An estimated 225,000 Americans are expected to be diagnosed with lung cancer this year.  Recurrent Small Cell Lung Cancer or accounts for 10% to 15% of all lung cancers. This type of lung cancer is very difficult to treat and most patients survive only a year or less after diagnosis. The standard initial therapy for SCLC is chemotherapy with etoposide and platinum-drug. The only FDA-approved therapy for recurrent SCLC is topotecan.
As shown during presentations at the annual meeting of the American Society of Clinical Oncology (ASCO), earlier this year, Rovalpituzumab tesirine, also known as Rova-T or SC16LD6.5, shows promising efficacy against recurrent small cell lung cancer (SCLC). This novel treatment, being developed by AbbVie, combines a novel anti-DLL3 antibody with a powerful anticancer agent, halted tumor growth in 89% of patients with high levels of DLL3 in the tumor and shrank tumors in 39%.
During the IASLC 17th World Conference on Lung Cancer, held December 4 – 7, 2016, in Messe Wien Exhibition & Congress Center in Vienna, Austria, Charles M. Rudin, MD, PhD, a medical oncologist and chief of Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center in New York. will present undated information related to a Phase I trial with Rova-T.
The trial enrolled 74 patients with SCLC that worsened despite at least one prior systemic therapy. About two-thirds of patients had extensive-stage disease at diagnosis, and the other third had limited-stage disease. When tissue samples were available, the researchers assessed levels of DLL3 protein in the tumor tissue
According to Rudin, “Rovalpituzumab tesirine seems to be the first targeted therapy to show efficacy in small cell lung cancer, and we may have identified DLL3 as the first predictive biomarker in this disease.”
About 80% to 85% of all lung cancers are non-small cell lung cancer (NSCLC).
The c-Met receptor is overexpressed in ~50% of patients with Non-Small Cell Lung Cancer or NSCLC. Telisotuzumab Vedotin, also known as ABBV-399 (AbbVie) is a first-in-class antibody-drug conjugate composed of ABT-700, an anti–c-Met antibody, conjugated to the microtubule inhibitor monomethyl auristatin E. Preclinical data support ABBV-399 as a unique strategy to deliver a potent cytotoxin directly to c-Met+ tumor cells.
Clinical data shows that ABBV-399 is well tolerated at a dose of 2.7 mg/kg every 21 days. The data also confirms antitumor activity in patients with c-Met+ NSCLC both as monotherapy and in combination with erlotinib. Updated data of antitumor activity and safety of ABBV-399 as monotherapy and in combination with erlotinib in c-Met+ NSCLC patients will be presented.
NaPi2b Antibody-Drug Conjugate: XMT-1536
Using Fleximer technology, Mersana Therapeutics is developing a novel antibody-drug conjugate that specifically recognizes the NaPi2b protein on the surface of cells.
NaPi2b is a sodium-phosphate transporter expressed at high levels in a majority of non-squamous non-small cell lung cancers. Hence, NaPi2b is an attractive therapeutic target for antibody-drug conjugate development for the treatment of this disease. However, since NaPi2b is also expressed at high levels in type II alveolar cells, there is a potential for normal tissue toxicity with this approach.
Mersana Therapeutics’ MaPi2b antibody-drug conjugate XMT-1536, comprised of a humanized antibody against NaPi2b and approximately 15 auristatin-derived payload molecules per antibody conjugated via the company’s multivaleunt hydrophilic polymer ‘Fleximer technology,’ is being evaluated in in non-squamous NSCLC and non-mucinous ovarian cancer tumor models, indications in which NaPi2b is highly expressed.
The auristatin payload included is enzymatically cleaved upon ADC trafficking to the endosome/lysosome compartment, releasing a cytotoxic auristatin-derivative that is capable of bystander effect killing.
The investigational agent has demonstrated significant efficacy in patient-derived xenograft models representative of the target patient populations. In three patient-derived models of NSCLC, including KRAS-mutant NSCLC, XMT-1536 induced tumor regressions after three weekly doses of 3 mg/kg.
XMT-1536 validates the ability of Mersana’s Fleximer platform to generate targeted therapies that have the potential to address unmet needs and improve outcomes for patients with cancer. At the same time, the investigational compound has shown durable tumor regressions in murine patient-derived NSCLC adenocarcinoma models at doses associated with good tolerability in cynomolgus monkey, and support evaluation of XMT-1536 in patients with NSCLC.
Small Molecule Drug Conjugates
During the IASLC 17th World Conference on Lung Cancer, researchers will present data from ongoing phase I trials of Endocyte’s Small Molecule Drug Conjugate or SMDC EC1456, a folic acid conjugated through a releasable linker system to the potent microtubule inhibitor tubulysin B hydrazine also known as TubBH.
TubBH is a member of the tubulysin class of anti-neoplastic agents that inhibits the polymerization of tubulin into microtubules, a critical component during cell division.
In itself, tubulysins are natural peptidic-like compounds produced by certain myxobacteria. Unlike taxanes and epothilones, tubulysins mimic the tubulysin-destabilizing ability of the Vinca class of agents. However, their in vitro GI50s are generally 20- to 1,000-fold greater. But because tubulysins display extraordinarily high toxicity when dosed in the untargeted form development of this class of compounds was halted. Researchers at endocyte a water-soluble, highly potent, and tolerable form of tubulysin that preferentially targets cells expressing the FR. 
Endocyte’s Small Molecule Drug Conjugate EC1456 targets folate receptor (FR)-expressing cancer cells, which occur in approximately 60% of NSCLC cases and 14% of SCLC.
The objective of the phase trial was to determine the safety, PK, and optimal dosing schedule of the investigational drug.
The drug is based on Endocyte’s proprietary drug conjugation technology for personalized targeted therapies. The company’s SMDCs actively targets receptors that are over-expressed on diseased cells relative to healthy cells. This approach is designed to enable the treatment of patients with highly active drugs at greater doses, delivered more frequently and over longer periods of time than would be possible with the untargeted drug alone.
|OA05.03||Single-Agent Rovalpituzumab Tesirine, a Delta-Like Protein 3 (DLL3)-Targeted Antibody-Drug Conjugate (ADC), in Small-Cell Lung Cancer (SCLC)||Spigel D, Pietanza MC, Bauer TM, et al||Dec. 5||2:20 – 03:50||Strauss 2||Ardizzoni A, Pujol J.|
|MA09.09||First-In-Human Phase 1 Study of ABBV-399, an Antibody-Drug Conjugate (ADC) Targeting C-Met, in Patients with Non-Small Cell Lung Cancer (NSCLC)||Angevin E, Stickler J, Weekes C, et al||Dec. 6||2:20 – 03:50||Strauss 2||Sebastian M, Garon EB.|
|MA09.10||A NaPi2b Antibody-Drug Conjugate Induces Durable Complete Tumor Regressions in Patient-Derived Xenograft Models of NSCLC (ID 5769)||Bergstrom D, Bodyak N, Yurkovetskiy A, et al.||Dec. 6||2:20 – 03:50||Strauss 2||Sebastian M, Garon EB|
|P3.02c-027||Phase I and PK Study of the Folate Receptor-Targeted Small Molecule Drug Conjugate (SMDC) EC1456 in Advanced Cancer: Lung Cancer Subset (ID 5202)||Edelman M, Sachdev J, Harb W, et al.||Dec. 7||02:30 – 03:45||Hall B (Poster Area)|