ESMO Commentary: Innovative approaches and drugs in early development phase show promising results in solid tumours

VIENNA, Austria – Novel approaches and drugs are showing promising results in solid cancers. “There are reasons to be optimistic for breaking new treatments in solid tumours,” Dr Markus Joerger, Attending Medical Oncologist at St Gallen Cancer Centre, Switzerland, commented as results were presented at the European Cancer Congress (ECC 2015) in Vienna. A humanised monoclonal antibody, antibody drug conjugates, FASN inhibition, and a multi-tyrosine kinase inhibitor are on the horizon for solid tumours.

New treatments are on the way for difficult to treat cancers and refractory/relapsing solid tumours. “Nasopharyngeal cancer (NPC) is an important cause of cancer deaths in middle-aged patients in Asia, particularly China and Taiwan,” said Joerger. “Systemic cytotoxic treatment alone is not very effective, but is used concurrently with radiotherapy as a radiosensitiser. For patients relapsing after chemoradiotherapy, there are currently no effective systemic treatments.”

Commenting on breaking findings in NPC, Joerger said: “The KEYNOTE-028 clinical trial demonstrated clinical activity of the anti-PD1 monoclonal antibody pembrolizumab in patients with PD-L1-positive NPC (abstract 2801). This is a very important new finding that gives hope for this group of patients with an otherwise very poor prognosis.”

“Pembrolizumab is a highly selective, humanised monoclonal antibody against PD-1 that is designed to block the negative immune regulatory signaling of the 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.”

Novel approaches are also on the way in triple-negative breast cancer (TNBC) and platinum-refractory ovarian cancer. Joerger said: “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 (ADC) (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.”

Patients with relapsing or refractory small-cell lung cancer (SCLC) have a particularly poor prognosis, and it is a long time since significant progress has been made. But Joerger said: “There is hope with Rovalpituzumab Tesirine (Rova-T), an antibody-drug conjugate that targets DLL3 which is highly expressed in about two-thirds of SCLC. In a new phase 1 clinical study (LBA 7), Rova-T exhibited a good safety profile, and a substantial response rate of 34% in patients with DLL3-positive, relapsed SCLC.” 

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),” said Joerger. “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,” said 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.”

Inhibition of fatty acid synthase (FASN) is an entirely original approach to treat solid malignancies. Joerger said: “It involves the disruption of palmitate biosynthesis and results in apoptosis of tumour 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 stabilisations in 31 patients with solid tumours (LBA 27). TVB-2640 proved to be safe when given alone or in combination with paclitaxel monotherapy.”

The ongoing clinical evaluation of novel agents in early development phase will now need to show if the encouraging results can be translated into benefits for patients with several solid tumours.


Abstracts presented at ECC 2015, held 25–29 September in Vienna, Austria:

LBA 7: 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). M.C. Pietanza, USA. Monday 28th September 2015 – 14:35-17:25 Presidential Session III HALL D1

LBA 27: 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. H.T. Arkenau, UK. Sunday 27th September 2015 – 17:00-18:10 Proffered Paper Session LEHAR 1

LBA 28: A phase 1 study of PF-06647020, an antibody-drug conjugate targeting PTK7, in patients with advanced solid tumors. A.W. Tolcher, USA. Sunday 27th September 2015 – 17:00-18:10 Proffered Paper Session LEHAR 1

LBA 29: Entrectinib (RXDX-101), an oral pan-Trk, ROS1, and ALK inhibitor in patients with advanced solid tumors harboring gene rearrangements. S. Siena, Italy. Sunday 27th September 2015 – 17:00-18:10 Proffered Paper Session LEHAR 1

LBA 30: 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. L.S. Rosen, USA. Sunday 27th September 2015 – 17:00-18:10 Proffered Paper Session LEHAR 1

2801: Antitumor activity and safety of pembrolizumab in patients with PD-L1–positive nasopharyngeal carcinoma: Interim results from a phase 1b study. C. Hsu, Taiwan. Saturday 26th September 2015 – 10:30-12:50 Proffered Paper Session HALL C1

Information contained in this commentary was provided by the interviewee.