A number of novel anticancer drugs are showing very promising results in the treatment of solid cancers. These cancers, including various forms of lung cancers, breast cancers, ovarian cancer, etc. generally have a high patient base with a high unmet need.
During the biennial European Cancer Congress (ECC 2015), being held in Vienna, Austria (September 25 – 29, 2015) which combines the efforts of the most important European oncology professionals with the aim of improving the prevention, diagnosis, treatment and care of cancer patients, results of a variety of ongoing clinical trials and new treatment options were presented. Among the novel treatment options are a humanized monoclonal antibody, a number of antibody-drug conjugates or ADC and other (targeted) therapies, including FASN inhibition, and a multi-tyrosine kinase.
“There are [real good] reasons to be optimistic for breaking new treatments in solid tumors,” Markus Joerger, MD, attending medical oncologist at the St. Gallen Cancer Centre (Kantonsspital St.Gallen) in St. Gallen, Switzerland, noted after reviewing the trial results presented at the 2015 European Cancer Congress.
Refractory/relapsing solid tumors
The results presented are especially interesting for the treatment of difficult to treat cancers and refractory/relapsing solid tumors. “Nasopharyngeal cancer (NPC) is an important cause of cancer deaths in middle-aged patients in Asia, particularly China and Taiwan,” explained Joerger. “Systemic cytotoxic treatment alone is not very effective, but is used concurrently with radiotherapy as a radiosensitiser. For patients relapsing after chemo-radiotherapy, there are currently no effective systemic treatments.”
However, important new findings in the treatment of nasopharyngeal cancer, may offer some hope for patients with an otherwise poor prognosis. “The KEYNOTE-028 clinical trial demonstrated clinical activity of the anti-PD1 monoclonal antibody pembrolizumab (Keytruda®, Merck; formerly MK-3475 and lambrolizumab) in patients with PD-L1-positive NPC (abstract 2801),” Joerger noted.
“Pembrolizumab is a highly selective, humanised monoclonal antibody against PD-1 that is designed to block the negative immune regulatory signaling of the programmed cell death 1 or PD-1 receptor expressed by T-cells. Future studies will focus on combinatorial immunotherapeutic approaches in patients not responding to anti-PD-(L)1 monoclonal antibodies.”
Triple negative breast cancer
Novel approaches are also on the way in triple-negative breast cancer (TNBC) and platinum-refractory ovarian cancer.
Researchers have found that in solid cancers, in contrast to hematological malignancies, only a limited number of antibody-drug conjugates are internalized. Due to the limited number of receptors on the cell surface, many trial drugs fail.
Novel antibody-drug conjugates with a variety of MOAs are rapidly changing this. This is especially important in the treatment of patients with triple-negative breast cancer and ovarian cancer.
Commenting on this phenomenon, Joerger observed: “Both diseases are difficult to treat, and novel approaches are urgently needed. Encouraging clinical activity has been shown with PF-06647020, an antibody drug conjugate being developed by Pfizer (late-breaking abstract [LBA] 28). PF-06647020 is comprised of a humanized monoclonal antibody directed against PTK7, linked to an auristatin microtubule inhibitor payload. PTK7 is frequently expressed in solid malignancies,” .
Refractory Small-Cell Lung Cancer
Patients with relapsing or refractory small-cell lung cancer or SCLC have a particularly poor prognosis. High-grade pulmonary neuroendocrine tumors, which includes SCLC, as well as large cell neuroendocrine carcinoma or LCNEC, represent ~18% of primary lung neoplasms in older patients with a history of smoking. Today, these cancers remain among the most deadly malignancies. One of the reasons is that it has been more than 30 years since significant progress has been made in developing viable therapeutic options. But, based on the research presented this year, Joerger noted: “There is hope with Rovalpituzumab Tesirine, an antibody-drug conjugate being developed by Stem CentRx, that targets delta-like 3 or DLL3 which is highly expressed in [human neuroendocrine tumors and their tumor-initiating cells including about] two-thirds of SCLC.” However, DLL3 is not expressed at detectable levels in normal, healthy, tissues.
“In a new phase I clinical study (LBA 7), Rovalpituzumab Tesirine exhibited a good safety profile, and a substantial response rate of 34% in patients with DLL3-positive, relapsed SCLC,” Joerger said.
The DLL3-targeted antibody-drug conjugate Rovalpituzumab Tesirine, also known as Rova-T or SC16LD6.5 is comprised of a humanized anti-DLL3 monoclonal antibody conjugated, via a dipeptide linker, to a DNA-damaging pyrrolobenzodiazepine (PBD) dimer toxin with a drug-to-antibody ratio (DAR) of 2.
In preclinical trials Rovalpituzumab tesirine induced tumor regression and prolonged time to progression significantly outperforming cisplatin (Platinol®, Platinol®-AQ)/etoposide (Toposar®, VePesid®, Etopophos®) in DLL3-expressing SCLC patient-derived xenograft tumor models. Based the promising activity, a first-in-human phase I trial, researchers initiated a first-in-humans clinical trials in patients with recurrent SCLC.
The preliminary phase I study data presented at ECC 2015, for example, confirms that patients with SCLC who were sensitive to first-line combination chemotherapy and were positive for DLL3 gene expression, experienced an objective response rate or ORR of 64%. The data also showed that in the third-line setting, where a standard treatment is currently not available, the ORR in DLL3-expressing patients (n = 15) was 45%. The researchers further confirmed that across all patients in the third-line setting (n = 35), the ORR was 20%. The researchers found that the trial drug had a manageable toxicity and demonstrated significant anti-tumor activity as a single agent in second- and third-line patients with refractory small-cell DLL3 positive lung cancer.
Tyrosine kinase inhibitor targeting
Tyrosine kinase inhibitor targeting is another innovative approach. “A novel multi-tyrosine kinase inhibitor, entrectinib, targeting TrkA,-B,-C, ROS1 and EML-ALK has been explored in molecularly-selected patients with advanced or metastatic solid tumours (LBA 29),” Joerger said. “Toxicity was manageable, and 10 out of 11 patients harbouring gene rearrangements of NTRK 1/2/3, ROS1 or EML-ALK and receiving entrectinib at the recommended dose experienced a partial tumour response. Targeting NTRK gene rearrangements is a novel approach and could benefit subgroups of patients suffering from e.g. non-small-cell lung cancer (NSCLC).”
Researchers are also exploring the use of Notch3 targeting. “The Notch pathway plays an important role in the growth of several solid tumours, including breast and ovarian cancer and melanoma,” explained Joerger. “In particular, Notch3 alterations such as gene amplification and upregulation are associated with poor patient survival. Research using Notch3 targeting as an innovative approach to treat solid malignancies included 27 patients unselected for Notch3 who received increasing doses of the anti-Notch3 antibody-drug conjugate PF-06650808. Responses were seen in two breast cancer patients (LBA 30). While preliminary, targeting Notch3 may become a new treatment approach in patients with selected solid tumours.”
The anti-Notch3 antibody-drug conjugate PF-06650808 is being developed by Pfizer.
Fatty Acid Synthase
Fatty acid synthase or FASN expression increases with tumor progression and is linked with chemoresistance, tumor metastasis, and diminished patient survival in a variety of tumor types. Based on initial results, researchers believe that FASN inhibition may have anti-tumor activities in a number biologically diverse preclinical tumor models.
Although inhibition of fatty acid synthase or FASN is an entirely original approach to treat solid malignancies, this research provides mechanistic and pharmacologic evidence that FASN inhibition offers a promising therapeutic strategy for treating a solid tumors, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. Joerger explains: “Fatty Acid Synthase of FASN involves the disruption of palmitate biosynthesis and results in apoptosis of tumor cells. The first-in-human study of the first-in-class FASN inhibitor, TVB-2640, led to one partial remission and several long-term disease stabilizations in 31 patients with solid tumours (LBA 27). TVB-2640 proved to be safe when given alone or in combination with paclitaxel mono therapy.” This novel drug is being developed by 3-V Biosciences, based in Menlo Park, CA.
In preclinical studies, 3-V Biosciences’ FASN inhibitor TVB-2640 have shown good tolerability profiles, potent anti-tumor properties in vitro and in vivo, modulation of tumor signaling pathways, alteration of tumor membrane structure and impact on tumor metabolism and strong synergy with paclitaxel.
Many of the approached mentioned by Joerger are still in early clinical investigation. Further, ongoing, clinical trials designed to evaluate these novel agents will be required to show if these initially encouraging results can be translated into benefits for patients with several solid tumors.