Welcome to PRIME Lines, a monthly electronic newsletter created for practicing medical oncologists and hematologists. The purpose of the newsletter is to provide busy practitioners with the latest news in their specialty in a convenient and accessible format.

We welcome your comments and suggestions regarding content and format at primelines@primeoncology.org.

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REGULATORY AGENCY ACTIONS

• Merck KGaA has submitted an application to the European Medicines Agency (EMEA) to broaden the indication for cetuximab (Erbitux^TM) to include first-line treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. The submission is based upon data from a 442-patient, randomized phase III trial, the EXTREME study, which demonstrated that cetuximab plus platinum-based chemotherapy significantly increased overall survival (OS). The median OS for patients in the cetuximab plus chemotherapy arm was 10.1 months compared to 7.4 months for those treated with platinum-based chemotherapy alone. The application was submitted on June 24, 2008. Cetuximab has been licensed in the European Union (EU) for use in combination with radiotherapy for locally advanced squamous cell carcinoma of the head and neck since April 2006.
  

• On May 30, 2008 the European Medicines Agency (EMEA) recommended approval of cetuximab as a first-line treatment in combination with chemotherapy for patients with metastatic colorectal cancer. Merck KGaA states that recommendations for marketing approval by the agency’s Committee for Medicinal Products for Human Use (CHMP) are normally endorsed by the European Commission within a couple of months.

• On June 20, 2008 the U.S. Food and Drug Administration (FDA) approved bortezomib (Velcade®, Millennium Pharmaceuticals, Inc., The Takeda Oncology Company, and Johnson and Johnson Pharmaceutical Research and Development) for the treatment of newly diagnosed patients with multiple myeloma. The approval was based on an international, multicenter randomized trial in 682 previously untreated patients with symptomatic multiple myeloma. Patients were randomized to receive either oral melphalan (M) plus prednisone (P) or MP plus bortezomib. The primary endpoint was time-to-progression (TTP) with secondary endpoints of OS, PFS, and RR. Eligible patients were age ≥ 65 years. The trial was discontinued following a pre-specified interim analysis that demonstrated a statistically significant improvement in TTP with the addition of bortezomib to MP (median 20.7 months) compared with MP alone (median 15 months) [HR 0.54, p=0.000002]. OS, PFS, and RR also were significantly superior for the bortezomib-MP combination. The treatment was well tolerated with no unexpected toxicity attributable to the addition of bortezomib.

NSCLC Trial:

Dual-Action Kinase Inhibitor and Unique Study Design Yield Encouraging Results

Abstract #8014: A randomized discontinuation phase II study of sorafenib (Nexavar®, Bayer HealthCare and Onyx Pharmaceuticals, Inc.) versus placebo in patients with NSCLC who have failed at least two prior chemotherapy regimens: ECOG 2501, was presented during a lung cancer oral presentation at the 2008 ASCO Annual Meeting.

Sorafenib (S) inhibits Raf kinase and is an inhibitor of angiogenesis (VEGF receptors) as well. Since other angiogenic inhibitors have activity in NSCLC, sorafenib was chosen for this randomized, placebo (P) controlled phase II study in third-line and beyond disease. The investigators utilized a unique study design, known as a randomized discontinuation trial (RDT).

Why use the randomized discontinuation design?

• Optimal for agents with cytostatic activity, where the primary clinical benefit might be stabilization of disease.
  
• It represents an enrichment design, in which all patients receive study drug (sorafenib) for an initial “run-in” period, followed by random assignment of patients with stable disease (SD) to either the study drug or placebo.
  
• Patients with rapidly progressive disease (PD) go off study before randomization.
  
• Based on the hypothesis that patients with rapidly progressive disease may not stay on drug long enough to derive a benefit.
  
• It enriches for patients with slower progressing disease, who might be more likely to benefit.

All patients received 400mg of S orally twice daily for 2 cycles (2 months); the “run-in” phase called Step 1. Responding patients on Step 1 continued on S; progressing patients went off study, and patients with stable disease were randomized to sorafenib (S) or placebo (Step 2). Patients randomized to placebo (P) were allowed to cross over to S on progression (PD). The primary endpoint of the study was the proportion of patients having stable or responding disease 2 months (8 weeks) after randomization. Eligibility: PS 0-1, progressive disease, and at least 2 prior chemotherapy regimens; however, prior treatment with biologics (EGFR, TKIs, and anti-angiogenics) did not count as a “line of therapy”. In fact, most patients were on their third, fourth, and fifth line of therapy, thus a heavily pre-treated population. Results: 342 patients enrolled in Step 1; 97 eligible patients were subsequently randomized to Step 2 and treated; 36 of 41 patients receiving P on Step 2 were crossed over to S. Primary endpoint: 83 patients evaluable overall (32 placebo, 51 sorafenib). The number of patients with stable or responding disease 2 months after randomization were placebo 6 (19%), sorafenib 24 (47%) (p=0.01). Outcomes: Step 2; for median PFS: 2.0 months placebo vs. 3.6 months for sorafenib (p=0.009; HR 2.16). For median survival: 9.0 months P vs. 11.9 months for S (HR= 1.50, p=0.18). Best overall response (Step 2): placebo CR 0%, PR 3%, stable 16%; sorafenib CR 0%, PR 2%, stable 47% (p=0.01 for CR, PR, + stable disease).

Conclusions:

• This trial met its primary endpoint of disease stabilization at 8 weeks (2 months) following randomization compared to placebo.
  
• Single agent sorafenib significantly improves PFS and maintains stable disease in a heavily pre-treated, enriched NSCLC patient population.
  
• Trend toward improvement in survival promising.
• Major toxicities manageable and as expected.
• Too few patients with squamous cell histology to make any definitive conclusions regarding either toxicity or efficacy in this single agent trial.
  
• These results warrant further investigations in larger randomized studies.
  

CLINICAL UPDATES: Thrombocytopenia and Multiple Myeloma

The first two clinical updates are based on information presented at “Emerging Therapies in Hematologic Malignancies,” a satellite symposium organized by PRIME Oncology and held in conjunction with the 13th Congress of the European Hematology Association, on June 12, 2008 in Copenhagen, Denmark. The entire symposium may be viewed as a webcast at www.primeoncology.org.

THROMBOCYTOPENIA:
Treatment with 2^nd Generation Thrombopoietic Growth Factors
The speaker for this topic was Adrian Newland, FRCP from The Royal London Hospital in London, United Kingdom.

Thrombopoietin (TPO) is involved in all stages of thrombopoiesis from the stem cell to the mature megakaryocytes that release platelets into the circulation. Thrombopoietic growth factors may stimulate platelet production by promoting proliferation, survival, and differentiation of megakaryocyte precursors into mature megakaryocytes, and by platelet release. The 2^nd generation thrombopoietic growth factors include TPO nonpeptide mimetics (eltrombopag, AKR 501), TPO peptide mimetics (romiplostim, AMG 531), and TPO agonist antibodies.

Eltrombopag is an orally bioavailable small molecule TPO-R (receptor) agonist that interacts with TPO-R differently than endogenous TPO. It stimulates megakaryocyte proliferation and differentiation, but does not prime platelets for activation. Given daily, eltrombopag increases platelet counts in a dose-dependent manner. In an early phase I trial in which daily doses of the drug were given, the platelet count started to increase at 7-10 days and continued to rise as long as eltrombopag was given. However, if the drug was stopped within 2 to 3 weeks the platelet count would drop to less than 10,000. A phase II dose-response study in which chronic ITP patients received daily eltrombopag (30mg, 50mg, or 75mg) resulted in progressive increase in platelet production and a steady decrease in bleeding as long as the drug was given.

Romiplostim (AMG 531) is a novel thrombopoiesis-stimulating peptibody (TPO peptide mimetic) that is structurally unrelated to TPO. It targets and affects the TPO-R and increases platelet production in a dose-responsive manner. It is administered subcutaneously once weekly. The median time to first response is 3.1 weeks, therefore, it is not an ideal candidate for use in acute, severe bleeding. When the ultimate platelet response did occur, the platelet count reached 350,000 to 450,000 in 60-70% of patients in a phase II trial; in fact if counts exceed 400,000 to 450,000 AMG 531 should be held to avoid risk of thrombosis. In a phase III chronic ITP trial, platelet responses were durable with long-term (up to 2 years) platelet counts double the baseline value and ≥50,000 in >50% of patients. The overall platelet response in this trial was 83% (splenectomized patients 79%; non-splenectomized patients 88%). Repeated treatment with AMG 531 is well tolerated and no antibodies to the drug have currently developed.

Thrombocytopenia associated with other clinical conditions has been treated in clinical trials with these agents with the following results:

• Hepatitis C virus associated – eltrombopag is effective at higher doses; 100% of patients able to complete their anti-viral therapy because thrombocytopenia improved or corrected.
  
• Chemotherapy-induced – will see a small response that only decreases the number of thrombocytopoenic days by 2 or 3; cost-effective??
  
• Myeloablative therapy – see very little response at all.
  
• MDS – romiplostim (AMG 531) effective in low and intermediate-1 risk, 41% durable response (median duration of response 23 weeks). No antibodies occurred; 3 deaths not related to thrombocytopoenia or AMG 531 therapy.

MULTIPLE MYELOMA
Front-Line Therapy
The speaker for this topic was Antonio Palumbo, MD from the University of Torino in Torino, Italy.

Over the last two decades three distinct groups of patients with newly diagnosed multiple myeloma have emerged. They are young patients (<65 years of age), elderly fit patients (≥ 65 years), and the elderly unfit patients (≥ 65 years) with concomitant medical illnesses. Improvements in our prognostic ability and in treatment options now make it possible to make appropriate therapeutic choices for patients in each group.

Several factors have contributed to our ability to better define these patient groups. First, increasing life span has resulted in an increased number of patients ≥65 years of age (the elderly group). Second, improved techniques for autologous stem cell transplantation (ASCT), improved supportive care options, and a group of novel anti-myeloma agents with impressive efficacy have resulted in improved survival for myeloma patients who are candidates for ASCT. These advances have made ASCT a viable option as front-line therapy for young patients and for some fit elderly patients as well. The final contributing factor is the influence of cytogenetics and beta-2-microglobulin (B₂MG) in defining risk and predicting outcomes in myeloma patients. Those with FISH(-), B₂MG <4 and some with del 13, B₂MG <4 have a 50% 5-year survival (S) of 80%. Those with FISH(-), B₂MG >4, del 13, B₂MG >4 and some with 4;14 or 17p, B₂MG <4 have a 50% 5-year S. All patients with 2 abnormal risk factors (4;14, 17p and B₂MG >4) have a poor prognosis even after tandem ASCT.

After that background information, Dr. Palumbo discussed his recommendations for management of the three patient groups. He stated that when you see a young patient, you generally think about ASCT and induction regimens used with that therapy. Lenalidomide (Len) + low-dose (LD) Dex has been proven to be more efficacious and less toxic (fewer severe A/Es and far fewer deaths) than Len + high-dose (HD) Dex – Len + LD-Dex is effective alone and as an induction therapy prior to ASCT. It is now proven in several trials to result in successful stem cell harvest in 97% to 100% of patients. Other induction regimens are Vel/Dex (bortezomib + Dex) and VTD (bortezomib + thalidomide + Dex).

The elderly fit patient group (≥65 years) certainly can be ASCT candidates with Len + LD-Dex or PAD (bortezomib + pegylated doxorubicin + Dex) induction. Non-ASCT patients in this group can benefit from regimens such as MPT (melphalan + prednisone + thalidomide) used in the IFM and Nordic Study Trials. VMP (bortezomib, melphalan + prednisone) was very effective in the VISTA registration trial.

The elderly unfit patients with concomitant illness should be evaluated perhaps for one of the non-ASCT regimens, but most will end up on best supportive care which is appropriate.

The speaker passed on two “clinical pearls” as take home messages:

• Aspirin is challenging low molecular weight heparin (LMWH) as the preferred prophylactic agent for thromboembolic events in myeloma patients.
  
• New effective regimens should be used early in the course of multiple myeloma.