Welcome to the inaugural issue of 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.

This goal will be achieved by utilizing a broad array of sources including clinical trial data updates, new drug approvals and other decisions from the EMEA (European Medicines Agency) or the FDA (U.S. Food and Drug Administration), other news releases from the industry, and special features such as reports from society meetings including the European Society for Medical Oncology (ESMO), the European Breast Cancer Conference (EBCC), the European Hematology Association (EHA), the American Society of Hematology (ASH), and the San Antonio Breast Cancer Symposium (SABCS). We welcome your comments and suggestions regarding content and format at primelines@primeoncology.org.

This inaugural issue will be dedicated to important presentations from the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago from May 30 to June 3, 2008.

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BREAST CANCER

Adjuvant Zoledronic Acid: A New Standard of Care in Premenopausal Breast Cancer?
The first efficacy results from a randomized phase III trial (ABCSG-12) which evaluated adjuvant ovarian suppression using goserelin in combination with endocrine therapy (tamoxifen vs. anastrozole), alone or in combination with zoledronic acid (4 mg IV q 6 months), in premenopausal women (N=1,803) with endocrine-responsive early breast cancer (stage I/II) demonstrate that the addition of zoledronic acid to adjuvant endocrine therapy significantly prolonged the primary endpoint, disease-free survival (DFS), and relapse-free survival (RFS) compared to endocrine therapy alone. The risk of DFS events was decreased by 36% (HR=0.64, p=0.01) and the risk of RFS events was decreased by 35% (HR=0.65, p=0.015) for zoledronic acid vs. endocrine therapy alone. At a median follow-up of 5 years, the overall 5-year DFS is 94% and the 5-year OS is 98.2%. There was no difference in DFS or PFS between patients who received tamoxifen alone vs. anastrozole alone (p=0.59).

Conclusion: Adjuvant zoledronic acid improves clinical outcomes beyond those achieved by endocrine therapy alone, and has benefits beyond bone (reduction in contralateral breast cancer, locoregional recurrence, and distant non-bone recurrence) indicative of significant antitumor activity.
Abstract #LBA4 M. Gnant, et al. Plenary Session-J Clin Oncol 26: 2008

A “No-Chemo” Option for HER2+ Metastatic Breast Cancer?
Results of the largest study (296 patients) of two targeted agents, lapatinib (L) and trastuzumab (T), in HER2+ metastatic breast cancer (MBC) demonstrate the synergy of L+T and improved clinical outcome with the combination compared to L alone in heavily pretreated patients whose disease progressed on trastuzumab therapy. The primary endpoint was PFS and secondary endpoints were clinical benefit rate (CBR), RR, OS. The trial’s primary endpoint was reached; for PFS median was 8.1 weeks for L alone and 12.0 weeks for L+T (HR=0.73, p=0.008) with a 27% reduction in risk of progression despite prior treatment with multiple T regimens. PFS at 6 months 28% for L+T and 13% for L. For OS median 39.0 weeks for L vs. 51.6 for L+T (HR=0.75, p=0.106); 6 month OS 70% for L vs. 80% for L+T; 12 month OS 36% for L and 45% for L+T. CBR (CR+PR+SD ≥ 6 months) was 12.4% for L and 24.7% for L+T.

Conclusion: The numbers above demonstrate the synergy and the improved clinical outcomes, but the most exciting thing is that the total HER2 blockade with L+T has the potential to provide a chemotherapy-free option for treatment of HER2+ MBC.
Abstract #1015 J. O’Shaughnessy, et al. J Clin Oncol 26: 2008

Vitamin D Deficiency: A Negative Prognostic Factor in Early Breast Cancer?
Women with vitamin D deficiency at the time of breast cancer diagnosis are at increased risk of distant recurrence and death compared to women with normal vitamin D levels, according to the results of a prospective cohort study of 512 consecutive patients diagnosed with T1-3 N0-1, M0 breast cancer. Vitamin D deficiency was found in 37.5% and insufficient levels were found in 38.5% of patients, therefore only 24% had sufficient vitamin D levels. Low vitamin D levels were associated with premenopausal status, high body mass index (BMI), high insulin levels, and high tumor grade (all with p<0.03). Distant DFS (DDFS) was significantly worse in those with deficient levels of vitamin D (HR=1.94, p=0.02) as was OS (HR=1.73, p=0.02). Vitamin D associations with OS were absent in ER negative breast cancer patients.

Conclusion: Vitamin D deficiency is common at breast cancer diagnosis and predicts a poor outcome for these patients, but should we now obtain vitamin D and insulin levels on all newly diagnosed premenopausal patients?
Abstract #511 P.J. Goodwin, et al. J Clin Oncol 26: 2008

BMD Loss Secondary to Chemotherapy-Induced Ovarian Failure: What Can Be Done?
CALGB trial 79809 evaluated the effect of zoledronic acid (ZA) on bone mineral density (BMD) in premenopausal women who develop ovarian failure due to adjuvant chemotherapy. The trial compared the effect of early ZA (begun with adjuvant chemo) or late ZA (one year after chemo) on change in BMD in the lumbar spine (LS). The primary endpoint was bone loss (percentage change in BMD) at 12 months. 439 patients (median age 47) were randomized to receive ZA q 3 months for 2 years or no ZA (controls). All patients were told to take vitamin D and calcium. Results of the first interim analysis: 38% of patients had ovarian failure at 12 months. Majority of ZA-related toxicity was grade 1-2. The mean percentage change in BMD in the spine from baseline to 12 months was a 2.2% increase in the ZA patients compared to a 6.6% decrease (ie a “bone loss”) in the control arm patients.

Conclusion: Zoledronic acid prevented bone loss with no added toxicity when administered every 3 months. Given the impressive efficacy results the ABCSG-12 trial achieved using ZA q 6 months, was the q 3 month ZA regimen in this trial the best choice?
Abstract #512 C.L. Shapiro, et al. J Clin Oncol 26: 2008

GASTROINTESTINAL CANCER

Can a Biomarker Predict Therapeutic Efficacy in Metastatic Colorectal Cancer?
You have heard of designer drugs and designer jeans, but what about “designer genes”? The KRAS gene mutation status has been shown to have predictive value for treatment with cetuximab plus FOLFIRI chemotherapy in the first-line therapy of patients with metastatic colorectal cancer (mCRC) in the phase III CRYSTAL trial. KRAS mutation status (normal or wild-type [wt] vs. mutated [mt]) was determined in the tumor tissue of 540 patients, and a retrospective analysis was done to evaluate the impact of the KRAS mutations. Treatment was FOLFIRI alone vs. cetuximab plus FOLFIRI (F+C) and primary endpoint was PFS with secondary endpoint RR. Results: PFS for all 1,198 patients favored F+C (HR=0.85, p=0.048) and RR 47% F+C vs. 39% F alone. KRAS wild-type (wt) PFS=HR 0.68, p=0.017 and PFS for KRAS mt (mutant type) HR=1.07, p=0.47; RR for KRAS wt 59% F+C vs. 43% for F alone (p=0.0025) and RR in KRAS mt 36.2% F+C vs. 40.2% F alone.

Conclusion: This large study shows that addition of cetuximab to FOLFIRI significantly increases the PFS compared to chemotherapy alone. The data demonstrate that the treatment effect of cetuximab in patients with KRAS wt is significantly enhanced compared to FOLFIRI alone, whereas patients with KRAS mt do not benefit from C+F. Cetuximab + FOLFIRI could now be considered a first-line option for mCRC in those with KRAS wild-type mutation.
Abstract #2 E. Van Cutsem, et al. Plenary Session-J Clin Oncol 26: 2008

Adjuvant Chemotherapy for Resectable Pancreatic Cancer:
Is There Light at the End of the Tunnel?
Final results of CONKO-001, a randomized phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in 354 eligible patients with resected pancreatic cancer (PC), were presented. After stratification for complete (RO or R1) resection, nodal involvement, and tumor stage patients were randomized to receive either gemcitabine (G) 1 g/m2 d1, 8, and 15 every 4 weeks for 6 months or observation (O). Primary endpoint was DFS, with secondary endpoints OS and toxicity. Results: The analyses confirm significant improvement for G in median DFS (G: 13.4 months, O: 6.9 months, p<0.001). Estimated DFS at 3 and 5 years was 23.5% and 16.0% in G vs. 8.5% and 6.5% in the O group. G significantly improves median OS (G: 22.8 months, O: 20.2 months, p=0.005). Estimated survival at 3 and 5 years was 36.5% and 21.0% for G patients vs. 19.5% and 9.0% for O group patients.

Conclusion: Treatment with gemcitabine for 6 months in patients after complete resection of PC significantly increases DFS and OS compared with O alone. Impressive results in this disease. I think we do see a light.
LBA4504 P. Neuhaus, et al. J Clin Oncol 26: 2008

GENITOURINARY CANCER

Targeting mTOR Produces Positive Results After VEGFr-TKI Therapy in Metastatic Renal Cell Carcinoma
Results from a randomized phase III trial of RAD001 (everolimus), an oral inhibitor of mTOR, an intracellular kinase that regulates cell proliferation and angiogenesis, versus placebo in 410 patients with metastatic renal cell carcinoma (RCC) after progression on VEGFr-TKI therapy (sunitinib, sorafenib, or both) demonstrate a significantly better PFS for patients receiving everolimus compared to those given placebo. The RCC had to have a clear cell component and both arms of the study received best supportive care (BSC) as well. An independent data monitoring committee recommended termination of the trial after interim results demonstrated the primary endpoint (PFS) was superior to placebo (HR=0.30, p<0.0001) with a median PFS of 4.0 months compared to 1.9 months for placebo.

Conclusion: RAD001 (everolimus) established clinical benefit and prolonged PFS with a favorable safety profile in this heavily pretreated patient population. We await the data on median OS.
LBA5026 R.J. Motzer, et al. J Clin Oncol 26: 2008

Tumor Vascular Disrupting Agents: Will They Play a Role in Hormone-Refractory Metastatic Prostate Cancer and Other Solid Tumors?
DMXAA (ASA404) is a novel small molecule tumor vascular disrupting agent (Tumor-VDA) that targets established tumor blood vessels causing apoptosis of tumor endothelial cells. It has synergistic anti-tumor effects in combination with cytotoxics, including taxanes in animal models. A randomized study in NSCLC reported a 5-month survival benefit when DMXAA was added to carboplatin plus paclitaxel. The randomized phase II study presented at ASCO evaluated efficacy and safety of DMXAA in combination with docetaxel in hormone-refractory metastatic prostate cancer (HRMPC). A prior report of this regimen quoted an increase in PSA response rate of 59% vs. 37% for docetaxel alone. This update involves patients with progressive metastatic disease and that have not been previously treated with cytotoxics. Efficacy endpoints include PSA response rate, RR, TTP, and median survival. 38 patients received docetaxel alone (control arm) and 33 patients received DMXAA plus docetaxel (DMXAA arm). 62.5% of patients in the DMXAA arm had at least a 30% reduction in PSA during the first 3 months of treatment compared to 47.4% of patients in the control arm. Response rates were 23.1% in DMXAA arm and 9.1% in the control arm. TTP was 7.3 months in the DMXAA arm and 6.9 months in the control arm.

Conclusion: Addition of the DMXAA to docetaxel was well tolerated and the data reported above support the previous PSA response findings in suggesting improved efficacy with a DMXAA + docetaxel combination compared to docetaxel alone. Further evaluation of DMXAA in HRMPC is warranted.
Abstract #5007 R. Pili, et al. J Clin Oncol 26: 2008

LUNG CANCER

Monoclonal Antibody Therapy Improves Outcomes for EGFR-detectable NSCLC
The FLEX trial, a randomized phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) vs. CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) demonstrated that cetuximab plus CV chemotherapy achieved superior survival over CV alone in patients with advanced EGFR-detectable NSCLC. This is the first study to demonstrate a survival benefit of an EGFR-targeted agent in combination with platinum-based chemotherapy as first-line treatment of NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC. The primary endpoint was OS. 1,688 patients, 85% EGFR(+), ECOG PS mostly 1, stage III B wet 6%/IV 94%. Results: OS (median) 11.3 months for CT + cetuximab vs. 10.1 months for CT (HR=0.87, p=0.044) and 1-year survival 47% CT + cetuximab vs. 42% for CT alone. Subgroup analysis detected difference in median OS for Caucasian compared to Asian patients (9.6 months vs. 19.5 months respectively). Side effects were as expected and manageable with acne-like rash the main cetuximab-related side effect.

Conclusion: Cetuximab added to platinum-based chemotherapy sets a new standard for the first-line treatment of patients with advanced EGFR-detectable NSCLC.
Abstract #3 R. Pirker, et al. Plenary Session-J Clin Oncol 26: 2008

Adjuvant Therapy for NSCLC: Are Patients Paying a Long-Term Price?
The long-term results of the International Adjuvant Lung Cancer Trial (IALT) evaluating adjuvant cisplatin-based chemotherapy in resected NSCLC were presented at the ASCO Annual Meeting and things have changed since the 5-year follow-up data were announced. At that update, the OS had a HR=0.86 and p=0.01 with a 3.9% absolute benefit from adjuvant chemotherapy. New data at the 8 year follow-up are OS HR=0.91, p=0.10. The DFS in the first 5 years was HR= 0.85, p=0.006 and after 5 years is now HR=0.88, p=0.02 at the 8 year follow-up. Non-lung cancer mortality HR is 1.34, p=0.06 now. The presenter stated that the chemotherapy continues to protect from recurrence for the first 5 years after surgery and the difference in the results between less than and more than 5 years of follow-up may suggest possible late adjuvant chemotherapy-related “over-mortality”. He stated that an unexpected excess of deaths after 5 years in the chemotherapy group may be due to late toxicity from chemotherapy—perhaps from etoposide (55% of patients received this drug). Reasons for the excess late mortality are unclear.
Abstract #7507 T. Le Chevalier, et al. J Clin Oncol 26: 2008

HEMATOLOGIC MALIGNANCY

Combining Targeted Agents in Newly Diagnosed Multiple Myeloma: Will Early Results Lead to a New Standard of Care?
Phase I/II safety and efficacy trial of lenalidomide (Len), bortezomib (Bz), and dexamethasone (Dex) in patients with newly diagnosed multiple myeloma. Primary objectives to define the MTD and assess response rate to Len/Bz/Dex. Patients: 68 enrolled, median age 58 years, 51% men, 67% IgG, 49% ISS stage II/III. Patients have received median of 6 cycles. Toxicities manageable with no unexpected toxicities, no G4 PN, 2 DVTs, no treatment related mortality. ORR 98% with 71% CR/nCR/VGPR. MTD reached: Len 25 mg d 1-14, Bz 1.3 mg/m2 on d 1-4, 5-8 for up to eight 21 day cycles.

Conclusions: Len/Bz/Dex is very active and well tolerated in newly diagnosed patients, and this regimen has no adverse affect on stem cell harvesting. These early results are encouraging and hopefully will be confirmed in phase III trials.
Abstract #8520 P.G. Richardson, et al. J Clin Oncol 26: 2008

Are Responses to Second Generation TKIs Durable in CML?
Extended 2-year follow-up data from the phase II START-C study of dasatinib therapy for patients with chronic phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib was reported at the ASCO Annual Meeting in Chicago. The starting dose of dasatinib was 70 mg BID. The primary endpoint was major cytogenetic response rate (M CyR) and 387 patients were evaluated. Results: 24 month response rates with dasatinib MCyR 62%, CCyR (complete cytogenetic response rate) 53%, and MMR (major molecular response) among CCyR 79%. Duration of MCyR at 24 months: 88% of patients without loss of MCyR; duration of CCyR=90% remain in CCyR at 24 months.

Conclusion: These data demonstrate continuing efficacy of dasatinib at 2 years. 70 mg BID dose well tolerated but more non-heme side effects (diarrhea, rash, headache, edema, and pleural effusions) at 24 months compared to 1 year. In a subsequent phase III dose-optimization study, 100 mg once daily was optimal and the most favorable risk-benefit ratio was with this dose that was approved for CML-CP.
Abstract #7009 M.Mauro, et al. J Clin Oncol 26: 2008

What Hematologic Response is Necessary To Get Clinical Benefits in Higher-Risk Myelodysplastic Syndromes?
A large international phase III trial (AZA-001) showed that azacitidine (AZA) is the first myelodysplastic syndromes (MDS) treatment to significantly extend OS vs. conventional care regimens (CCR). While the IWG 2000 emphasizes the importance of CR to extend survival, clinical validation in MDS is lacking. This analysis evaluated effects of AZA vs. CCR on 1-year survival of MDS patients from the AZA-001 trial including those with IPSS Int-2 or high risk. Patients (N=358) randomized to either AZA (75 mg/m2/day SC x 7d q 28d) + best supportive care (BSC) or to CCR (low dose Ara-C, induction 7+3 chemotherapy, or BSC only). One-year survival rates were determined for all treated patients and for AZA subsets according to IWG-defined CR or PR, stable disease (SD), or hematologic improvement as best response, or disease progression (DP). AZA maintained a significant survival benefit vs. CCR with exclusion of CR patients from the analysis (HR for OS=0.65) and 1-year survival rates were significantly higher in AZA-treated patients than in CCR-treated patients: 68.2% vs. 55.6% (p=0.015). When analyzed by IWG best response, all response categories including SD showed an OS benefit with AZA treatment.

Conclusion: Results are the first to show that achievement of CR is not an obligate endpoint to extend OS in higher-risk patients with MDS. IWG responses of HI, PR, or CR are associated with improvement in OS with AZA treatment. AZA is a disease-modifying agent that prolongs OS by effects that appear distinct from its cytotoxic or anti-leukemia action alone. IWG responses of HI, PR, or CR are associated with improvement in OS with AZA treatment.
Abstract #7006 A. List, et al. J Clin Oncol 26: 2008

Expanding the Options for Imatinib-Resistant Chronic Myelogenous Leukemia
Updated phase II results from a trial of nilotinib in patients with imatinib-resistant or –intolerant chronic myelogenous leukemia in chronic phase (CML-CP) confirm that the drug induces significant and durable responses in this patient population, it is well tolerated with minimal occurance of grade 3-4 adverse events (A/E), and minimal cross-intolerance to imatinib. Nilotinib dose was 400 mg p.o. BID (2 hours from meals) with the possibility to dose escalate to 600 mg BID. Primary endpoint was rate of major cytogenetic response rate (MCyR). Total of 321 patients (71% imatinib-resistant and 29% imatinib-intolerant). Results: 72% had received prior imatinib (I) doses >600 mg; of the 206 who did not have a complete hematological remission (CHR) at baseline, 77% achieved CHR during nilotinib therapy. Overall, MCyR observed in 57%; 41% had complete CyR (CCyR). MCyR in 55% of I-resistant and 63% of I-intolerant patients. Median time to CHR 1.0 months, and to MCyR was 2.8 months. 84% maintained MCyR at least 18 months and at 18 months the estimated OS rate was 91%. Nilotinib treatment is ongoing in >50% of patients enrolled. PFS at 12 months 79% and 67% at 18 months. OS at 12 months 95% and at 18 months is 91%. Toxicities: Most frequent grade 3-4 AEs: Thrombocytopenia 28%, neutropenia 30%, and anemia 10%. Non-heme A/Es were evaluated serum lipase 45% with 16% G 3-4. No pericardial or pleural effusions.

Conclusions: With the impressive efficacy, more tolerable safety profile, and minimal cross-intolerance nilotinib is a candidate for both single agent use and for future trials with combination regimens.
Abstract # 7010 H. M. Kantarjian, et al. J Clin Oncol 26: 2008