NEWS FROM ESMO

This section of the newsletter will be dedicated to summaries of several important abstracts from the 33rd European Society for Medical Oncology (ESMO) Congress in Stockholm, Sweden on 12-16 September 2008. A special Clinical Update based on information presented at a Satellite Symposium during ESMO entitled “Responding to the Challenge of Advanced Melanoma” will conclude this portion of the newsletter.

Targeted Therapy Better Than Chemotherapy for NSCLC?

In Asia, a high proportion of non-smokers develop NSCLC with adenocarcinoma histology. Fifty to sixty percent of them have tumors with mutations in the epidermal growth factor receptor (EGFR) that are responsive to therapy with EGFR tyrosine kinase inhibitors (TKIs). Investigators designed a phase III randomized trial of 1,217 Asian non-smokers with stage IIIB/IV adenocarcinoma of the lung, chemo-naive, to receive oral gefitinib (Iressa™) (G) 250 mg daily or carboplatin + paclitaxel (C/P) chemotherapy. Primary endpoint was to assess non-inferiority of G vs C/P for PFS. Results: G demonstrated superior PFS compared with C/P (HR 0.74; p<0.001), exceeding the primary endpoint. Treatment effect was not constant over time, favoring C/P for the first 6 months and G for the remaining 16 months, probably driven by differences in PFS outcomes for patients with EGFR mutation M(+) and M(-) tumors. ORR was significantly higher with G than C/P (43% vs 32.2%, odds ratio [OR] 1.59; p=0.0001). QoL and tolerability profiles were significantly higher for G. PFS was longer for G than C/P in M(-) patients. The authors conclude that this study has demonstrated superior treatment outcomes for G over standard chemoRx as first-line treatment for this clinically selected population. They believe that gefitinib should be one of the standard first-line therapies for such patients.

Comment: Gefitinib and other EGFR TKIs are now considered as second-line therapy after failure of chemoRx, but in this special patient population they should be considered for use as initial treatment.

Mok T, et al. LBA2 Annals of Oncology 19 (Supplement 8) 2008.

A Promising New Option for Relapsed/Recurrent Ovarian Cancer

Trabectedin (Yondelis®) is a novel agent originally extracted from sea squirts and now prepared by a semi-synthetic process. A phase III study of a trabectedin (T) combined with pegylated liposomal doxorubicin (PLD) vs PLD alone in relapsed, recurrent ovarian cancer (OC) has demonstrated that the PLD + T combination is superior to PLD in both the primary endpoint PFS, and secondary endpoint of response rate (RR). The trial enrolled 672 patients whose disease progressed after response to first-line therapy. The patients’ median age was 57, and 64% had a platinum-free interval (PFI) > 6 months. Results: Median PFS for PLD + T was 7.3 months and for PLD 5.8 months (HR=0.79; p=0.019). For patients with a PFI > 6 months, the median PFS was 9.2 months for PLD + T vs 7.5 months for PLD alone (HR=0.73; p=0.017). RR for all patients: 28% vs 19% (p=0.008) and if PFI > 6 months: 35% vs 23%. Adverse events were manageable with appropriate monitoring.

This is one of the largest studies designed to establish clinical activity of a non-platinum doublet in second-line treatment of OC. Positive trials in recurrent OC are rare, so these results are quite encouraging.

Monk BJ, et al. LBA4 Annals of Oncology 19 (Supplement 8) 2008.

TKI Shows Activity in Head and Neck Cancer

Lapatinib (Tyverb®), an orally active dual tyrosine kinase inhibitor (EGFR and HER2) currently approved in the United States for treatment of advanced breast cancer, has demonstrated single-agent activity in another cancer, locally advanced squamous cell carcinoma of the head and neck (SCCHN). EGFR overexpression is found with high frequency in many cancers including H+N cancer and typically is associated with a more aggressive clinical course. A phase II study of therapy-naive SCCHN patients randomized participants to receive either lapatinib or placebo for 2 to 6 weeks prior to standard concurrent platinum-based chemoRx and radiation. Results showed an improved response rate (CR and PR) for patients given lapatinib of 86% vs 63% for placebo. A CR rate after receiving chemoradiation was seen in 28% in lapatinib arm vs only 7% in the placebo arm, suggesting lapatinib may enhance the effect of subsequent chemoradiation.

Del Campo JM, et al. Abstract 6880 Annals of Oncology 19 (Supplement 8) 2008.

Clinical Update From ESMO: Advanced Melanoma

This Clinical Update is based on information presented during a satellite symposium at the ESMO Congress on 14 September 2008 entitled, “Responding to the Challenge of Advanced Melanoma”. Jeffrey Weber, MD, PhD, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida discusses the topic “Enhancing the Anti-Melanoma Activity of T-cells by Targeting the CTLA-4 Receptors,” and this update features highlights from his presentation. The entire program may be viewed as a webcast at www.primeoncology.org.

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is a negative regulator of T-cell response and can exert a suppressive effect on the immune response against melanoma cells. Two human monoclonal antibodies directed against CTLA-4 have been studied in clinical trials: ipilimumab (an IgG1) which fixes complement and tremelimumab (an IgG2) which does not fix complement. The focus of this update will be ipilimumab (Bristol-Myers Squibb and Medarex).

Ipilimumab has been studied as monotherapy and in combination with vaccines, cytokines (IL-2), and chemotherapy. Significant antitumor activity has been seen in each of these treatment regimens. Side effects seen with inhibition of CTLA-4 are called immune-related adverse events (IRAEs) and are inflammatory in character. The most common of the IRAEs are rash, colitis, and hepatitis, and the occurrence of these events is generally associated with favorable anti-melanoma response. The timing of occurrence of antitumor responses is quite variable. It is important for clinicians to recognize the unique kinetics of response following ipilimumab administration. Indeed, some patients treated with ipilimumab may initially show disease progression followed by either prolonged stable disease or an objective response.

Currently, a phase III registration trial of ipilimumab for first line therapy of metastatic melanoma is ongoing. This trial will randomize 500 treatment naive patients to receive ipilimumab (10 mg/kg q 3 weeks x 4 cycles) + DTIC vs DTIC alone.

PHARMACEUTICAL NEWS

• Oral Anticoagulant Approved By European Commission
  Bayer’s once-daily oral anticoagulant rivaroxaban (Xarelto®), has received final approval from the European Commission for the prevention of DVT and PE in patients undergoing hip or knee replacement surgery. Rivaroxaban, which does not require monitoring of coagulation tests, demonstrated superior efficacy compared to enoxaparin in a pivotal phase III trial.
  
  
  
• Can NSCLC Histology Affect Response to Therapy and Overall Survival?
  Last month, the United States FDA approved Eli Lilly and Company’s pemetrexed (Alimta®) for use in combination with cisplatin therapy for the first-line treatment of patients with locally advanced or metastatic non-squamous NSCLC. The approval was based on the results of a randomized study of 1,725 chemo-naive patients with stage IIIB/IV NSCLC comparing overall survival (OS) after treatment with either pemetrexed + cisplatin (AC) or gemcitabine + cisplatin (GC). Results: median survival (AC 10.3 months vs GC 10.3 months), median PFS (AC 4.8 months vs GC 5.1 months) and overall response (AC 27.1% vs GC 24.7%).
  
  A pre-specified analysis of the impact of NSCLC histology on OS was conducted in this trial and clinically relevant differences according to histology were observed. In the non-squamous cell NSCLC patient subgroup, median survival was 11.0 months in AC and 10.1 months in GC treated groups, but in the squamous cell histology subgroup the median survival was 9.4 months in AC vs 10.8 months in GC treated patients. This unfavorable effect on OS associated with squamous cell histology observed with pemetrexed was also noted in a retrospective analysis of the single agent trial of pemetrexed vs docetaxel in a similar patient population after prior chemotherapy. Current product labeling has been revised to recommend that pemetrexed is also not indicated in patients with squamous cell lung cancer after prior chemotherapy.
  
  These results demonstrate that NSCLC histology can impact treatment outcome and have an unfavorable effect on patients’ overall survival.
  
  
  
• Oral TKI Achieves Dramatic Reduction in Risk
  of GIST Recurrence
  On August 27, 2008 the United States FDA granted priority review status to Novartis’ imatinib mesylate (Glivec®), an oral tyrosine kinase inhibitor (TKI), as the first therapy for adjuvant use after surgery in KIT-positive gastrointestinal stromal tumors (GIST). Similar regulatory submissions have been filed by EMEA and other countries as well. The filings are based on clinical data from an international phase III randomized trial of 708 GIST patients who had complete surgical resection of their disease and then immediately began treatment with either imatinib 400 mg daily or placebo daily for one year. The primary endpoint was recurrence-free survival (RFS). Results: 98% of patients receiving imatinib remained recurrence-free at one year following surgery compared to 82% of those receiving placebo. This represents an unprecedented 89% reduction in risk of KIT-positive recurrence after surgery in patients treated with imatinib compared to placebo. A decision for final approval is expected within 6 months.
  
  Food for thought: With the adjuvant imatinib for GIST era about to begin, the question of treatment duration will become a hot topic. This trial addressed one year of therapy with trials of 2 years and 3 years ongoing now, but optimal duration is currently unclear.
  
  

FROM THE LITERATURE
Myeloma

A New Standard of Care in Multiple Myeloma?
Treatment with melphalan plus prednisone has been a standard of care for non-transplant candidates with newly diagnosed multiple myeloma for more than four decades. During the past 10 years, high-dose therapy with hematopoietic stem-cell transplantation (SCT) has become the preferred therapy for patients under the age of 65 years, but older patients and patients with significant co-existing illnesses usually cannot tolerate this treatment. The median age at diagnosis of myeloma is approximately 70 years, therefore more than half the patients with newly diagnosed myeloma may not be eligible for high-dose therapy. For these patients, improved treatment is needed.

Results of a phase III trial comparing melphalan + prednisone vs melphalan + prednisone plus bortezomib (Velcade®) in this patient population (n=682) demonstrate that the addition of bortezomib significantly improves the median time to progression (TTP), the primary endpoint by 7.4 months (HR=0.48; p<0.001). The bortezomib group was superior to the melphalan + prednisone for the following: partial response or better, 71% vs 35%; CR rate, 30% vs 4% (p<0.001); median duration of response, 19.9 months vs 13.1 months; overall survival, HR of 0.61 (p=0.008).

This study demonstrates the superior efficacy of bortezomib plus melphalan and prednisone compared to melphalan and prednisone alone for the front-line treatment of patients who are 65 years of age or older and cannot receive more aggressive therapy. The authors state that since superior efficacy in the treatment of myeloma has now been shown with bortezomib or thalidomide in combination with melphalan and prednisone, the two-drug combination should no longer be considered the standard of care in patients 65 years of age or older.

San Miguel JF, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359: 906-17.

Breast Cancer

How Many Prognostic Tests Do We Need?
The September 1, 2008 issue of the Journal of Clinical Oncology (JCO) includes an article and an accompanying editorial that address prognostic tests for breast cancer. For the reader, several questions immediately come to mind: Is one test “better” than the other(s)? Should we develop more tests to cover all of the various factors involved? Is there an “ideal” prognostic test for breast cancer?

• Currently two independently validated prognostic tests are widely used,
  Adjuvant! Online and the Oncotype DX^TM recurrence score (RS) assay. Adjuvant! is a mathematical algorithm that provides an estimate of risk of breast cancer (BC) related death at 10-year follow-up based on the tumor size, the number of involved nodes, and estrogen receptor (ER) status. Estimates of the efficacy of therapy are based primarily on the proportional risk reduction (PRR) analysis from the Oxford overview. The 21-Gene RS Assay, a genomic classifier, provides individualized risk estimates based on measurement of the expression of 16 cancer-related genes and has the potential to more accurately identify individuals who benefit from chemotherapy.
  
  
• The trial by Goldstein et al compared these two very different prognostic tests in a retrospective study of BC patients with hormone receptor (HR) positive disease and zero to three positive axillary nodes who received contemporary chemohormonal therapy. It should be noted that the study population is quite different from the originally intended clinical target population (ER+, axillary node negative BC treated with tamoxifen) for RS assay. Result: RS was a highly significant predictor of recurrence, in both node (-) and node (+) disease (p<0.001 for both). RS also predicted recurrence more accurately than clinical variables when integrated by an algorithm modeled after Adjuvant! that was adjusted to 5-year outcomes. The 5-year recurrence rate was only 5% or less for the estimated 46% of patients who have a low RS (<18). The 21-Gene RS Assay may be useful to select low-risk patients for abbreviated chemotherapy regimens or high-risk patients for more aggressive regimens or clinical trials evaluating novel therapies.
  
  
• The most significant information from this trial is that RS and Adjuvant! are independent of each other with a modest concordance, BUT within each risk category defined by Adjuvant!, RS provided additional prognostic information and vice-versa. For the 43% of those who were in the low Adjuvant! risk group, the risk of recurrence was increased 2.6-fold and 4.0-fold respectively for intermediate and high RS. For the 30% of patients in the intermediate Adjuvant! risk group, the risk of recurrence was increased 9.6-fold and 5.8-fold respectively for intermediate and high RS. For the 24% of patients in the high Adjuvant! risk group, only high RS was associated with a significantly increased risk of relapse (2.6-fold). It is also clear that Adjuvant! can also provide additional information for risk groups defined by RS. Thus the best scenario for a patient is to have a low RS score and low risk according to Adjuvant!. If either of the two shows poor risk, then the risk of relapse appears to be increased.
  
  
• Lastly, this study also demonstrated a need to integrate RS and Adjuvant! into a single prognostic algorithm. There are some technical hurdles to overcome, but new trials to implement this strategy are underway. So which test is better? A combined approach appears to provide the best of both worlds.
  
  Goldstein LJ, et al. J Clin Oncol 26: 4063-4071, 2008
  Paik S. J Clin Oncol 26: 4058-4059, 2008

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