Staccato pulse interleukin-2 (IL-2) in metastatic melanoma (MM) previously treated with checkpoint inhibitors (CPI).

e21022 Background: The CPI ipilimumab, nivolumab, and pembrolizumab have been adopted into common use for patients (pts) with MM. While their clinical activity is undeniable, a substantial fraction of pts treated with these agents experience disease progression. Additional approaches are therefore needed. Intravenous IL-2 given via daily single intravenous infusions (pulses) has been developed to mitigate toxicity while maintaining anticancer activity against MM. Staccato pulse IL-2 is based on three prior observations. Daily IL-2 schedules have previously been demonstrated to induce Lymphokine Activated Killer cell (LAK) activity [Mitchell, 1989]. LAK generated by IL-2 then subsequently exposed to more IL-2 display enhanced cytotoxicity in vitro [Hank, 1990]. Increased numbers of LAK are seen in pts with melanoma treated with daily IL-2 [Quan, 2011]. Methods: In this retrospective study, ten pts with MM were treated with IL-2 18 Million IU/M2 intravenously over 15-30 minutes on days 1-3 and 21.6 Million IU/M2 intravenously over 15-30 minutes on day 5 on an outpatient basis. Cycles were repeated every 3 weeks. Results: Characteristics: 8 females/ 2 males, median age-56 (range: 21-74), median ECOG-1 (0-1); common disease sites: lymph nodes (12), subcutaneous (6), lungs (5), soft tissue (4). Prior CPI: Ipilimumab (8); Pembrolizumab (5); Nivolumab (2). Common toxicities: nausea/emesis (8), myalgia/arthralgia (5), sinus/catarrhal symptoms (5), fatigue (5), and hypotension requiring intravenous fluids (5). No pts required hospitalization for toxicity related to therapy. Median number of cycles: 3 (2-8). Four pts have had partial responses (total response rate = 40%; 95% CI: 10-70%). The median duration of response exceeds 7.4+ months. One pt having had resolution of prior lung, lymph node, and peritoneal metastases (partial response of 24.5+ months) underwent surgical resection of the residual intraabdominal disease focus and is free of disease at 36.5+ months. Overall, responses have occurred in lung, lymph nodes, subcutaneous, bones, peritoneum, small bowel, and soft tissue sites. Conclusions: Staccato pulse intravenous IL-2 has activity in melanoma pts previously treated with CPI.

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Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.440 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 440-440 ◽

Cited By ~ 7

Author(s):

Petros Grivas ◽

Yohann Loriot ◽

Susan Feyerabend ◽

Rafael Morales-Barrera ◽

Min Yuen Teo ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Parp Inhibitor ◽

Single Agent ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Clinical Activity ◽

Open Label ◽

Platinum Based Chemotherapy ◽

Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

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Phase I study of subcutaneously administered interleukin-2 in combination with interferon alfa-2a in patients with advanced cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1996.14.8.2234 ◽

1996 ◽

Vol 14 (8) ◽

pp. 2234-2241 ◽

Cited By ~ 21

Author(s):

B L Gause ◽

M Sznol ◽

W C Kopp ◽

J E Janik ◽

J W Smith ◽

...

Keyword(s):

Advanced Cancer ◽

Killer Cell ◽

Interleukin 2 ◽

Serum Levels ◽

Interferon Alfa ◽

High Dose ◽

Outpatient Basis ◽

Significant Activity ◽

Prognostic Features ◽

Ifn Alpha

PURPOSE Although high-dose interleukin-2 (IL-2) can produce durable remissions in a subset of responding patients with renal cell carcinoma (RCC), this occurs in the setting of significant toxicity. The purpose of this study is to define the maximum-tolerated dosage (MTD) of IL-2 and interferon alfa-2a (IFN alpha-2a) that can be administered chronically on an outpatient basis. PATIENTS AND METHODS Fifty-three patients with advanced cancer of variable histology with good prognostic features were treated in six cohorts. Patients in cohorts one through five received IL-2 (1.5 or 3.0 x 10(6) million units (mU)/m2) Monday through Friday and IFN alpha-2a (1.5 or 3 x 10(6) mU/m2) daily for a 4-week cycle. In cohort six, IFN alpha-2a was given three times a week. Immunologic monitoring, including serum levels of soluble IL-2 receptor (sIL-2R) and neopterin, flow cytometry, and natural killer cell (NK) activity, were measured. Patients were evaluated for toxicity, response, and survival. RESULTS Almost all patients developed grade I/II toxicities commonly associated with cytokine therapy. Symptoms were most severe with the first treatment of each week. Dose-limiting toxicities included grade III fatigue, hypotension, and creatinine elevations. The MTD was 1.5 mU/m2 daily x 5 given subcutaneously repeated weekly for IL-2 and 1.5 mU/m2 daily subcutaneously (dose level 3) for IFN. Six of 25 assessable patients with RCC (24%) achieved a partial response (PR), including four of eight patients who were previously untreated. There were no objective responses in patients with other tumors, including 12 melanoma patients. CONCLUSION IL-2 and IFN alpha-2a can be given with tolerable toxicities on an outpatient basis and shows significant activity in patients with metastatic RCC.

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Randomized phase Ib study to evaluate safety, pharmacokinetics and therapeutic activity of simlukafusp α in combination with atezolizumab ± bevacizumab in patients with unresectable advanced/ metastatic renal cell carcinoma (RCC) (NCT03063762).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4556 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4556-4556

Author(s):

Jose Luis Perez-Gracia ◽

Aaron Richard Hansen ◽

Rikke Helene Loevendahl Eefsen ◽

Carlos A. Gomez-Roca ◽

Sylvie Negrier ◽

...

Keyword(s):

T Cells ◽

Objective Response ◽

Interleukin 2 ◽

Recommended Dose ◽

Clinical Activity ◽

Therapeutic Activity ◽

Liver Transaminases ◽

Previously Treated ◽

Malignant Lesions ◽

Grade 3

4556 Background: Simlukafusp α ([SIM], FAP-IL2v) is a novel IL-2v immunocytokine engineered to preferentially activate effector CD8 T and NK cells, but not regulatory T cells (Tregs), due to abolished binding to Interleukin-2 receptor α (IL-2Rα) and retained affinity to IL-2Rβγ. High affinity binding of SIM to fibroblast activation protein (FAP), expressed on cancer-associated fibroblasts, mediates its accumulation in malignant lesions. Methods: The Dose-Escalation (DE) consisted of: Arm A: SIM 5-25 mg weekly for 4 weeks, and every 2 weeks (Q2W) thereafter in combination with atezolizumab [ATZ] 840mg Q2W; and Arm B: same as Arm A + bevacizumab [BEV] 10 mg/kg Q2W. Patients (pts) not previously treated were evaluated in the Extension Part: Arm C (n=3): SIM + ATZ every 3 weeks (Q3W); or Arm D (n=25): SIM + ATZ + BEV (“triplet”) Q3W. Primary objectives were: finding the recommended dose of SIM and assessment of objective response rate (ORR) by RECIST v1.1. Results: We enrolled 69 pts with unresectable advanced/ metastatic clear-cell and/or sarcomatoid RCC. Median age of patients was 57 years (range: 35-78). The recommended dose for extension of SIM was 10 mg. Median treatment duration in days in each arm were: A: 106 (range: 1-877); B: 324 (8-940); C: 659 (71-768); D: 437 (1-682). Twenty-five pts are evaluable for therapeutic activity in Arm A [ORR: 24% (6 PR; 90% CI 12.95, 40.12)]; 15 in Arm B [46.7% (1 CR, 6PR; 90% CI 27.67, 66.68)]; 3 in Arm C [33.3% (1PR; 90% CI 7.83, 74.65)]; and 23 in Arm D [47.8% (2 CR, 9 PR; 90% CI 35.74, 68.15)]. Twelve patients are ongoing on study treatment. Treatment related grade 3 and 4 adverse events (AE) occurred respectively in 69.7% and 9.1% patients. The most common serious AEs were pyrexia (10.6 %) and infusion-related reactions (9.1%). 65.2% Of the patients reported at least one AE of elevations in liver transaminases/GGT/ alkaline phosphatase/bilirubin. Drug-related AEs led to dose modification/interruption in 37.9 % of the pts, and treatment discontinuation in 3% of the patients. SIM led to preferential expansion and activation of NK and CD8 T cells (but not Tregs) in peripheral blood and augmented tumor infiltration and tumor inflammation. Intriguingly responses were observed not only in pts with PD-L1 positive or inflamed tumors, but also in pts with PD-L1 negative tumors (n=13) or poorly infiltrated tumors classified as immune deserts (n=2). Conclusions: The combination of SIM with ATZ ± BEV was feasible with an acceptable safety profile. Clinical activity was more favorable for the triplet among the study Arms, but comparable to the ATZ + BEV combination in the IMmotion151 (Rini B, et al 2019). Observed pharmacodynamic findings were consistent with the expected effects. Clinical trial information: NCT03063762.

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Faculty Opinions recommendation of An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718028323.793480222 ◽

2013 ◽

Author(s):

Richard Riedel

Keyword(s):

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Phase 2 ◽

Efficacy And Safety ◽

Open Label ◽

Phase 2 Study ◽

Open Label Phase ◽

Metastatic Soft Tissue Sarcoma ◽

Previously Treated

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274 Tumoral and peripheral immunophenotype of refractory vs relapse to PD-(L)1 blockade in patients with advanced non-small cell lung cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0274 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A299-A299

Author(s):

Maria Ascierto ◽

Matthew Hellmann ◽

Nathan Standifer ◽

Song Wu ◽

Han Si ◽

...

Keyword(s):

Gene Expression ◽

Informed Consent ◽

Checkpoint Inhibitors ◽

Patient Response ◽

Calcium Dependent ◽

Immune Exhaustion ◽

Previously Treated ◽

Expression Pathways ◽

Relapsed Disease ◽

Written Informed Consent

BackgroundDespite the encouraging successes of immune checkpoint inhibitors, many patients do not benefit and are either refractory or relapse. The mechanisms of refractory or relapsed disease following PD-(L)1 blockade are largely unknown. To identify characteristics associated with refractory or relapsed disease we explored the immune and genomic landscape of samples derived from NSCLC patients who previously received PD-(L)1 blockade and had blood and fresh tumor biopsies collected at the time of progression.MethodsPatient response categories were defined prospectively; ‘refractory’ defined as progression within 16 weeks of initiating PD-(L)1 and ‘relapse’ defined as initial clinical benefit (CR, PR, SD) followed by progression. RNAseq (n=52) and PD-L1 IHC (n=22) were performed on tumor tissue. Immune profiling of whole blood was assessed using flow cytometry or Biomark HD (Fluidigm) gene expression panel (n=54 and n=62, respectively). Differential gene expression was defined as unadjusted p<0.05 and fold-difference >1.5. Pathways analysis was conducted by David tool. Patient samples were collected during screening for clinical trial of second line immunotherapy. Written informed consent was obtained from the patients for publication of this abstract.ResultsIn patients with NSCLC previously treated with PD-(L)1 blockade, tumors of relapsed patients were characterized by increased expression of genes associated with interferon signaling (e.g. CXCL9, SPIC, IFNg), immune suppression (e.g. ARG1, TGFB), immune exhaustion (e.g. ADORA2A), and increased PD-L1 expression (by gene expression and IHC). Refractory disease was associated with increased cadherin signaling and calcium-dependent-cell-adhesion gene expression pathways. In the periphery, reduced quantities of B cells and activated (HLA-DR+ or CD38+) or proliferating (Ki67+) CD8+ T cells were observed in refractory patients.ConclusionsThe tumor and peripheral compartments of patients with NSCLC previously treated with PD-(L)1 blockade differ based on prior response. Relapsed patients tend to have signals of sturdy immune activation and chronic inflammation thus ultimately leading to immune exhaustion. These results may help inform rational therapeutic strategies to overcome resistance to PD-(L)1 blockade in NSCLC.Trial RegistrationNCT02000947Ethics ApprovalResearch on human samples here analyzed have been performed in accordance with the Declaration of Helsinki.ConsentWritten informed consent was obtained from the patient for publication of this abstract.

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