Sarcoma Clinical Science Symposium and Oral Presentation June 1, 2009

Post by David R. D’Adamo, MD, PhD:

There were two sarcoma sessions that I will report on today, a Clinical Science Symposium and the Oral presentation session. I will again use the same categories: Cytotoxic Therapy, Targeted Therapy and GIST.

1. Cytotoxic Therapy

A trial by Blay et al (Abs 10505) failed to demonstrate any benefit for high dose therapy with Ifosfamide Carboplatin Etoposide and stem cell support, after response to MAID therapy. Outside of the Ewing’s family of tumors, it is unlikely this approach will be explored further.

Final Overall Survival data was presented for the randomized trial of weekly versus q 3 week trabectadin (Abs #10509). This trial has previously been reported to have reached its primary endpoint of statistically improved PFS for the q 3 week arm (4.2 v 2.5 months) leading to its approval in Europe, but not in the US. OS was numerically longer in the q3 week schedule, 13.9 v 11.8 months, but not statistically significant (p=0.19). Of note, the trial was not powered to detect a survival difference, and crossover was permitted

2. Targeted therapy

Dr. Patel (Abs #10503) presented the much anticipated results of the SARC011 trial of the Roche anti-IGFR antibody R1507. Multiple preclinical studies have shown the involvement of this pathway in the oncogenic transformation of multiple tumor types, including sarcoma. Safety data showed that this agent is remarkably well tolerated. Notably other IGFR inhibitors have reported significant hyperglycemia/diabetes which is not reported for this antibody, presumably because this has less cross reactivity with the insulin receptor. Anecdotal responses were shown in multiple subtypes including Ewings sarcoma, Osteosarcoma, Rhabdomyosarcoma and Alveolar Soft Parts Sarcoma. Most of the responses shown were in Ewings sarcoma. PET data was shown, implying that some patients had significant metabolic response without dramatic radiologic response. Disappointingly (and somewhat inexplicably) for a protocol that has enrolled over 200 patients, response rates, time to progression and overall survival data were not presented.

Dr. Goldberg presented preliminary results on a phase II trial of ARQ197 an oral c-Met inhibitor in so called MiT (Microphthalmia Trancription factor) family tumors (Clear Cell sarcoma, Alveolar Soft Parts sarcoma and Translocation Associated Renal Cell Carcinoma. Only one partial response was observed. Although there was substantial stable disease, this may be difficult to evaluate for these slowly growing tumors.

As a proof of concept trial, the Denosumab in Giant Cell tumor trial (Abs #10510) was a great demonstration of what can happen when a big pharmaceutical company pays attention to a small disease. Amgen has been developing this RANK ligand antibody as a treatment for breast cancer metastatic to bone, and even for osteoporosis. It turns out that RANK ligand activation is part of the pathologic transformation of Giant Cell Tumors of bone. Although this is primarily a surgical disease, when it becomes metastatic, it can cause significant morbidity and even mortality. The authors managed to treat 37 patients with this extremely rare disease. Radiologic benefit was demonstrated in 86% of patients, with many experiencing improvement in pain. This agent has already completed phase 3 testing in breast cancer and may be FDA approved for that indication within the year.

3. GIST
Dr. Heinrich and colleagues (Abs#10500) reported on in vitro sensitivity of GIST cells with various mutations, including those that confer imatinib resistance, to the multi-targeted tyrosine kinase inhibitor, sorafenib. They showed certain (activation loop) mutations that were insensitive to imatinib, and even sunitinib, were still sensitive to sorafenib. Sorafenib and sunitinib has similar efficacy for c-kit binding pocket mutations, that are imatinib resistant. This nicely explains the clinical activity in this doubly resistant population reported by Kindler last year and Reichardt this year.

Dr. Le Cesne (Abs #10507) presented results of a phase 2 trial of masatinib, a novel c-kit inhibitor in untreated GIST patients. This agent showed a response rate of 57% (3% CR) and a time to progression of 27 months, in a previously untreated patient population. A phase 3 trial has been proposed to compare this drug with imatinib. In my opinion it will be difficult to beat imatinib in either efficacy or toxicity endpoints.

Until next year,

Sarcoma General Poster Session 5-31-09

Post by David R. D’Adamo, MD, PhD:

Welcome back to the Sarcoma Highlights. Today was the General Poster Session.
I am going to use the same categories as yesterday, Cytotoxic Therapy, Targeted Therapy and GIST.

1. Cytotoxic Therapy

There was a retrospective report on the use of trabectadin (ET-743, Yondelis) in 245 previously treated sarcoma patients on a compassionate use program. The authors reported a RR of 8%, TTP of 3 months and OS of 10 months. Superior outcomes were seen for patients with myxoid and round cell liposarcoma. These data were consistent with results reported previously in phase 2 and phase 3 trials.

Palifosfamide is a novel formulation of the old sarcoma standard, ifosfamide. It lacks the nephrotoxicity and hemorrhagic cystitis. It does not need to be administered with mesna or spread out over multiple days. A phase 1 trial of palifosfamide with doxorubicin at 75 mg/m2 reported an MTD of palifosfamide of 150 mg/m2, with a response rate of 25% in sarcoma. A randomized trial of doxorubicin with or without palifosfamide is planned. Even if this new medicine is no more effective than ifosfamide, a more convenient, less toxic alternative to ifosfamide would be welcome to sarcoma patients and oncologists alike.

2. Targeted Therapy / Rare Subtypes of Sarcoma

Two posters reported results on Solitary Fibrous tumor / Hemangiopericytoma, a rare intermediate grade but highly vascular tumor. Most of the time surgery alone is sufficient to cure this tumor, however, when this disease becomes metastatic it is typically resistant to standard therapy. Casali et al reported on 5 patients with metastatic SFT treated with sunitinib. Four out of five had decreased vascularity of their tumors, with stabilization of disease. Last year Benjamin et al reported responses treating this tumor with bevacizumab and temozolomide. This would seem to indicate that even though the malignant cells are not vascular in origin (the old name of hemangiopericytoma is now known to be something of a misnomer), that targeting the vasculature and stroma can be effective therapy when this tumor becomes metastatic.

A retrospective trial from my institution looked at systemic therapy for Desmoid tumors/aggressive fibromatosis. Of 682 patients, 70 were treated with systemic therapy, including doxorubicin/liposomal doxorubicin, hormonal therapy, imatinib and methotrexate based therapy. An overall response rate of 20% was observed, with higher numeric efficacy with anthracycline based treatments compared to other agents.

3. GIST

Numerous trials reported patterns of care for GIST, including a large cohort of untreated GIST patients from the pre-imatinib era. Biomarkers including PKC theta and IGFR were explored along with their relationships to the known c-Kit mutational status. Therapeutically perifosine failed to reverse imatinib resistance in a report from the MD Anderson center. Sirolimus in combination with imatinib was able to control several PDGFR mutant GISTs (typically unresponsive to imatinib), but at the cost of greater than anticipated toxicity.

The most interesting therapeutic report however was one from Europe on 32 patients treated off trial with sorafenib, after progression on imatinib, sunitinib and most patients had received nilotinib. The authors reported a 19% PR rate, 44% SD, PFS of 5 months and OS of 10 months. This confirms the activity of this agent reported by Kindler et al. (including our group) at last years ASCO, in this poor prognosis group.

Poster Discussion Sarcoma 5-30-09

Post by David R. D’Adamo, MD, PhD:

Sarcoma Highlights of the Day Saturday May 30, 2009

Since this is my first stab at blogging, I will quickly introduce myself before rushing headlong into today’s updates from the sarcoma Poster Discussion session. I am a medical oncologist at Sloan Kettering, where I have been for the past 10 years. Before becoming a full time clinician I spent 8 years in the laboratory working on oncogene signal transduction and angiogenesis research. I initially trained in GI oncology and still half of my practice is composed of GI patients most of whom have colon cancer, but my research focus, and the other half of my practice is patients with sarcoma. My research concentrates on incorporating novel therapeutics, particularly angiogenesis inhibitors into the treatment of sarcomas.

ASCO always presents a challenge because there are so many things going on often simultaneously. Because of my interests, I try to catch some of the highlights of GI oncology, angiogenesis inhibition in multiple tumor types, and new drug development, in addition to all of the developments in sarcoma. I can only imagine the challenges for the general practice oncologist. This blog lets me focus on only one subject, that which I know best, sarcoma.

Sarcomas are a tricky disease to treat because they can be so heterogeneous. Of course the most significant development in the past 10 years has been the advent of anti c-kit therapy for GIST, but progress is slowly being made in treating other subtypes as well. I will divide my blog into 3 headings, to try to organize all of the important developments. Those categories will be:
1. Cytotoxic therapies, 2. Targeted therapies and 3. GIST.

Cytotoxic Therapies.

There were two trials about the Sea Squirt derived minor DNA groove binding agent Trabectadin (aka ET-743 or Yondelis). ET-743 was licensed in sarcoma in Europe in 2007 based on randomized data from refractory sarcoma patients. A retrospective trial from Italy looked at 56 previously treated patients with uterine leiomyosarcoma. They reported a response rate of 18%, with PFS of 3.6 months and a Clinical Benefit Response (CBR= CR+PR+SD) rate of 51%. A second study was reported on the use of this drug as neoadjuvant therapy for patients with localized myxoid and round cell liposarcoma, the subtype reported to me most sensitive to this agent. Patients with non-metastatic disease were treated preoperatively with up to 6 cycles of trabectadin followed by surgery. Responses were graded both radiologically be RECIST and histologically. Five of 23 patients had radiologic responses, two of which were pathologic complete remissions. Long term follow up data was not provided.

Perhaps one of the most interesting trials was a Spanish randomized phase 2 trial of two older medicines, dacarbazine compared with the doublet of dacarbazine and gemcitabine. The primary objective of this trial was to determine if the doublet had a superior 3 month PFS rate. The trial met its stated objectives with a 3 month progression free rate of 54% for the doublet compared with 36% for DTIC. Interestingly secondary objectives of RR (4% v 12%), TTP (2 v 4.2 months) and even OS (8 v 16 months) all favored the combination arm. These data are not significantly different from those of gemcitabine and docetaxel compared with gemcitabine monotherapy.

Targeted Therapy

In the realm of targeted therapy imatinib continues to make waves even in the non-GIST world. In the extremely rare tumor of Dermatofibrosarcoma Protuberans, Schuetze et al presented the combined results of 2 trials of imatinib, one EORTC one SWOG of patients with metastatic DFSP. DFSP is the result of a somatic chromosomal translocation putting Platelet Derived Growth Factor (PFGF) under the control of the collagen promoter. This is the human equivalent of the viral oncogene v-sis. This results in a locally aggressive cutaneous and dermal disease that has low malignant potential. Due to its potent anti PDGFR activity, imatinib therapy had a 46% response rate for patients with metastatic DFSP, with a TTP of 1.7 years. This was sufficient to convince the FDA to grant approval for this indication on the basis of response rate alone, in this orphan disease.

Other interesting trials in this category included a trial of single agent bevacizumab in angiosarcoma, showing 3 PRs out of 26 patients (12%) consistent with results previously reported for sorafenib and sunitinib, validating VEGF inhibition, in this sarcoma subtype. The oral VEGF inhibitor Cedarinib showed remarkable activity of 5 PRs out of 7 patients treated with Alveolar Soft Parts Sarcoma (ASPS), an indolent disease, but nevertheless, one that is generally considered refractory to standard agents.

GIST

GIST is really the poster child of targeted therapy in the solid tumor world. There is no other single agent with such high activity (50-75% RR), TTP (~ 2 yrs v 6 weeks for standard therapy) and a favorable toxicity profile, in any other tumor type, not even hormonal therapy for metastatic Breast cancer. Although some interesting retrospective data was presented, I found the most interesting presentation to be that on the use of the class of HSP 90 inhibitors. This family of agents has strong preclinical rationale to be active in TKI refractory GIST by degrading mutant c-kit, regardless of genotype. Unfortunately the clinical development has failed to live up to its promise. In a mouse model system however synergy was seen with the combination of imatinib c-Kit suppression along with HSP90 inhibition. It may be that in a 3rd line or later setting, as we are seeing multiply drug resistant tumors, that effective therapies may need to be combination regimens.

Until Tomorrows Sarcoma Poster Session,