1. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 4523)
High-dose (HD) IL-2 for metastatic renal cell
carcinoma (mRCC) in the targeted therapy era: Extension of
OS benefits beyond complete response (CR) and partial response (PR).
Michael Morse, David F. McDermott, Gregory A. Daniels,Howard Kaufman, Michael K.K. Wong, Sandra Aung, James N. Lowder.
Duke University Medical Center, Durham, NC; Beth Israel Deaconess Medical Center, Boston, MA; UC San Diego Moores Cancer Center, La Jolla, CA; Rush University Medical Center, Chicago, IL; University of Southern California, Los Angeles, CA; Prometheus Labs, San Diego, CA; Prometheus Laboratories Inc., San Diego, CA
Background: HD IL-2 has been reported to have a overall response rate (ORR) for mRCC of 15% and a median OS of 19 months (Fyfe,1995), however, the studies that led to its regulatory approval are >15 years old and were performed in an era preceding targeted therapies.
Methods: The PROCLAIM registry (www.proclaimregistry.com), a HD IL-2 observational database currently with over 30 participating sites, consists of a retrospective cohort (treated between 2007 and 2012) informing an ongoing prospective cohort (~ 600 patients). We report on the retrospective mRCC subjects (n=97, 13 sites) with survival status determined as of November 2013 and a median follow-up of 32 months. Sites were encouraged to enroll patients sequentially. Inclusion criteria required that patients have received at least one dose of HD IL-2.
Results: The ORR was 22% (8% CR and 14% PR). Of 97 subjects, 36 were confirmed deceased and 61 were known to be alive, none were lost to follow-up. The median OS was 51 months, compared to a median OS range of 5-35 months for FDA-approved targeted agents (Harrison, 2013). There was significant clinical benefit in patients with CR, PR, and stable disease (SD), none of which reached median OS compared to 37.9 months in patients with progressive disease (PD). There is a significant advantage in PROCLAIM for those patients treated 1st vs. 2ndline HD IL-2; the median OS was 61.8 months (n=82) vs 15.3 months (n=15), respectively. The clinical benefit of HD IL-2 therapy as front line is consistent with published data (Birkhauser, 2013). No deaths due to IL-2 related toxicity were reported in the retrospective cohort.
Conclusions: The PROCLAIM registry documents a vastly improved OS for HD IL-2 compared to historical results during a time interval marked by the advent of targeted therapy for advanced RCC. Response to IL-2 (CR or PR) is associated with prolonged survival, however, stable disease as well as front line use also appears to positively impact survival. Issues including patient selection characteristics and treatment sequencing are hypotheses currently being explored in the prospective database.
2. Citation: J Clin Oncol 32, 2014 (suppl; abstr e15550)
Prior high-dose IL-2 therapy (HDIL2) may
improve the outcome of sunitinib (Su) treatment (tx) in
patients (pts) with metastatic renal cell carcinoma (mRCC).
Eli Rosenbaum, Maya Gottfried, Hans J. Hammers, Mario A. Eisenberger, Michael Anthony Carducci, Victoria J. Sinibaldi, Victoria Neiman, David Sarid, Eliahu Gez, Henry Hayat, Avivit Peer, Avishay Sella, Wilmosh Mermershtain, Keren Rouvinov, Raanan Berger, Daniel Keizman.
Department of Oncology, Rabin medical center, Petach Tikva, Israel; Lung Cancer Unit, Meir Medical Center, Kfar Saba, Israel; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva, Israel; Division of Oncology, Tel-Aviv Sourasky Medical center, Tel Aviv, Israel; Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Department of Oncology, Wolfson Medical Center, Holon, Israel; Rambam Health Care Campus, Haifa, Israel; Assaf Harofeh Medical Center, Zerifin, Israel; Soroka Medical Center, Beersheba, Israel; Uro-oncologist, Tel Hashomer, Tel Hashomer, Israel; Department of Oncology, Meir Medical Center, Kfar Saba, Israel.
Background: Targeted txs are the tx of choice in most mRCC pts. However, HDIL2 which may produce durable responses in a small percentage of cases, is still an option in carefully selected pts. While the effect of prior HDIL2 on the outcome of targeted txs in mRCC pts is poorly defined, a recent single center report (Birkhäuser FD, Cancer J 2013) revealed an improved disease-specific survival in pts treated with prior HDIL2. We aimed to study the effect of prior HDIL2 tx on outcome of mRCC pts treated with sunitinib.
Methods: Records from 302 mRCC pts treated with Su from 2004 to 2013 in 9 centers across 2 countries were retrospectively reviewed. We compared the response rate, progression free survival (PFS), and overall survival (OS), between post HDIL2 pts (n=27) and individually matched tx naïve pts (n=27). Progression free survival and overall survival were determined by Cox regression.
Results: All pts had prior nephrectomy and clear cell histology. The groups were matched by age (median 61), gender (male 74%), Heng risk (favorable 37%, intermediate 59%, poor 4%), sunitinib induced hypertension (67%), sunitinib dose reduction/treatment interruption (41%), smoking status (active 7%), use of angiotensin system inhibitors (41%), the presence of more than one metastases site (96%), and pre-tx neutrophil to lymphocyte ratio (> 3 in 22%). Furthermore, they were balanced regarding the presence of lung (68%), liver (31%), and bone (43%) metastases, and the use of bisphosphonates (32%). In prior HDIL2 versus tx naïve pts, objective response was partial response/stable disease 89% (n=24) versus 74% (n=20), and progressive disease at first imaging evaluation within the first 3 months (mos) 11% (n=3) versus 26% (n=7) (p=0.29, OR 2.4). Median progression free survival was 21 versus 12 mos (HR 2.3, p=0.005), and median overall survival 25 versus 20 mos (HR 2.2, p=0.013).
Conclusions: In metastatic renal cell carcinoma patients treated with sunitinib, prior high dose IL-2 therapy may improve the outcome.
1. Citation: J Clin Oncol 32, 2014 (suppl; abstr e20002)
Tumor response and patient survival after
intralesional therapy with low-dose GM-CSF and IL-2 in
metastatic and primary cutaneous melanoma: An exploratory study.
E. George Elias, Bhuvnesh K Sharma.
University of Maryland at St. Joseph Medical Center, Towson, MD; ScyTek Laboratories, Logan, UT
Background: Dermal and subdermal metastatic melanoma can give us an excellent opportunity to evaluate the local and systemic effects of intralesional therapy. While GM-CSF administration can activate and induce autologous dendretic cells (APCs), IL-2 administration can stimulate autologous T cells at the tumor site.
Methods: Patients with derma and subdermal metastases, regardless to the extent of their disease or previous therapy, who consented to the study, each received intralesional GM-CSF 500 μg once/week for 4-6 weeks. If no complete clinical response (CR) was observed at the injection sites, intralesional IL-2 was substituted at 18 million IU weekly for the same length of time. One patient with primary invasive melanoma with a satellite lesion and regional lymph node (LN) metastasis, who remained a surgical candidate, received both cytokines at th skin lasions one week before surgery.
Results: Four patients had > 126 small in-transit metastases, each lesion measuring few mm up to 1 cm. All had CR confirmed pathologically 6-8 weeks after cessation of therapy, with disease-free survival of 37-54 months. Another three patients with large sclerotic skin lesions failed to respond to either cytokine. One of two patients with distant metastases who had palpable subdermal tumors had CR of all metastases for 6 months. The resected tissues from the patient with primary melanoma with a satellite lesion revealed complete tumor necrosis at both injection sites with massive pigmented histiocytosis at the skin sites and in some LNs. Immunohistochemical studies showed overexpression of CD3+, CD4+, CD8+ and CD83+cells at the primary site, the satellite and in some of the LNs. This patient is alive disease-free for over 48 months.
Conclusions: Intralesional therapy seemed to utilize the tumor site as a source for tumor-specific antigens giving rise to autoimmunization with strong antitumor response regardless of tumor antigenic or genetic profiles. These observations open up new aspects for clinical trials to standardize the management of in-transit metastases and to initiate new approaches to adjuvant therapy in high-risk melanoma patients.
2. Citation: J Clin Oncol 32, 2014 (suppl; abstr e20008)
The experience of administration of high-dose recombinant interleukin-2 in combination with chemotherapy in the management of disseminated skin melanoma.
Olga Streltsova, Yauheni Valerievich Baranau, Edvard Javrid, Maxim Barmotska; Minsk City Clinical Oncologic Dispensary, Minsk, Belarus.
N.N.Alexandrov National Cancer Centre of Belarus, Minsk, Belarus; N.N. Alexandrov National Cancer Centre of Belarus, Minsk, Belarus
Background: Interleukin-2 (Biotech, Russia) is a complete structural and functional analogue of human endogenous interleukin-2 produced from nonpathogenic Saccharomyces cerevisiae. Our retrospective study evaluated the results of the first-line chemoimmunotherapy of 71 patients with disseminated skin melanoma treated with interleukin-2 from 2004 till 2012.
Methods: We retrospectively evaluated efficacy and safety of chemotherapy dacarbazine 800 mg/m2, d 1 and cisplatin 20 mg/m2, d 1–4 (control arm, n=31). In the treatment arm chemotherapy was supplement of one of the following immunotherapy regiments: high-dose IL-2 (9 mg/m2, d 1–5) or gradual dose reduction IL-2 (18 mg/m2, d 1; 9 mg/m2, d 2; 4 mg/m2, d 3–4) (n=71). The median follow –up was 10, 0 months.
Results: The objective response rate was 33.8 % and 19.4% in the treatment and control arms respectively. Four complete responses were registered in the treatment arm only (5.6%). The median PFS was 5.3 and 3.2 (p=0.04), the median overall survival was 12.4 and 8.4 months (p=0.1) among the patients treated with chemoimmunotherapy and with chemotherapy alone respectively. The blood serum level of lactate dehydrogenase (LDH) exceeding more than 1.5 fold the upper reference value was an unfavourable prognostic factor with no impact of the treatment type (chemotherapy or chemoimmunotherapy) on its efficacy. At the same time, chemoimmunotherapy for disseminated skin melanoma patients with the LDH level not exceeding more than 1.5-fold the upper reference value increased the median PFS up to 6.3 months and the median overall survival up to 14.7 months. All adverse effects were overcome with conventional medications and had not caused cancels of immunotherapy.
Conclusions: Our experience confirmed that immunochemotherapy with high-dose interleukin-2 is an effective treatment of disseminated skin melanoma, is satisfactily tolerated and may be beneficial in patients with the LDH level not exceeding more than 1.5-fold the upper reference value.
3. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 9047)
Biochemotherapy with interleukin-2
for metastatic melanoma: Long-term results in 100 patients.
David R. Minor, Mohammed Kashani-Sabet; California Pacific Medical Center Research Institute, San Francisco, CA.
California Pacific Center for Melanoma Research and Treatment, San Francisco, CA
Background: As the limitations of new melanoma treatments are seen, we felt an evaluation of long-term results of biochemotherapy (BC) for metastatic melanoma (MM) would be useful.
Methods: Retrospective single-institution review of 100 consecutive patients (pts) who began therapy between 9/30/2002 and 6/20/2006. Median follow-up is 9 years. Staging: IIIC-1; M1A-17; M1B-35; M1C-47. Patients were treated with the O’Day regimen which is similar to ECOG BC except Temozolomide 150mg/m2 used for DTIC; 6 cycles of BC given, not 4; decrescendo IL-2 dosing 36-18-9-9 miu/day dosing not based on BSA; and patients received maintenance inpatient “pulse IL-2” 108miu/42 hrs monthly for 6-18 months after BC.
Results: 28 pts are still alive, all without evidence of melanoma (NED). One patient died NED due to a pulmonary embolus, one died from sepsis during BC, and 70 died from MM. 17 pts achieved CR with BC and never relapsed. Two patients achieved PR, had surgery for solitary sites of residual disease, and are NED. 6 pts progressed soon after BC, received ipilimumab (ipi) on various schedules, and are now NED. Two patients had late relapses over 3 years after BC. The first received ipi and is now NED off therapy. The second responded to ipi, progressed, and is now NED on therapy with anti-PD-1. One patient received BC in 2005, relapsed in 2007 and is NED after multiple continuous treatments over 7 years with chemo, RT, surgery, ipi, and vemurafenib. Of the 28 patients alive, only the last two are currently receiving therapy.
Conclusions: First-line decrescendo BC can give durable remissions in many patients; late relapses are uncommon. Durable responses to ipilimumab may follow progression with BC. Biochemotherapy should now be systematically studied as second line or consolidation therapy.
4. Citation: J Clin Oncol 32:5s, 2014 (suppl; abstr 9054)
Improved median overall survival (OS) in patients with
metastatic melanoma (mM) treated with high-dose (HD)
IL-2: Analysis of the PROCLAIM 2007-2012 national registry.
Gregory A. Daniels, Michael Morse, Michael K.K. Wong, Howard Kaufman, David F. McDermott, Sandra Aung, James N. Lowder.
UC San Diego Moores Cancer Center, La Jolla, CA; Duke University Medical Center, Durham, NC; University of Southern California, Los Angeles, CA; Rush University Medical Center, Chicago, IL; Beth Israel Deaconess Medical Center, Boston, MA; Prometheus Labs, San Diego, CA; Prometheus Laboratories Inc., San Diego, CA.
Background: HD IL-2 has been reported to have a overall response rate (ORR) for mM of 16% and a median OS 11.4 months (Atkins,1999), however, the studies that led to its regulatory approval are >15 years old and were performed in an era predating checkpoint inhibition and targeted therapies.
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