Randomized phase II study of stereotactic body radiotherapy and interleukin-2 versus interleukin-2 in patients with metastatic melanoma

BackgroundA pilot study of stereotactic body radiation therapy (SBRT) followed by high-dose interleukin-2 (IL-2) showed a higher than anticipated objective response rate (ORR) among patients with metastatic melanoma (MM). We performed a prospective randomized study to determine if the ORR of SBRT + IL-2 was greater than IL-2 monotherapy in patients with advanced melanoma.MethodsPatients with MM who had adequate physiological reserve for IL-2 and at least one site suitable for SBRT were eligible. There was a 1:1 randomization to SBRT + IL-2 or IL-2 monotherapy. Patients received one or two doses of SBRT (20 Gy per fraction) with the last dose administered 3 days before starting the first cycle of IL-2. IL-2 (600,000 IU per kg via intravenous bolus infusion) was given every 8 hours for a maximum of 14 doses with a second cycle after a 2-week rest. Responding patients received up to six IL-2 cycles. Patients assigned to IL-2 monotherapy who exhibited progression of melanoma after cycle 2 were allowed to crossover and receive SBRT and additional IL-2. Response Evaluation Criteria in Solid Tumors 1.1 criteria were applied to non-irradiated lesions for response assessment.Results44 patients were included in the analysis. The ORR in the SBRT + IL-2 group was 54%: 21% complete response (CR), 33% partial response (PR), 21% stable disease (SD) and 25% progressive disease (PD). The ORR in patients receiving IL-2 monotherapy was 35%: 15% CR, 20% PR, 25% SD and 40% PD. Seven patients assigned to IL-2 subsequently received SBRT + IL-2. One CR and two PRs were observed in the crossover group. There was no difference in progression-free or overall survival (OS). At 5 years the OS was 26% in the SBRT + IL-2 group and 25% in the IL-2 monotherapy group. The disease control rate (DCR) was higher in the SBRT + IL-2 group (75% vs 60%, p=0.34).ConclusionsSBRT + IL-2 induced more objective responses with a higher DCR compared to IL-2 monotherapy in MM. IL-2 monotherapy resulted in a significantly higher ORR than anticipated. Some patients in the crossover group also achieved objective responses.Trial registration numberNCT01416831.

Download Full-text

Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.8.1553 ◽

1994 ◽

Vol 12 (8) ◽

pp. 1553-1560 ◽

Cited By ~ 88

Author(s):

M B Atkins ◽

K R O'Boyle ◽

J A Sosman ◽

G R Weiss ◽

K A Margolin ◽

...

Keyword(s):

Metastatic Melanoma ◽

Performance Status ◽

Objective Response ◽

Eastern Cooperative Oncology Group ◽

Interleukin 2 ◽

Complete Response ◽

Phase Iii ◽

Survival Duration ◽

High Dose ◽

Ecog Performance Status

PURPOSE To evaluate the activity and toxicity of combined high-dose cisplatin, dacarbazine (DTIC), and tamoxifen chemotherapy and high-dose bolus interleukin-2 (IL-2) in patients with metastatic melanoma. PATIENTS AND METHODS Patients with metastatic melanoma, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and normal organ function were enrolled onto this multiinstitutional Cytokine Working Group trial. Patients received intensive chemoimmunotherapy consisting of cisplatin (50 mg/m2) and DTIC (350 mg/m2) intravenously (IV) on days 1 to 3 and 43 to 45, IL-2 600,000 IU/kg IV every 8 hours on days 12 to 16 and 26 to 30 (maximum, 28 doses), and tamoxifen 20 mg orally each day. Patients were evaluated for response at day 63 of each cycle, and responding patients were given a second cycle of therapy beginning on day 71 to 85. RESULTS Thirty-eight patients were entered onto this study. Toxicities were as expected for the chemotherapy and immunotherapy components of this regimen. Overlapping toxicity consisted primarily of thrombocytopenia (76% of patients required platelet transfusions), neutropenia, anemia, fatigue, and weight loss. Despite these cytopenias, bleeding and infectious complications were rare. There were no treatment-related deaths. Three patients achieved a complete response (CR; 8%), and 13 achieved a partial response (PR). The overall objective response rate was 42% (95% confidence interval [CI], 26% to 58%). Six additional patients had greater than 50% tumor reduction at day 63, which did not persist until a subsequent evaluation. The median duration of response was 5 months (range, 2 to 20+), and the median survival duration was 11 months. CONCLUSION This intensive treatment regimen appears to possess activity in metastatic melanoma comparable, but not superior, to that of other less intensive cisplatin- and IL-2-based chemoimmunotherapy regimens. Although the toxicity and complexity of this regimen make it unsuitable for phase III testing and impractical for more widespread use, the results of this study support a potential favorable interaction between IL-2 and chemotherapy in this disease and highlight the need for appropriately designed phase III trials.

Download Full-text

Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.21.00612 ◽

2021 ◽

pp. JCO.21.00612

Author(s):

Amod A. Sarnaik ◽

Omid Hamid ◽

Nikhil I. Khushalani ◽

Karl D. Lewis ◽

Theresa Medina ◽

...

Keyword(s):

Disease Control ◽

Metastatic Melanoma ◽

Treatment Options ◽

Objective Response ◽

Interleukin 2 ◽

Advanced Melanoma ◽

Disease Control Rate ◽

High Dose ◽

Tumor Infiltrating Lymphocyte ◽

Programmed Death

PURPOSE Effective treatment options are limited for patients with advanced (metastatic or unresectable) melanoma who progress after immune checkpoint inhibitors and targeted therapies. Adoptive cell therapy using tumor-infiltrating lymphocytes has demonstrated efficacy in advanced melanoma. Lifileucel is an autologous, centrally manufactured tumor-infiltrating lymphocyte product. METHODS We conducted a phase II open-label, single-arm, multicenter study in patients with advanced melanoma who had been previously treated with checkpoint inhibitor(s) and BRAF ± MEK targeted agents. Lifileucel was produced from harvested tumor specimens in central Good Manufacturing Practice facilities using a streamlined 22-day process. Patients received a nonmyeloablative lymphodepletion regimen, a single infusion of lifileucel, and up to six doses of high-dose interleukin-2. The primary end point was investigator-assessed objective response rate (ORR) per RECIST, version 1.1. RESULTS Sixty-six patients received a mean of 3.3 prior therapies (anti–programmed death 1 [PD-1] or programmed death ligand 1 [PD-L1]: 100%; anticytotoxic T-lymphocyte-associated protein-4: 80%; BRAF ± MEK inhibitor: 23%). The ORR was 36% (95% CI, 25 to 49), with two complete responses and 22 partial responses. Disease control rate was 80% (95% CI, 69 to 89). Median duration of response was not reached after 18.7-month median study follow-up (range, 0.2-34.1 months). In the primary refractory to anti–PD-1 or PD-L1 therapy subset, the ORR and disease control rate were 41% (95% CI, 26 to 57) and 81% (95% CI, 66 to 91), respectively. Safety profile was consistent with known adverse events associated with nonmyeloablative lymphodepletion and interleukin-2. CONCLUSION Lifileucel demonstrated durable responses and addresses a major unmet need in patients with metastatic melanoma with limited treatment options after approved therapy, including the primary refractory to anti–PD-1 or PD-L1 therapy subset.

Download Full-text

Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.461 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 461-461

Author(s):

Neeraj Agarwal ◽

Kinjal Parikh ◽

Srinivas Kiran Tantravahi ◽

Hilda Crispin ◽

Joan Van Atta ◽

...

Keyword(s):

Clinical Benefit ◽

Clear Cell ◽

Objective Response ◽

Interleukin 2 ◽

Progression Free Survival ◽

Standard Of Care ◽

Complete Response ◽

High Dose ◽

Select Group ◽

Best Response

461 Background: HD IL-2, an immunotherapy, is a standard of care for a select group of patients (pts) with mRCC. Generally objective response (OR) rates, i.e. complete response (CR) + partial response (PR), of 16-20% are discussed with pts, but not disease stabilization (SD). Recent data suggest that cancer immunotherapy may improve survival without inducing OR. Thus, treatment with HD IL-2 may provide survival benefit to an additional group of pts not experiencing OR, but only SD as the best response. Here we report CB ( OR+SD), and specifically report outcomes of cc mRCC pts experiencing SD as the best response, on treatment with HD IL-2. Methods: All sequential cc mRCC pts treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000-2012 were included. Pts were evaluated for best response, progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS). Two practitioners independently reviewed HD IL-2 response with discrepancies adjudicated by a third reviewer. Results: 85 pts, 79% male, were identified with a median age of 56 (range 32-76) years. Pts belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. A CR was identified in 9 (11%), PR in 5 (6%), SD in 26 (31%), progressive disease (PD) in 38 (45%), and unknown/not evaluable (NE) in 7 (8%) pts; yielding a clinical benefit in 40 (47%) pts. The median PFS, TNT, and OS in these individual groups of pts are compared in the table. Conclusions: A clinical benefit of HD IL-2 was achieved in nearly half of all clear cell mRCC pts. OS was not significantly different in OR and SD groups. Even though OR favorably determine outcomes, SD is also an important response criterion, and may be discussed during counseling pts for treatment with HD IL-2. [Table: see text]

Download Full-text

Randomized Study of High-Dose and Low-Dose Interleukin-2 in Patients With Metastatic Renal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2003.02.122 ◽

2003 ◽

Vol 21 (16) ◽

pp. 3127-3132 ◽

Cited By ~ 569

Author(s):

James C. Yang ◽

Richard M. Sherry ◽

Seth M. Steinberg ◽

Suzanne L. Topalian ◽

Douglas J. Schwartzentruber ◽

...

Keyword(s):

Overall Survival ◽

Low Dose ◽

Performance Status ◽

Randomized Study ◽

Cell Cancer ◽

Interleukin 2 ◽

Complete Response ◽

High Dose ◽

Metastatic Renal Cancer ◽

Survival Difference

Purpose: This three-arm randomized study compares response rates and overall survival of patients with metastatic renal cell cancer (RCC) receiving high-dose or one of two low-dose interleukin-2 (IL-2) regimens. Patients and Methods: Patients with measurable metastatic RCC and a good performance status were randomized to receive either 720,000 U/kg (high-dose [HD]) or 72,000 U/kg (low-dose [LD]), both given by intravenous (IV) bolus every 8 hours. After randomly assigning 117 patients, a third arm of low-dose daily subcutaneous IL-2 was added, and an additional 283 patients were randomly assigned. Results: A total of 156 patients were randomly assigned to HD IV IL-2, and 150 patients to LD IV IL-2. Toxicities were less frequent with LD IV IL-2 (especially hypotension), but there were no IL-2-related deaths in any arm. There was a higher response proportion with HD IV IL-2 (21%) versus LD IV IL-2 (13%; P = .048) but no overall survival difference. The response rate of subcutaneous IL-2 (10%, partial response and complete response) was similar to that of LD IV IL-2, differing from HD IV (P = .033). Response durability and survival in completely responding patients was superior with HD IV compared with LD IV therapy (P = .04). Conclusion: Major tumor regressions, as well as complete responses, were seen with all regimens tested. IL-2 was more clinically active at maximal doses, although this did not produce an overall survival benefit. The immunological factors which constrain the curative potential of IL-2 to only a small percentage of patients need to be further elucidated.

Download Full-text

High-Dose Recombinant Interleukin 2 Therapy for Patients With Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993

Journal of Clinical Oncology ◽

10.1200/jco.1999.17.7.2105 ◽

1999 ◽

Vol 17 (7) ◽

pp. 2105-2105 ◽

Cited By ~ 1307

Author(s):

Michael B. Atkins ◽

Michael T. Lotze ◽

Janice P. Dutcher ◽

Richard I. Fisher ◽

Geoffrey Weiss ◽

...

Keyword(s):

Metastatic Melanoma ◽

Performance Status ◽

Objective Response ◽

Interleukin 2 ◽

Response Duration ◽

High Dose ◽

Large Tumor ◽

Median Response ◽

Recombinant Interleukin 2 ◽

Prior Systemic Therapy

PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

Download Full-text

Maintenance interleukin-2 (IL-2) and sargramostim (GM-CSF) following high-dose IL-2 (HD IL-2) therapy for metastatic melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e20049 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e20049-e20049

Author(s):

Melinda Bernabe Chu ◽

Mark Fesler ◽

Eric Armbrecht ◽

Scott Fosko ◽

Eddy C. Hsueh ◽

...

Keyword(s):

Partial Response ◽

Metastatic Melanoma ◽

Maintenance Treatment ◽

Interleukin 2 ◽

Package Insert ◽

Complete Response ◽

Small Sample ◽

High Dose ◽

Gm Csf ◽

Duration Of Response

e20049 Background: At our institution, patients with metastatic melanoma who achieve partial response (PR) to HD IL-2 therapy undergo monthly maintenance treatment with IL-2 and GM-CSF with the thought that the continuous stimulation of the immune system may improve response. Our aim was to describe our experience with maintenance treatment following HD IL-2 therapy. Methods: A retrospective chart review was performed on patients with metastatic melanoma seen at Saint Louis University from January 1999-June 2011 who were partial responders to HD IL-2 therapy (720,000 IU/kg per dose intravenously; 14 doses, 2 cycles per course, maximum 2 courses) that received maintenance IL-2 therapy (continuous 42 hour infusion of three consecutive doses of 18,000,000 IU/m2 over 6, 12 hours, then 24 hours) and GM-CSF (daily subcutaneous injection of 125 mcg/m2 for 3 days) every 4 weeks for 13 cycles or until disease progression. Duration of response for this cohort was compared to established data for partial responders using the Mann-Whitney test. Results: Five patients were included in the analysis. Median duration of response was 9 months (3.9-53.4 months). Median overall survival was 20.6 months (15-53.4+ months). One patient who initially showed PR to HD IL-2 therapy converted to complete response during maintenance IL-2 and has the longest duration of response in the study dataset. Duration of response for the maintenance group (9 months) was longer than a benchmark of 5.9 months as reported in the literature and package insert for partial responders to HD IL-2 without maintenance therapy, p = 0.068. Conclusions: Subjects who received maintenance IL-2 and GM-CSF therapy had a longer duration of response compared to previous reports, which trended toward statistical significance in this small sample. Maintenance IL-2 and GM-CSF after HD IL-2 therapy may help to prolong partial response, possibly lead to conversion to complete response and is worthy of additional study.

Download Full-text

Factors Associated With Response to High-Dose Interleukin-2 in Patients With Metastatic Melanoma

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.15.3477 ◽

2001 ◽

Vol 19 (15) ◽

pp. 3477-3482 ◽

Cited By ~ 231

Author(s):

Giao Q. Phan ◽

Peter Attia ◽

Seth M. Steinberg ◽

Donald E. White ◽

Steven A. Rosenberg

Keyword(s):

Metastatic Melanoma ◽

Objective Response ◽

Interleukin 2 ◽

Thyroid Stimulating Hormone ◽

High Dose ◽

Thyroid Function Tests ◽

Free T4 ◽

Prior Therapy ◽

Patient Demographics ◽

Significant Difference

PURPOSE: The present study attempted to identify characteristics that correlated with clinical response to interleukin (IL)-2 therapy in patients with metastatic melanoma. PATIENTS AND METHODS: We retrospectively evaluated laboratory and clinical characteristics of 374 consecutive patients with metastatic melanoma treated with high-dose intravenous bolus IL-2 (720,000 IU/kg) from July 1, 1988, to December 31, 1999, at the Surgery Branch of the National Cancer Institute. RESULTS: The overall objective response rate was 15.5%. Pretreatment parameters such as patient demographics, laboratory values, and prior therapy did not correlate with response; however, 53.6% of patients with only subcutaneous and/or cutaneous metastases responded, compared with 12.4% of patients with disease at other sites (P2 = .000001). During therapy, patients who were responders tended to have received more doses during course 1 (16.2 ± 0.3 doses v 14.5 ± 0.2 doses; P2 = .0095); however, when limited to patients who were able to complete both cycles of course 1, there was no statistically significant difference (P2 = .27). Responders had a higher maximum lymphocyte count immediately after therapy compared with nonresponders (P2 = .0026). The development of abnormal thyroid function tests and vitiligo after therapy was associated with response (thyroid-stimulating hormone, P2 = .01; free T4, P2 = .0049; vitiligo, P2 < 10−6), although thyroid dysfunction may have been related more to the length of IL-2 therapy than to response. CONCLUSION: The presence of metastases only to subcutaneous and/or cutaneous sites, lymphocytosis immediately after treatment, and long-term immunologic side effects, especially vitiligo, were associated with antitumor response to IL-2 therapy.

Download Full-text

Lymphodepletion with high-dose interleukin-2 (IL-2) and granulocyte macrophage-colony stimulating factor (GM-CSF) in metastatic melanoma patients: An interim analysis

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.8034 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 8034-8034

Author(s):

S. L. Ketchum ◽

B. Cole ◽

K. Margolin ◽

D. McDermott ◽

T. Crocenzi ◽

...

Keyword(s):

T Cells ◽

Metastatic Melanoma ◽

Interleukin 2 ◽

Subcutaneous Administration ◽

Complete Response ◽

High Dose ◽

Gm Csf ◽

Macrophage Colony Stimulating Factor ◽

Melanoma Patients ◽

Macrophage Colony

8034 Background: Lymphocyte depletion followed by homeostatic recovery has been shown to break tumor-specific tolerance. We have initiated a clinical trial of chemotherapy-induced lymphodepletion followed by high-dose (HD) IL-2 + GM-CSF in metastatic melanoma (MM) patients (pts). Methods: Pts with PS 0–1, normal organ function and with measurable MM were treated with intravenous cyclophosphamide 60 mg/kg (day 1–2), fludarabine 25 mg/m2 (day 3–7) followed by two 5-day (d) courses of intravenous HD bolus IL-2 600,000 IU/kg (d 8–12 and 21–25) and daily subcutaneous administration of GM-CSF 250 mcg/m2 (d 8 until granulocyte recovery). Results: 8 pts are presently evaluable in this first stage of accrual to confirm safety and immunomodulation. A mean of 25/28 IL-2 doses were delivered. All pts experienced transient myelosuppression with ANC < 500 cells/mm3 for a median of 7d (range 5–11d) and platelets <50,000/mm3 for a median of 5.5 days (range 0–7d). Pts exhibited reversible capillary leak associated with high-dose IL-2. With the exception of myelosuppression, no grade 4 toxicities occurred. All pts experienced neutropenic fever and 2 developed line infections. CD4+/CD25high/CD62L+ T cells rebounded by d 14, peaked around d 28 and returned to baseline by d 85. CD8+/CD28- T cells recovered to levels lower than baseline for the first 28d but then showed persistent elevation through d 113. Skewing of T-cell populations based on TCR Î² chain expression was observed. One pt achieved complete response, 2 achieved partial responses, and 5 progressed. Conclusions: Lymphodepletion followed by high-dose IL-2 can be safely administered, affects immune reconstitution, and has activity in MM that may be useful as a platform for enhancing immunotherapeutic strategies. The trial continues to accrue in order to better estimate antitumor activity and immunomodulation. No significant financial relationships to disclose.

Download Full-text

Long-term progression-free survival of patients with metastatic melanoma or renal cell carcinoma following high-dose interleukin-2

Journal of Investigative Medicine ◽

10.1136/jim-2020-001650 ◽

2021 ◽

Vol 69 (4) ◽

pp. 888-892

Author(s):

Joseph I Clark ◽

Brendan Curti ◽

Elizabeth J Davis ◽

Howard Kaufman ◽

Asim Amin ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Melanoma ◽

Systemic Therapy ◽

Renal Cell ◽

Interleukin 2 ◽

Progression Free Survival ◽

High Dose ◽

Free Survival

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

Download Full-text