hydroxybutyl nitrosamine (BBN) in drinking water (0.05% w/v) for 12 weeks. The presence of BBN evoked tumor was ascertained by unenhanced T2 weighted MRI at week 11 prior to single intravesical dosing by 24G transurethral catheter under isoflurane anesthesia of 0.1mL vehicle (sterile water) with or without 0.3mg of Pembrolizumab (Lipella Pharmaceuticals). 6 weeks later, T2 weighted MRI was repeated together with T1 mapping by ICE-MRI prior to organ harvest. Results: BBN feeding evoked multiclonal tumors (red*) of comparable size on T2 weighted MRI at week 11 but repeat MRI 7 weeks after treatment revealed that tumor progression and perivesical invasion noted in vehicle group was arrested in pembrolizumab group. Longest dimension of BBN tumor in vehicle treated mice was ≥ 1mm longer (p<0.05) than in pembrolizumab treated mice. T1 mapping revealed thickened bladder wall missed by T2 MRI. Conclusions: These findings on single intravesical dose of pembrolizumab (10mg/kg) in mice are consistent with human study on multiple intravesical dosing of BCG plus pembrolizumab (1-2mg/kg) in BCG resistant NMIBC patients. Intravesical pembrolizumab mirrors the limited systemic uptake of radiolabelled antibodies together with substantially higher ingress into tumor foci. The tumor selective ingress for BCa immunotherapy without any toxicity will be enhanced with Lipella Pharmaceutical’s liposomal delivery of Pembrolizumab.

Risk of VTE in TNBC treated with neoadjuvant immunotherapy.

e12658 Background: Triple-negative breast cancer (TNBC) has limited treatment options. KEYNOTE 522 led to the approval of neoadjuvant (NT) Pembrolizumab in July 2021 changing the treatment paradigm for early stage TNBC. While improving pathologic complete response it also slightly increased treatment related adverse events. Some studies show increased risk of venous thromboembolism (VTE) with Pembrolizumab; however, it is unclear if immunotherapy (IO) increases the risk of VTE in a NT setting. Breast cancer is not classically associated with high risk for VTE. Here, we assess the incidence of VTE in TNBC patients receiving NT Pembrolizumab. Methods: All women diagnosed with TNBC and treated with NT Pembrolizumab between August 2021-December 2023 (t = 29 months) at our institution were included (N = 26). Stage 4 disease at time of diagnosis was excluded. The study endpoint was the development of VTE at any time following the initiation of Pembrolizumab as identified by CT chest angiography or venous duplex ultrasound. Risk factors and protective factors for VTE including body mass index, prior VTE, concurrent chest port, illicit drug use, smoking, hypertension, diabetes, kidney disease, hyperlipidemia, and prior antiplatelet/anticoagulant use were assessed for each patient. Results: In our study population, 1 patient developed VTE following initiation of Pembrolizumab (3.8%). This patient developed a pulmonary embolism 13 days after the 2nd dose of Pembrolizumab (179 days after 1st dose). Risk factors for this patient were obesity (BMI = 52.9), concurrent chest port, and hypertension. Protective factors included no prior history of VTE, illicit drug use, smoking, diabetes, kidney disease, or hyperlipidemia. A comparison of the risk factors is summarized (Table). Conclusions: The cumulative VTE incidence for all immune therapies is reported as 7-10% in the 1st year. Patients with breast cancer have a 6% incidence of VTE in the 1st year. This rate does not account for cancer subtype, stage, or treatment type. Our exploratory study is novel in looking at incidence of VTE in the NT immunotherapy use setting. These results suggest a lower incidence compared to the cumulative studies previously mentioned. There is a possible synergistic interaction between Pembrolizumab therapy and other traditional risk factors in the development of VTE in TNBC. Further analysis will seek to stratify the individual risk of Pembrolizumab in VTE compared to other risk factors. Future work will include expanding our study population to additional solid tumors utilizing NT Pembrolizumab including melanoma and non-small cell lung carcinoma. Once risk is definitively established, it will be important to take measures to mitigate the risks to improve cancer related outcomes. [Table: see text]

Effect of alternative dosing strategies on sustainable healthcare: A carbon footprint analysis of nivolumab and pembrolizumab treatment in the Netherlands.

e13564 Background: Hospitals contribute significantly to greenhouse gas (GHG) emissions and face a moral obligation to prioritize reduction of GHG emissions. Drugs constitute an important component of the GHG emissions of hospitals. Alternative dosing strategies (ADS) have been implemented to improve the cost-effectiveness of pembrolizumab and nivolumab (Table). However, the impact of these ADS on GHG emissions remains unknown. Therefore, this study aimed to analyse the effect of ADS implementation on the carbon footprint of treatment with pembrolizumab and nivolumab. Methods: Life Cycle Assessment (LCA) methodology was used to quantify the environmental impact. The impact category climate change was used to quantify the carbon emissions (CO2e). The GHG Protocol was used to categorize the emissions into scopes 1, 2 and 3. Life Cycle Inventory and Impact data from an academic hospital in Rotterdam were used in the LCA to calculate the CO2e for pembrolizumab and nivolumab, their different dosing intervals, and the impact of ADS. Results: In 2022, the carbon emissions related to nivolumab and pembrolizumab treatment were 445 tons CO2e, with an average of 94 kg CO2e per dosage. Pharmaceutical production was the main driver of treatment-related GHG emissions (93% of total emissions on average). Applying ADS, resulted in carbon emission reductions of 21.4-26.2% and 9.3-11.2% for pembrolizumab and nivolumab respectively (table 1). Conclusions: This study shows the substantial environmental impact of cancer treatments with pembrolizumab and nivolumab and calls for further implementation of ADS for pembrolizumab and nivolumab and other anti-PD-(L)1 monoclonal antibodies and more sustainable pharmaceutical production processes. These findings help to create environmental awareness and contribute to the promotion and understanding of sustainable low-carbon healthcare practices. Overview of registered doses of pembrolizumab and nivolumab, alternative dosing strategies and potential reductions in GHG emissions, based on real world data in The Erasmus University Medical Center in Rotterdam, the Netherlands. [Table: see text]

Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.

TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .

Efficacy and safety of olomorasib (LY3537982), a second-generation KRAS G12C inhibitor (G12Ci), in combination with pembrolizumab in patients with KRAS G12C-mutant advanced NSCLC.

8510 Background: While immunotherapy (IO) is established as the cornerstone of first-line treatment for KRAS-mutant NSCLC, outcomes remain suboptimal. Further progress may be achieved with the addition of targeted therapy to IO, an established first-line paradigm in some other cancer types (RCC), but historically challenging in NSCLC. Here, we study pembrolizumab plus olomorasib, a potent and highly selective second-generation inhibitor of GDP-bound KRAS G12C, in NSCLC patients treated on LOXO-RAS-20001, a phase 1/2 study of olomorasib in KRAS G12C-mutant solid tumors (NCT04956640). Methods: Patients (pts) with advanced KRAS G12C mutant NSCLC (tissue or plasma) in any treatment line, including prior KRAS G12Ci and/or prior IO were eligible. Dose escalation of olomorasib plus pembrolizumab followed a mTPI-2 method. Safety was evaluated across all pts dosed with the combination. Antitumor activity per RECIST v1.1 was studied in all pts who had ≥1 post-baseline response assessment (PBRA) or had discontinued before the first PBRA. Results: As of 30 October 2023, 50 pts with advanced NSCLC received 50-150 mg BID PO olomorasib plus 200 mg Q3W pembrolizumab. Median age was 66 yrs (range, 42-83), median number of prior systemic therapies was 2 (range, 0-8), and 34% had received a prior KRAS G12Ci. During escalation, 2 of 6 ptstreated at 150 mg BID developed grade ≥3 LFTs, precluding further evaluation of this dose. In 44 pts treated at 50 or 100 mg BID, TRAEs ≥10% (related to olomorasib and/or pembrolizumab) were diarrhea (30%), ALT increased (20%), AST increased (18%), fatigue (14%), nausea (14%) and pruritus (11%); grade 3 TRAEs in ≥10% of pts were diarrhea (16%); pneumonitis was seen in 3 pts (grades 2/3/4). TRAEs led to olomorasib dose reduction in 14% of pts, olomorasib dose hold in 27%, and pembrolizumab dose hold in 18%. Due to TRAEs, 9% of pts discontinued olomorasib or pembrolizumab and 9% discontinued both. 27 pts remain on treatment, and 17 discontinued treatment (10 due to PD, 4 due to AE). Among the 30 efficacy evaluable KRAS G12Ci-naïve pts (60% IO pre-treated, 60% chemotherapy pre-treated), at a median follow-up of 6 months (95% CI, 4-7) ORR was 63% (15 PR, 4 unconfirmed PR pending/ongoing; 95% CI, 44-80) and DCR was 93% (28/30; 95% CI, 78-99); the median PFS was not estimable (95% CI, 5-NE); ORR was 75% (9/12) in PD-L1 ≥50%, 56% (10/18) in PD-L1 < 50%/unknown (3 pts PD-L1 unavailable). In 9 first-line pts, ORR was 78% (6 PR, 1 unconfirmed PR pending/ongoing; 95% CI, 40-97) and DCR was 100%. Conclusions: Olomorasib (50 or 100 mg BID) in combination with pembrolizumab demonstrated favorable safety and antitumor activity in pts with KRAS G12C-mutant advanced NSCLC, supporting further development in first-line NSCLC. A global, registrational study investigating this combination in first-line NSCLC is currently enrolling (SUNRAY-01, NCT06119581). Clinical trial information: NCT04956640 .

International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI).

4007 Background: The optimal second-line treatment for HCC after ICI is not established. Regorafenib is approved for treatment of advanced HCC after sorafenib. The primary aim of this study was to evaluate the activity of regorafenib plus pembrolizumab in patients with advanced HCC who progressed on only one prior ICI regimen. Methods: Patients aged ≥18 years, CP Class A, BCLC stage B or C, and ECOG PS of 0 or 1 received oral regorafenib 90 mg once daily 3 weeks (wk) on/1 wk off plus i.v. pembrolizumab 400 mg every 6 wk. The daily regorafenib dose could be escalated to 120 mg after the first 4-wk cycle of regorafenib if tolerated. Pembrolizumab dose reductions were not allowed. Cohorts were defined by prior treatment: Cohort 1 = atezolizumab + bevacizumab; Cohort 2 = any other ICI regimen (alone or combination). Primary endpoint was overall response rate (ORR) by independent central review (RECIST 1.1). Results: 95 patients were treated in 8 countries; Cohort 2 appeared to have more favorable disease characteristics (Table). Most common prior ICIs in Cohort 2 were durvalumab (30%), nivolumab (30%), ipilimumab (22%), and pembrolizumab (19%). Overall, median follow up was 7.1 months (mo). Median duration of regorafenib/pembrolizumab treatment (including interruptions, delays) was shorter in Cohort 1 vs Cohort 2 (11.0/9.4 wk vs 21.4/24.1 wk). ORR was 5.9% in Cohort 1 and 11.1% in Cohort 2; stable disease rates were 48.5% and 63.0%, respectively. Median PFS was 2.8 mo in Cohort 1 and 4.2 mo in Cohort 2. Overall, treatment-emergent adverse events (TEAE) were grade 3 in 56% of patients and grade 4 in 5%; drug-related grade 3 and 4 TEAE occurred in 37% and 3%, respectively. One patient (Cohort 1) had a grade 5 drug-related TEAE (cardiac arrest). Most common drug-related TEAE were palmar-plantar erythrodysesthesia syndrome (39%), asthenia (33%), decreased appetite (32%), diarrhea (28%), and hypertension (20%). Biomarkers assessed in paired biopsies (baseline and wk 6/day 1) showed on-treatment reductions in macrophages and angiogenesis RNA signatures. Conclusions: To our knowledge, this is the first prospective evaluation of a kinase inhibitor plus an ICI following first-line ICI therapy for HCC. Regorafenib plus pembrolizumab had modest activity in second line after first-line ICI regimens. The safety profile of the combination was consistent with those of either drug. Optimal treatment for patients with advanced HCC who progress after an ICI regimen remains an unmet need. Biomarker findings will be detailed in presentation. Clinical trial information: NCT04696055 . [Table: see text]