One consequence of understanding the molecular underpinnings of cancer is that the disease has become increasingly fragmented. What was once a monolithic disorder is becoming, in one sense, a group of orphan diseases a fact that has brought spectacular successes in the form of molecularly targeted therapies for some patients, but also brings obvious challenges for an industry still used to, or at least still pining for, blockbusters.
But the converse can also be true. As molecular decoding of cancers becomes more common, cancers across different organ systems can be revealed as having common molecular origins which can simultaneously lead to more appropriate treatments for patients and larger markets for targeted drugs.
One famous example is the writer Christopher Hitchens, who is being treated with chronic myelogenous leukemia (CML) drug Gleevec (imatinib, Novartis AG) for esophageal cancer. Gleevec is not usually indicated for esophageal cancer, but a molecular analysis of Hitchens' tumor suggested he is likely to respond to the drug.
More generally, Gleevec, which was specifically developed for CML patients with the Philadelphia chromosome, has also proven useful to treat certain forms of gastrointestinal stromal tumors.
A study presented at this week's AACR-NCI-EORTC (American Association for Cancer Research, National Cancer Institute and European Organization for Research and Treatment of Cancer) International Conference: Molecular Targets and Cancer Therapeutics meeting in San Francisco suggested that inhibiting the anaplastic lymphoma kinase (ALK) is similarly making its way in the world.
As its name suggests, ALK's relevance to cancer was originally discovered in anaplastic lymphoma, where the kinase is frequently amplified, mutated or rearranged.
But the drug is currently better known as the target of Pfizer Inc.'s Xalkori (crizotinib), which targets an EML4-ALK fusion and was approved last year for the 5 percent to 10 percent of non-small-cell lung cancer patients with such a fusion.
At the AACR-NCI-EORTC meeting, researchers presented results that indicated ALK may be mutated in the majority of a particularly hard-to-treat form of breast cancer: inflammatory breast cancer.
Inflammatory breast cancer, Fredika Robertson told reporters at a press conference describing her team's findings on Sunday, is relatively rare but the most lethal subtype of breast cancer, with a five-year survival rate of only around 40 percent. The odds are so bad, in fact, that 'these patients have typically been excluded from clinical trials.' Robertson is professor in the department of experimental therapeutics at the University of Texas M.D. Anderson Cancer Center and a member of the Morgan Welch Inflammatory Breast Cancer Research Program.
The reason inflammatory breast cancer is so lethal is that it has a high propensity to metastasize. Furthermore, when inflammatory breast cancer cells do metastasize they tend to do so as clusters or 'tumor emboli,' not as single cells.
In their studies, Robertson and her team used genomics and proteomic methods to look at tumor samples from 15 patients with inflammatory breast cancer. They found that 13 of those samples had amplified levels of ALK.
'It's early days yet,' Robertson stressed. 'The molecular signature of [inflammatory breast cancer] has only begun to be elucidated . . . but we see a high proportion of amplification of ALK.'
A Phase I trial of Novartis' experimental ALK inhibitor LDK378 is being conducted based on the findings.
In other news from the AACR-NCI-EORTC meeting:
ACT Biotech Inc., of San Francisco, reported Phase II results showing gastric cancer patients who were treated with a combination regimen containing telatinib, an oral VEGF inhibitor, along with Xeloda (capecitabine, Roche AG) and cisplatin and who responded with a large decrease of a specific angiogenesis biomarker the soluble form of VEGFR2, or sVEGFR2 were found to have a lower risk of disease progression and death compared to patients with smaller decreases. Researchers found that both overall survival (OS) and progression-free survival (PFS) were longer for patients with a greater than 33 percent decrease in sVEGFR2 following telatinib treatment. PFS increased to 11.6 months for those patients compared to 4.7 months for patients with smaller decreases, while OS was 7.6 months for patients with smaller decreases and has not yet been reached for those with larger sVEGFR2 decreases.
Cerulean Pharma Inc., of Cambridge, Mass., presented clinical and nonclinical data on its lead candidate, CRLX101 , that demonstrated encouraging progression-free survival (PFS) times in non-small-cell lung cancer (NSCLC). Combined data from the company's 62-patient Phase I/IIa study showed that median PFS time was 4.4 months for 21 of the 38 Phase IIa patients. The nonclinical findings presented at the conference highlighted the activity of CRLX101 in xenograft tumor models of highly treatment refractory subtypes of lung cancer. The data indicated CRLX101 achieved antitumor activity by localizing and penetrating deep into tumor tissue and releasing its cytotoxic payload inside the tumor cells. Cerulean is recruiting in Russia and Ukraine for a randomized Phase II trial in NSCLC patients who have progressed through one or two prior regimens of chemotherapy. The primary endpoint is overall survival.
CureFAKtor Pharmaceuticals LLC, of Buffalo, N.Y., presented preclinical results showing FAK inhibitor CFAK-Y15 decreased glioblastoma brain tumor growth in vivo, increased cell death in vitro and reduced tumor growth in vivo in colon cancer and non-small-cell lung cancer (NSCLC). Y15, in combination with chemotherapy drug temozolomide, demonstrated a statistically significant 98 percent reduction in glioblastoma tumor volume in mice compared with the untreated group, and it significantly reduced tumor volume compared with each drug alone. When used in combination with other chemotherapy drugs, Y15 caused time and dose-dependent death in six out of nine lines of NSCLC tested, with almost 100 percent cell death at 10 uM dose. In addition, it enhanced paclitaxel-induced cell death. A third preclinical study found that the growth of colon cancer cells treated in combination with Y15 and 5-fluorouracil was significantly less than cells treated with either agent alone. Separately, CureFAKtor presented preclinical data showing that analogues of FAK inhibitor CFAK-C4 disrupted FAK-vascular endothelial growth factor receptor 3 nteraction and inhibited pancreatic cancer tumor growth as single agents. The analogues demonstrated minimum toxicity and high specificity, triggering a 40 to 60 percent reduction in mouse pancreatic tumor growth after 30 days.
Enzon Pharmaceuticals Inc., of Piscataway, N.J., presented clinical and preclinical data from three messenger ribonucleic acid (mRNA) candidates based on the company's locked nucleic acid (LNA) technology platform. A Phase I, open-label, dose-escalation study of EZN-3042, an LNA oligonucleotide targeting survivin mRNA, in combination with docetaxel, in 16 patients with advanced solid malignancies demonstrated good tolerability and antitumor activity in previously treated patients and established a maximum-tolerated dose of 6.5 mg/kg for EZN-3042 combined with docetaxel 75 mg/m2. Preclinical studies using its other LNA-based compounds, showed that EZN-3920, a HER3 mRNA antagonist, reduced HER3 mRNA and protein expression associated with antitumor effects in animal models where EGFR or HER2 are known to drive tumor growth. The data suggested that the LNA-based antagonist of HER3 may have utility in a wide variety of cancer patients when given alone or in combination with other agents that target the EGFR/HER2 signal transduction axis. Data for EZN-3892, a β-catenin mRNA antagonist, suggested the compound may be useful in treating tumor types where growth is driven by β-catenin.
Exelixis Inc., of South San Francisco, reported data from two ongoing clinical trials exploring lower starting doses of cabozantinib in cancer patients, including a Phase I investigator-sponsored trial to assess the lowest effective dose of cabozantinib for metastatic bone lesions in patients with metastatic castration-resistant prostate cancer (CRPC). Preliminary data suggested that a daily starting dose of 40 mg resulted in high rates of bone scan response assessed by computer-aided detection in men with CRPC and bone metastases. Separately, the company reported interim data on pain relief and related reduction in narcotic analgesic use with cabozantinib in CRPC patients with bone metastases. Of 27 patients with average worst pain or greater than or equal to 4 and taking narcotics at baseline, 15 (56 percent) decreased their dose by at least 30 percent, including seven (26 percent) who discontinued narcotic drugs, four (15 percent) on a stable dose (no change or change less than or equal to 30%), and eight (30 percent) who increased narcotic drug usage.
MethylGene Inc., of Montreal, presented Phase I results of in oral Met/VEGF receptor tyrosine kinase inhibitor MGCD265 administered as a single agent in advanced solid cancers refractory to standard therapy. The open-label, dose-escalation study of 47 patients showed the compound was tolerable, with no treatment-related serious adverse events, and showed early signs of clinical benefit when dosed in an intermittent (week on, week off) schedule.
Myrexis Inc., of Salt Lake City, reported Phase I data showing that heat-shock protein inhibitor MPC-3100 was generally safe and well tolerated at doses below 600 mg per day in 26 patients with recurrent cancer or cancer refractory to available systemic therapy. The best clinical response was stable disease (12/26; 46 percent), with a median duration of 11.1 weeks. In a separate poster, the firm reported preclinical data showing that MPC-8640, the lead compound in its nicotinamide phosphoribosyltransferase inhibitor program, produced complete tumor growth inhibition at lower doses and substantial tumor regression at higher doses in a mouse model.
Oncolytics Biotech Inc., of Calgary, reported interim Phase II results on the intravenous administration of Reolysin in combination with gemcitabine (Gemzar, Eli Lilly and Co.) in advanced pancreatic cancer. All but one of 12 patients reported symptomatic improvement, including seven with stable disease (SD) for 12 weeks or longer, for a clinical benefit rate of 58 percent. Two patients had SD for 36 weeks or longer. The treatment was well tolerated with manageable adverse events.
Oncothyreon Inc., of Seattle, presented data from two Phase I/II trials of PX-866, its irreversible, pan-isoform phosphatidylinositol-3-kinase inhibitor. The Phase I portion evaluating PX-866 in combination with docetaxel enrolled 43 patients with advanced cancer and found no dose-limiting toxicities, with the combination of PX-866 and docetaxel generally well tolerated. In 28 patients evaluable for response, best response was stable disease in 21 patients and progressive disease in seven patients, for a disease control rate of 75 percent. The Phase I evaluating PX-866 in combination with cetuximab enrolled 11 patients with either incurable metastatic colorectal carcinoma or incurable progressive, recurrent or metastatic squamous cell carcinoma of the head and neck, also finding no dose-limiting toxicities. Of eight patients evaluable for response, four patients had a confirmed partial response, three patients had stable disease and one patient had progressive disease, for a disease control rate of 88 percent. Both trials have progressed to Phase II.
Plexxikon Inc., of Berkeley, Calif., a member of the Daiichi Sankyo Group, reported preclinical findings showing that treatment with PLX3397, an oral candidate designed to target macrophages and osteoclasts, reprogrammed the tumor microenvironment, supporting further development of the single-agent treatment for certain cancers and malignancies. Results from a preclinical prostate cancer model specifically showed significant tumor growth inhibition, reduction in cancer bone pain and prevention of pathologic bone remodeling. In a separate presentation, Plexxikon reported preclinical data from next-generation BRAF inhibitors showing that they were able to avoid the drug-induced skin lesions observed with other BRAF inhibitors.
Syndax Pharmaceuticals Inc., of San Francisco and Waltham, Mass., said a pharmacodynamic analysis in a subset of patients from ENCORE 301, its placebo-controlled, randomized Phase II study of exemestane with and without entinostat in postmenopausal estrogen-receptor positive breast cancer patients, demonstrated an association of the pharmacodynamic marker lysine hyperacetylation with clinical outcome. The company previously reported that the study achieved its primary endpoint of improving progression-free survival.
TetraLogic Pharmaceuticals, of Malvern, Pa., reported data on its Smac mimetic candidate TL32711, which is nearing completion of a single-agent Phase I study in solid tumors and lymphomas and a Phase Ib five-arm combination study in solid tumors. The data suggested that TL32711 caused potent and sustained suppression of inhibitor of apoptosis protein cIAP1 in patient peripheral blood mononuclear cells and tumor biopsies over seven days at tolerable dose levels with evidence of apoptosis pathway activation and early signs of antitumor activity. Tumor growth inhibition was observed in primary melanoma tumor xenografts following treatment with TL32711 as a single agent, and combining the compound with carboplatin and paclitaxel resulted in a further enhancement in antitumor efficacy.
Ziopharm Oncology Inc., of New York, presented Phase Ib data showing that Zymafos (palifosfamide, ZIO-201) in combination with etoposide and carboplatin in patients with non-small-cell lung cancer and other selected cancers can be given at a maximum-tolerated dose of 130 mg/m2, with a dose-limiting toxicity of neutrpenic fever. Of 13 evaluable patients, five had partial responses, four had stable disease and four had progressive diseases. Separately, the company reported preclinical data on the effect of darinaparsin (Zinapar, or ZIO-101), an organic arsenic, on the Hedgehog signaling pathway in prostate cancer. Data suggested that darinaparsin is a potent inhibitor of DU145 prostate cells, which inhibited prostate spheroid growth and prostate stem cell colony formation. Combination studies with taxotere showed synergistic cell destruction at high fixed doses.