A great number of novel anticancer drugs are showing promising results in the treatment of solid cancers. 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 ongoing research and new treatment options are presented.
?There are 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 on the results were presented at the European Cancer Congress (ECC 2015) in Vienna. A humanised monoclonal antibody, antibody drug conjugates (ADCs), FASN inhibition, and a multi-tyrosine kinase inhibitor are on the horizon for solid tumors.
… There [many] are reasons to be optimistic for breaking new treatments in 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 1or 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. ?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 or ADC being developed by Pfizer (late-breaking abstract [LBA] 28). PF-06647020 is comprised of a humanised monoclonal antibody directed against PTK7, linked to an auristatin microtubule inhibitor payload. PTK7 is frequently expressed in solid malignancies,? Joerger observed.
Refractory Small-Cell Lung Cancer
Patients with relapsing or refractory small-cell lung cancer or SCLC have a particularly poor prognosis, and it is a long time since significant progress has been made in developing treatment options of this disease. But, based on the research presented this year, Joerger noted: ?There is hope with Rovalpituzumab Tesirine, an antibody-drug conjugate that targets delta-like 3 orDLL3 which is highly expressed in about two-thirds of SCLC. In a new phase I clinical study (LBA 7), Rovalpituzumab Tesirineexhibited a good safety profile, and a substantial response rate of 34% in patients with DLL3-positive, relapsed SCLC.?
The phase I study data presented at ECC 2015 confirms that patients with SCLC who were sensitive to first-line combination chemotherapy and were positive for DLL3 gene expression and were treated with Rovalpituzumab Tesirine,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 DLL3-targeted antibody-drug conjugate Rovalpituzumab Tesirine, also known asRova-TorSC16LD6.5 which is being developed byStem CentRx, a biotechnology company based in South San Francisco (CA), iscomprised of a humanized anti-DLL3 monoclonal antibody conjugated to a DNA- damaging pyrrolobenzodiazepine (PBD) dimer toxin.
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).?
Notch3
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 orFASN 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 offatty acid synthaseor 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 by3-V Biosciences, based inMenlo Park, CA.
In preclinical studies, 3-V Biosciences’FASN inhibitor TVB-2640have shown good tolerability profiles, potent anti-tumor propertiesin vitroandin vivo, modulation of tumor signaling pathways, alteration of tumor membrane structure and impact on tumor metabolism and strong synergy with paclitaxel.
Many of the approaches 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.
For more information/references
[1] Safety, activity, and response durability assessment of single agent rovalpituzumab tesirine, a delta-like protein 3 (DLL3)-targeted antibody drug conjugate (ADC), in small cell lung cancer (SCLC). LBA 7. Pietanza MC. Monday 28th September 2015 ? 14:35-17:25 Presidential Session III HALL D1. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
[2] Evidence of activity of a new mechanism of action (MoA): A first-in inhuman study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640, as monotherapy or in combination. LBA 27 Arkenau HT. Sunday 27th September 2015 ? 17:00-18:10 Proffered Paper Session LEHAR 1. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
[3] A phase 1 study of PF-06647020, an antibody-drug conjugate targeting PTK7, in patients with advanced solid tumors. Tolcher AW. Sunday 27th September 2015 ? 17:00-18:10 Proffered Paper Session LEHAR 1. LBA 28. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
[4] Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements. Siena S. Sunday 27th September 2015 ? 17:00-18:10 Proffered Paper Session LEHAR 1. LBA 29. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
[5] A Phase 1 dose escalation, safety, and pharmacokinetic study of PF-06650808, an anti-Notch3 antibody drug conjugate, in adult patients with advanced solid tumors. Rosen LS. Sunday 27th September 2015 ? 17:00-18:10 Proffered Paper Session LEHAR 1. LBA 30. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
[6] Antitumor activity and safety of pembrolizumab in patients with PD-L1?positive nasopharyngeal carcinoma: Interim results from a phase 1b study. Hsu C. Taiwan. Saturday 26th September 2015 ? 10:30-12:50 Proffered Paper Session HALL C1. 2801. Abstract presented at ECC 2015, held 25?29 September in Vienna, Austria.
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