Conrad Jacobs

Lymphomas of the head and neck arise in Waldeyer's ring, the salivary glands, nasal cavity, paranasal sinuses, thyroid gland, and orbit. Though anatomically in close proximity, lymphomas arising in these sites have distinct clinical characteristics. Factors that appear to influence the pattern of disease include concurrent conditions, such as Sjögren's syndrome, and geographic factors, particularly with regard to nasal lymphomas. The treatment and prognosis of patients with head and neck lymphoma depends on the histologic grade of disease and extent of involvement at time of presentation. Most lymphomas are of intermediate-grade histology and early stage at presentation. A thorough understanding of clinical disease patterns and treatment options will allow the optimum management of these patients.

15550 Background: High-grade neuroendocrine carcinoma (HGNEC) are rare but aggressive characterized by high mitotic rate. Metastatic disease is incurable. Systemic treatments for HGNEC have been extrapolated from those for small cell lung carcinoma. Effective regimens for HGNEC alone have not been established. The combination of Irinotecan (I), and Cisplatin (P) was evaluated among patients with metastatic or unresectable HGNEC. Methods: Eligible patients were histologically confirmed HGNEC, previously untreated with unresectable or metastatic, measurable disease, adequate bone marrow, renal function, hepatic function and Zubrod performance status < 2. Patients were treated with IP (I 65mg/m2 IV D1+8 and P 25mg/m2 D1+8, every 21 days cycle). Primary endpoints were objective responses and toxicity profile. Response assessed by RECIST every 3 cycles. Dose modification of both drugs was allowed for grade 3/4 toxicities. Results: 20 patients were enrolled from 2003 until 2007, with 19 were evaluable for response and all were evaluable for toxicities. Patients received median of 5 cycles (2–14). 2 (11%) achieved complete response (CR), and 9 (47%) with partial response (PR), with overall objective response in 11 (58%). 3 (16%) attained stable disease (SD) and 5 (26%) with progressive disease (PD). Overall median time to progression (TTP) is 16 weeks (5–43), and among responders TTP 26 weeks (12 weeks for non-responders, p < 0.001). 25 grade 3 toxicities without any patients experiencing grade 4. Specifically, there were 32% leucopenia, 8% anemia, 20% fatigue, 12% nausea, 8% diarrhea, 8% hyponatremia, 4% hypokemia, 4% myalgia, and 4% dyspnea. Total accrual was expected to be 36, but the study was ended early because of slow accrual. Conclusions: The combination of irinotecan and cisplatin is feasible and a well-tolerated option for patients with advanced HGNEC. Responders specifically show a better time to progression. No significant financial relationships to disclose.

Thirty patients with recurrent squamous cell carcinoma of the head and neck were treated with methotrexate (250 mg/m2) followed 1 hour later by 5-FU (600 mg/m2). One patient had a complete response and four had partial responses, for an overall response rate of 16%. The response rate in patients with no prior chemotherapy was 21%. Toxic effects included neutrophenia in ten patients, with one associated death from infection; severe mucositis in three patients; and severe diarrhea in seven patients. Three patients had acute abdominal pain requiring hospitalization, with one associated death. The combination of methotrexate and 5-FU as given in our study was not superior to methotrexate alone and had substantial toxicity.

Abstract Background: Pembrolizumab is approved for use across multiple cancers at a dose of 200 mg or 2 mg/kg Q3W or 400 mg Q6W administered as an IV infusion. Alternative subcutaneous (SC) formulations can provide added convenience and flexibility in the clinic. KEYNOTE-555 (NCT03665597) Cohort A is an open-label, phase 1 study examining the relative bioavailability of 2 different concentrations of pembrolizumab SC formulations versus pembrolizumab IV. Methods: Patients with advanced melanoma were randomly assigned to receive (in a cross-over design) 1 dose of pembrolizumab 200 mg IV and 2 doses of pembrolizumab 285 mg SC (one of each SC formulation) during the first 3 treatment cycles; thereafter, all patients receive pembrolizumab IV for up to 2 years. Bayesian analysis of pembrolizumab serum concentration data collected from 31 patients through cycles 1, 2, and 3 in the current study and previously published pembrolizumab IV data were used to characterize the pharmacokinetics (PK) of pembrolizumab SC. Distribution and elimination parameters, time-dependent clearance, and covariate effects from the previously established pembrolizumab IV PK model were used, as these phases were expected to be similar for IV and SC administrations. Injection site reactions were evaluated by monitoring patients for local skin reactions approximately 1 hour after pembrolizumab SC or IV administration during the first 3 cycles, and through use of a pt questionnaire following monitoring. Results: The model simultaneously described pembrolizumab PK after IV and SC administrations. The SC absorption was characterized by a first-order absorption rate with lag time and bioavailability parameters. The PK of both pembrolizumab SC formulations were similar with an estimated bioavailability of 64% (95% CI, 54-74); this is consistent with the reported bioavailability of other SC monoclonal antibodies that range from 50% to 85%. Inclusion of a covariate effect of the SC formulation on bioavailability, lag time, or absorption rate was not statistically significant, indicating no significant difference between the 2 SC formulations in the absorption phase. In addition, no anti-drug antibody was observed after 3 treatment cycles. In general, pembrolizumab SC formulations were well tolerated over the first 3 cycles, with no significant injection-site reactions. Two grade 2 adverse events (AEs) of pruritus and rash were reported from the SC formulations and IV infusion, respectively; the other AEs were grade 1. Conclusions: The bioavailability of SC pembrolizumab was characterized from KEYNOTE-555 Cohort A data. SC formulations will be further assessed clinically in other tumor types. Citation Format: Conrad R. Jacobs, Bernardo Leon Rapoport, Graham Lawrence Cohen, Mallika Lala, Carolina De Miranda Silva, Pavan Vaddady, Ferdous Gheyas, Dinesh de Alwis, Vikram Sinha, Omobolaji Oyekunle Akala, Elliot Chartash, Lokesh Jain. Pembrolizumab bioavailability after subcutaneous administration: analysis from the KEYNOTE-555 Cohort A in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT143.

9541 Background: In KEYNOTE-555, a model-based approach suggested expected drug exposure with pembro 400 mg Q6W is similar to that observed with approved doses of pembro 200 mg or 2 mg/kg Q3W. The pembro Q6W dose is now approved. We present interim efficacy, safety and PK of 1L pembro 400 mg Q6W for patients (pts) with advanced melanoma in KEYNOTE-555 Cohort B (NCT03665597). Methods: Eligible pts had unresectable stage III or IV melanoma, ECOG PS ≤1, and no prior systemic therapy for advanced disease.Pts received pembro 400 mg Q6W for up to 18 cycles (≈2 years).The primary efficacy endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included PFS by BICR per RECIST v1.1 and safety. PK profile and exposure were evaluated for cycle 1 and steady state (cycle 4). Results: Between May 2019 and Jan 2020, 101 pts were enrolled and received ≥1 dose of pembro. Baseline characteristics were generally similar to pt cohorts of historical pembro studies in advanced melanoma. As of the data cutoff date of August 6, 2020, all pts had ≥6 mo of follow-up and 40.6% of pts had discontinued study treatment. Median (range) duration of treatment and doses administered were 8.2 mo (1 day–13.9 mo) and 6 (1–11) doses, respectively. Observed exposure with pembro 400 mg Q6W had lower variability than model predictions and was within PK parameters from clinical experience with other pembro regimens (Table). ORR was 50.5% (95% CI 40.4–60.6). 12.9% of pts had CR and 37.6% had PR. Median PFS was 13.8 mo (95% CI 3.0–not reached). Estimated PFS rates were 56.5% at 6 mo and 54.3% at 12 mo. Treatment-related AEs of any grade occurred in 79.2% of pts (grade 3–4: 6.9% of pts; no deaths due to a treatment-related AE). The most common immune-mediated AEs were hyperthyroidism (6.9%) and hypothyroidism (6.9%). Conclusions: 1L treatment with pembro 400 mg Q6W yielded a clinically meaningful ORR in pts with advanced melanoma. PK, efficacy and safety results from KEYNOTE-555 Cohort B support prior findings from the model-based assessment and indicate that the benefit-risk profile for the more practical pembro 400 mg Q6W regimen is consistent with that of 200 mg or 2 mg/kg Q3W regimens. Clinical trial information: NCT03665597. [Table: see text]