CONFERENCE NEWS

Highlights from the 35th European Society for Medical Oncology Congress

The 2010 European Society for Medical Oncology (ESMO) congress in Milan, Italy, hosted a record number of attendees, with over 15,000 individuals from 124 different countries in attendance. Approximately 130 sessions were offered, featuring the latest scientific developments in cancer research. The following brief summaries cover some of the most important research findings presented at the meeting, including several with immediate impact on clinical practice. Full text of meeting abstracts can be accessed at http://annonc.oxfordjournals.org/content/21/suppl_8.

Breast Cancer

PARP Inhibitor, Iniparib (BSI-201), Significantly Improves Overall Survival in Triple-Negative Breast Cancer (TNBC) When Added to Gemcitabine/Carboplatin

This abstract presented the updated results of a randomized, phase II study in 123 patients with metastatic triple-negative breast cancer (TNBC). Patients were randomized to iniparib (5.6 mg/kg) plus gemcitabine (gem; 1000 mg/m²) and carboplatin (carbo; AUC = 2) or gem/carbo alone. The addition of iniparib to chemotherapy significantly improved ORR (52.5% vs 32.3%), PFS (median 5.9 months vs 3.6 months), and overall survival (OS) (median 12.3 months vs 7.7 months). Safety profiles were similar between treatment arms, although iniparib was associated with a nonsignificant increase in hematologic toxicity. If the phase III study, which has completed accrual, confirms these results, iniparib will likely be integrated into the management of TNBC.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA11.

Combination of Cetuximab Plus Cisplatin Improves Clinical Outcomes in Triple-Negative Breast Cancer

This abstract presented the results of a randomized, phase II study (BALI-1) of weekly cetuximab (Erbitux^®; 400 mg/m² initial dose, then 250 mg/m²) plus up to six 3-weekly cycles of cisplatin (75 mg/m², day 1) compared with cisplatin alone until disease progression. The combination of cetuximab plus cisplatin significantly increased the ORR (20% vs 10%) and significantly improved PFS (median 3.7 months vs 1.5 months; hazard ratio [HR] = 0.675; P = .032). These results confirm the activity of epidermal growth factor receptor (EGFR) antibodies in TNBC.

Ann Oncol. 2010;21(Suppl 8): Abstract 2740.

Favorable Results of a Randomized Phase II Study of Trastuzumab-DM1 as First-Line Therapy for Metastatic HER2-Positive Breast Cancer

This abstract presented preliminary results at a median follow-up of approximately 6 months. Patients (N = 137) were randomized to trastuzumab-DM1 (an immunoconjugate containing the antimicrotubule agent DM1) at a dose of 3.6 mg/kg or trastuzumab (6 mg/kg) plus docetaxel (75 mg/m² or 100 mg/m² on day 1) every 3 weeks until disease progression. The ORR at 4 months was comparable (48% for trastuzumab-DM1 and 41% for trastuzumab plus docetaxel); however, trastuzumab-DM1 was associated with a much lower incidence of grade 3/4 adverse events (37% versus 75%).

Ann Oncol. 2010;21(Suppl 8): Abstract LBA3.

Gynecologic Cancer

The ICON7 Trial Confirmed PFS Benefit of Bevacizumab in Ovarian Cancer

In this phase III, Gynecologic Cancer InterGroup trial, 1528 women with newly diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer were randomized to 6 cycles of standard 3-weekly chemotherapy with carboplatin (AUC 6) plus paclitaxel (175 mg/m²) or the same regimen plus concurrent bevacizumab (Avastin^®; 7.5 mg/kg) followed by maintenance bevacizumab every 3 weeks for up to 12 additional cycles. Progression-free survival was the primary endpoint. Patients in the bevacizumab arm had significantly prolonged PFS (HR = 0.81; P = .004). The ICON7 trial confirms the results of the Gynecologic Oncology Group (GOG) 0218 trial presented at this year’s American Society of Clinical Oncology (ASCO) annual meeting, which showed 3.8 months improvement of PFS when bevacizumab was added to first-line chemotherapy for ovarian cancer.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA4.

Lung Cancer

EGFR Inhibitors Are Optimal Therapy for NSCLC Patients with Activating EGFR Mutations

Two important late-breaking abstracts on the topic of first-line therapy in non-small cell lung carcinoma (NSCLC) were presented. The first provided results of the randomized, phase III OPTIMAL (CTONG 0802) trial comparing first-line erlotinib (Tarceva^®; 150 mg/day until progression) versus carboplatin (AUC 5) plus gemcitabine (1000 mg/m²) every 3 weeks for up to 4 cycles, in Chinese patients with advanced NSCLC and activating mutations in the EGFR. Tumors that harbor exon 19 deletions or an exon 21 L858R mutation are particularly sensitive to EGFR inhibitors. This study showed that erlotinib was significantly superior to chemotherapy in these patients. Median PFS was 13 months with erlotinib versus 5 months with chemotherapy (HR = 0.16; P<.001), and the ORR was 83% with erlotinib versus 36% with chemotherapy (P<.001).

The second of these abstracts provided the mature results of the OS analysis of a phase III, randomized study of first-line treatment comparing gefitinib (Iressa^®) with carboplatin/paclitaxel in Asian patients with advanced NSCLC (IPASS [Iressa Pan Asian Study] trial), failed to show an OS benefit of gefitinib over chemotherapy in the overall study population and in the subset of patients with EGFR mutations. However, this outcome is likely due to extensive crossover of patients in both arms to the alternative therapy at disease progression. As previously reported in the IPASS study, superior PFS and response rates to gefitinib compared with chemotherapy were shown for EGFR mutation–positive NSCLC, similar to results of the OPTIMAL trial. Based on the results of both of these large trials, the role of EGFR inhibitors in first-line therapy of EGFR mutation–positive NSCLC, at least for Asian patients, is clearly established.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA13.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA2.

Neuroendocrine Tumors

Everolimus Effective in Neuroendocrine Tumors (NET)

Two likely practice-changing clinical trials regarding treatment of advanced neuroendocrine tumors (NET) were presented. In the randomized, placebo-controlled, multicenter, phase III RADIANT-3 (RAD001 In Advanced Neuroendicrine Tumors) trial, everolimus (Afinitor^®;10 mg/day) plus best supportive care (BSC) significantly prolonged PFS by more than 6 months compared to placebo plus BSC (median 11 months vs 4.6 months; HR = 0.35; P<.001). The most common grade 3/4 adverse events associated with everolimus were stomatitis, anemia, and hyperglycemia. In the randomized, placebo-controlled, phase III RADIANT-2 trial, everolimus combined with octreotide long-acting repeatable (LAR) (Sandostatin^® LAR^®) has also demonstrated meaningful clinical benefit and prolonged median PFS by 5 months for patients with metastatic pNET.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA9.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA8.

Prostate Cancer

Abiraterone Acetate Improves Overall Survival in CRPC

Recently, cabazitaxel (Jevtana^®), a novel taxane, has shown a survival advantage over mitoxantrone (Novantrone^®) in patients with castration-resistant prostate cancer (CRPC) who progressed on docetaxel. However, there is evidence that many of these patients’ tumors remain androgen-dependent. Abiraterone acetate is a selective androgen biosynthesis inhibitor that blocks CYP17. In the study presented at the ESMO presidential symposium, 1195 patients with metastatic CRPC who had progressed after docetaxel-based chemotherapy were randomized 2:1 to receive abiraterone (1000 mg) plus low-dose prednisone (5 mg BID) or placebo plus prednisone. A planned interim analysis showed that abiraterone significantly improved median OS (14.8 months vs 10.9 months; P <.001), time to prostate-specific antigen (PSA) progression, radiographic PFS, and PSA response rate compared with placebo. Based on these findings, abiraterone sets a new standard of therapy in the hormonal treatment of metastatic CRPC post-docetaxel.

Ann Oncol. 2010;21(Suppl 8): Abstract LBA5.

FROM THE LITERATURE

The Role of EGFR Antibodies in Colorectal Cancer

What is the role of EGFR antibodies (cetuximab and panitumumab [Vectibix^®]) in the treatment of metastatic colorectal cancer (mCRC): Where do they belong? That is the central question addressed by Axel Grothey, MD, in an editorial that accompanies the reports of two large randomized phase III trials of panitumumab plus standard chemotherapy for the treatment of mCRC. The PRIME (Panitumumab Randomized Trial In Combination with Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) study compared panitumumab plus infusional 5FU, leucovorin, and oxaliplatin (FOLFOX4) with FOLFOX4 alone as first-line treatment (Douillard et al), and the study reported by Peeters et al compared panitumumab plus fluorouracil, leucovorin, and irinotecan (FOLFIRI) with FOLFIRI alone as second-line therapy. In both studies, patients were stratified by KRAS mutational status. Both studies showed that the addition of panitumumab to standard chemotherapy significantly improved PFS in the KRAS wild-type subset. As expected, the benefit of panitumumab was restricted to patients with KRAS wild-type tumors. In the KRAS mutant subset, second-line therapy with panitumumab plus FOLFIRI provided no efficacy benefit, whereas first-line therapy with panitumumab plus FOLFOX4 significantly decreased PFS (HR = 1.29; P = .02) and shortened median survival by nearly 4 months (HR = 1.24; P = .068) compared with FOLFOX4 alone.

Dr Grothey commented that these two studies add substantially to the body of evidence regarding the efficacy and safety of EGFR antibodies in the treatment of mCRC. Based on all the available data in this setting, two things are clear. First, panitumumab and cetuximab appear to have a similar efficacy and are probably interchangeable in clinical practice either as monotherapy or in combination with chemotherapy. Second, when combined with chemotherapy, the benefit of both antibodies is restricted to tumors harboring wild-type KRAS. However, there remain many unanswered questions, and reliable predictive biomarkers are needed. Apart from the negative predictive value of KRAS, one cannot predict which patients are most likely to benefit from treatment with an EGFR antibody. Ongoing translational studies will hopefully shed further light on this topic. It is also unclear why, in the KRAS mutant subset, the addition of an EGFR antibody to FOLFOX consistently results in worse clinical outcomes. This was demonstrated again in the PRIME study. Finally, Dr Grothey pointed out that the benefit of EGFR antibodies, as judged by the hazard ratio for PFS, appears to be greatest when they are used as single-agent salvage therapy or in combination with chemotherapy as second-line therapy. Therefore, he argues that EGFR antibodies could be reserved for later lines of therapy. However, he does point out that there exist some clinical situations in which addition of an EGFR antibody to chemotherapy may be advantageous as initial therapy.

J Clin Oncol. 2010;28(31):4668-4670.

J Clin Oncol. 2010; 28(31):4697-4705.

J Clin Oncol. 2010;28(31):4706-4713.

JAK 1/2 Inhibitor, INCB018424: New Agent on the Horizon for Myelofibrosis

Myelofibrosis is a chronic myeloproliferative disease associated with a poor prognosis. The disease is characterized by clinical signs (eg, progressive anemia, bone marrow fibrosis, and splenomegaly) and a constellation of debilitating symptoms including fatigue, night sweats, pruritis, weakness, bone pain, a hypercatabolic state, and weight loss. Current therapies are palliative with the goal of controlling myeloproliferation, alleviating symptoms due to splenomegaly, and improving anemia and other cytopenias.

Until recently, no molecular targets had been identified in myelofibrosis. Then, in 2005, a common mutation in Janus kinase 2 (JAK2) was discovered, leading to a better understanding of the underlying pathophysiology of myeloproliferative disorders (MPD). A V617F point mutation in the JAK2 gene was identified in more than 90% of patients with polycythemia vera (PV) and approximately 60% of patients with primary myelofibrosis or essential thrombocythemia (ET). It is now clear that the JAK2 pathway, regardless of the mutational status of JAK2, is an important driver in MPD. Clinical development of JAK inhibitors closely followed the discovery of a V617F point mutation, and there are now several agents in late-stage development.

The phase I/II study reported by Verstovsek and colleagues investigated the clinical benefits of an oral Janus kinase 1 (JAK 1) and JAK2 inhibitor, INCB018424 (Incyte Corp/Novartis), in patients with myelofibrosis who required therapy or whose disease was resistant to previous therapy. At the recommended phase II dose (15 mg twice-daily followed by individualized dose titration), 17 of 33 patients (52%) had a rapid ≥50% reduction of splenomegaly lasting ≥12 months. The majority of patients also had rapid improvement in symptoms and quality of life, and many gained weight. These clinical improvements correlated with reductions in plasma levels of many inflammatory cytokines. Patients responded to INCB018424 regardless of whether they had the V617F mutation, but treatment had little effect on improving blood counts or reducing the frequency of cells harboring the mutation. The primary dose-limiting toxicity was thrombocytopenia.

In an accompanying editorial, Alessandro Vannucchi, MD, commented that these results demonstrate the importance of both JAK1 and JAK2 in myelofibrosis and that meaningful clinical benefits can be achieved by inhibiting these targets. However, many questions remain unanswered. For example, it is not clear how INCB018424 induces such dramatic reductions in spleen size, whether a JAK inhibitor can reverse bone marrow fibrosis or improve survival, or whether reducing inflammatory cytokines by inhibiting JAK1 might slow disease progression or development of bone marrow fibrosis. The ongoing phase III trials of INCB018424 (COMFORT [Controlled MyeloFibrosis Study with ORal JAK Inhibitor Treatment]–I and COMFORT-II) will provide further evidence to help answer these questions. Dr Vannucchi anticipates that JAK inhibitors will likely have the greatest clinical utility when combined with other active agents in this disease.

N Engl J Med. 2010;363(12):1117-1127.

N Engl J Med. 2010; 363:1180-1182.

BRIEF REPORTS

Optimizing Bone Health in Breast Cancer Patients

This CME journal supplement provides an overview of the pathophysiology of bone metastases in patients with breast cancer, discusses current management strategies, and describes future directions in optimizing bone health in these patients. Bisphosphonates are the cornerstone of the management of skeletal-related events (SREs) in breast cancer patients with bone metastases. Recently, other novel bone-targeted agents such as the anti–receptor activator of NF-κB ligand (RANKL) monoclonal antibody, denosumab (Xgeva^®), have demonstrated promising activity in this setting. This review also explores the evidence supporting the use of bisphosphonates in prevention of aromatase inhibitor−induced bone loss and addresses potential anticancer activity of zoledronic acid in the adjuvant and neoadjuvant settings.

Recent clinical trial data regarding bone-targeted therapies in breast cancer are discussed in the context of a comprehensive strategy to improve patient management.

Curr Med Res Opin. 2010;26(s3):3-20.

BFR14 Study Suggests Imatinib Treatment Should Not Be Discontinued in Responders With GIST

Imatinib mesylate is the standard-of-care therapy for advanced GIST. The question of stopping treatment with imatinib in long-term responders with advanced GIST was addressed in the randomized BFR14 study of the French Sarcoma Group, which evaluated interruption of imatinib therapy after 1, 3, and 5 years (J Clin Oncol. 2010;28(15S): Abstract 10032). Interruption of imatinib after 1 year of treatment in patients with nonprogressive disease resulted in progression after a median 6.1 months from interruption. In a recent Lancet Oncology article, results of interruption of imatinib after 3 years are reported. Fifty patients with GIST who had received 3 years of treatment with imatinib and had nonprogressive disease were randomized to either continue or interrupt their treatment (25 patients in each group). Unfortunately, the majority of patients who stopped imatinib therapy progressed within 2 years. The 2-year PFS rate was 80% among patients who continued imatinib therapy and only 16% among those who interrupted imatinib therapy (P < .001). Moreover, there was no difference in grade ≥3 adverse events between the two groups. Therefore, the authors concluded that as long as imatinib is tolerated, discontinuing imatinib therapy is not recommended outside of clinical trials.

Lancet Oncol. 2010;11(10):942-949.

For more information on this study, please go to http://primeoncology.org/gist_blay-demetri to view the prIME Oncology interview with Dr Blay, an author of the Lancet Oncology article.

ADDITIONAL PUBLICATIONS WORTH READING

• International Consensus Recommendations on Treating Breast Cancer During Pregnancy. The consensus panel concluded that in most circumstances, breast cancer can be successfully treated during pregnancy. However, treatment should be conducted by experienced specialists in a multidisciplinary setting and should adhere as closely as possible to standard protocols (ie, radiotherapy should be avoided during the third trimester, and chemotherapy avoided during the first trimester). Eur J Cancer. 2010 Oct 5. [Epub ahead of print].
• Prognostic Factors in Chronic Lymphocytic Leukemia (CLL). This review discusses the evidence in support of prognostic factors for CLL, a disease with a highly variable clinical course. The authors propose the use of 5 factors in clinical practice: Clinical staging, lymphocyte doubling time, chromosomal aberrations, physical fitness (comorbidity), and response to therapy. Other prognostic factors remain investigational and are not currently recommended to guide treatment decisions in CLL. Nat Rev Clin Oncol. 2010 Oct 19. [Epub ahead of print].
• Consensus Statement on Renal Impairment in Patients with Multiple Myeloma. Renal impairment is a common complication of multiple myeloma, and rapid intervention to reverse renal dysfunction is critical, especially for patients with light chain cast nephropathy. The consensus panel recommended bortezomib (Velcade^®) with high-dose dexamethasone for these patients; lenalidomide (Revlimid^®) in reduced dose according to renal function is also effective in this setting and can reverse renal insufficiency in a substantial subset of patients when administered at reduced doses according to renal function. J Clin Oncol. 2010;28(33):4976-7984.
• Drug Resistance in Metastatic Castration-Resistant Prostate Cancer. This article review mechanisms of resistance to docetaxel in CRPC. These include cellular mechanisms of resistance such as continued androgen receptor signaling and molecular crosstalk between the androgen receptor and oncogenic survival pathways, resistance related to interactions with the surrounding microenvironment, and impaired drug delivery. New promising therapies that either target or evade these mechanisms of drug resistance are discussed. Nat Rev Clin Oncol. 2010 Sep 21. [Epub ahead of print].

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