Background

AVID100, an anti-EGFR-DM1 conjugate, showed potent activity in preclinical models in vitro and in vivo including in cell lines resistant to approved anti-EGFR mAbs.

Methods

Patients with advanced or metastatic epithelial malignancies without available therapy and likely to express EGFR are being enrolled into sequential dose escalation cohorts (Phase 1a) to assess safety, tolerability, and PK parameters to identify the recommended Phase 2 dose (R2PD) of 1-hour infusions on an every 3 week schedule. In the Phase 2a segment preliminary antitumor activity will be assessed in expansion cohorts of patients with breast cancer (BC) and squamous cell carcinoma of the head and neck (SCCHN) with EGFR overexpression (3+ in ≥ 50% of tumor cells).

Results

No cycle 1 dose limiting toxicities (DLTs) have been observed in Cohorts 1-6 (dose (N); 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (3) mg/m² every 3 weeks). Currently, patients are being evaluated in Cohort 7 (270 mg/m²; approximately 6.9 mg/kg). Preliminary clinical PK results show exposure levels of AVID100 have been achieved that exceed therapeutic levels predicted from preclinical studies. Safety and tolerability have been acceptable with G2-3 lipase elevations without clinical sequelae, infusion-related reactions ameliorated by premedication and infusion prolongation, reversible thrombocytopenia, and reversible transaminase elevations without other evidence of hepatic toxicity. Other G1-2 treatment-related adverse events reported include: rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, diarrhea, elevated amylase, elevated alkaline phosphatase, hypomagnesemia, and hypokalemia. Patients entered to the Phase 1a segment were not screened for EGFR overexpression and included patients with: colorectal cancer (9); breast cancer (2); and single cases of ovarian, pancreatic, urothelial, and cervical cancer. Prolonged disease stabilization has been observed in 3 of these unselected patients (colorectal, ovarian, cervical).

Conclusions

AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity will be evaluated in EGFR-overexpressing patients with BC and SCCHN.

Clinical trial identification

NCT03094169

Legal entity responsible for the study

Formation Biologics

Funding

CPRIT

Disclosure

A. Tolcher: Former investigator for Formation Biologics and am currently a member of the Board of Directors of Formation Biologics. K. Papadopoulos: Investigator on a clinical study for Formation Biologics. Y. Cole, K. Rivas: Research nurse working on a clinical study for Formation Biologics. S. Chandana, N. Lakhani: Investigator on a study for Formation Biologics. S. Sinclair: Employee of Formation Biologics. D. Wood, P.I. Nadler: Medical consultant for Formation Biologics.

Background

Targeted alpha therapy (TAT) involves selective delivery of isotopes that emit highly energetic alpha particles to cancer cells leading to their ultimate destruction, while minimizing collateral damage to healthy surrounding cells. The high linear energy transfer of alpha particles makes it possible to consider targets with relatively low cellular expression levels (or concentration) and to treat hypoxic and chemotherapy resistant tumors. The limited emission of beta and gamma radiation from the appropriate alpha emitting isotopes significantly reduces the complexities of administration and decreases the chance of exposure to caregivers and family members. Despite the potential, clinical development of targeted alpha therapeutics has been slow due to a variety factors that will be discussed.

Radium-223 dichloride, the only approved alpha therapy in clinical medicine, provides the proof of concept for internal alpha emitting radioisotope therapy in cancer treatment. ²²³RaCl₂ is “targeted” via its fundamental physicochemical properties as it incorporates into the bone matrix at sites of bone formation. The interest in TAT is based partly on the clinical usefulness of ²²³RaCl₂ in castration resistant prostate cancer. However, ²²³RaCl₂ is only suitable for treating bone metastases, so new targeted therapies that aim to treat liquid and solid soft tissue tumors are now under clinical development. The clinical experience to date with TAT will be reviewed focusing on the status, advantages and disadvantages of different radioisotope payloads (²¹³Bi, ²²⁵Ac, ²¹¹At, ²¹²Pb and ²²⁷Th), targets (CD33, CD20, CD22, PSMA, HER2, somatostatin receptor and others), and targeting agents (small molecules, peptide and antibodies) that have been employed to date.

The momentum in the TAT field is illustrated by a growing number of promising TAT compounds that are in or near starting clinical trials. The current status of these TAT molecules (²²⁵Ac-PSMA-617, ²¹²Pb-AR-RMX, ²²⁵Ac-lintuzumab, FPX-01, ²¹¹At-BC8-B10, BAY1862864) will be discussed with particular attention to those agents that use ²²⁵Ac (t½ 10 days) and ²²⁷Th (t½ 18.7 days) as the therapeutic payload. The half-life of these two alpha emitting isotopes permits manufacturing and delivery of ready-to-use doses to patients. Biodistribution and dosimetry may require the use of a separate imaging radioimmunoconjugate when alpha isotopes with limited gamma emission are used.

The potential role of TAT in hematological malignancies and in solid tumor treatment will also be discussed along with systemic and local administrations strategies, both of which may prove to have clinical utility in coming years.

Legal entity responsible for the study

Fusion Pharmaceuticals

Disclosure

I. Molnar, E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals Inc. E. Burak, J. Valliant: Employee and stockholder of Fusion Pharmaceuticals. J. Forbes, R. Simms: Employee of Fusion Pharmaceuticals.

Funding

Fusion Pharmaceuticals

Background

Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices. Antibody drug conjugates (ADCs) can offer significant benefit to patients suffering from a variety of solid and liquid tumors by combining the specificity of monoclonal antibodies and the cellular cytotoxicity of antineoplastic small molecules. While ADCs have tremendous potential, dose-limiting toxicity remains the largest barrier to robust patient responses. Through the utilization of proprietary protease cleavable N-acyl sulfonamide (NAcS) linked hemiasterlin and auristatin payloads, we have generated highly efficacious ADCs with improved therapeutic indices.

Methods

Antibodies against HER2 and three additional known clinical targets were conjugated with our N-acyl sulfonamide auristatin (NAcS-ADCs) or with MMAE or DM4 controls (control ADCs) via cleavable linkers and used to assess in vitro binding and cytotoxicity. The therapeutic window of NAcS-ADCs and control ADCs was compared by assessing efficacy in mouse xenograft models and tolerability/pharmacokinetics in non-human primates (NHPs).

Results

NAcS-ADCs demonstrated similar in vitro binding and cytotoxicity compared to control ADCs. This activity was recapitulated in vivo with similar tumor growth inhibition in mouse xenograft models. In an NHP tolerability/pharmacokinetic study, the trastuzumab NAcS-ADC was well tolerated with a highest non-severely toxic dose (HNSTD) of 18 mg/kg, as compared to an HNSTD of 3 mg/kg for the trastuzumab MMAE control ADC. NAcS-ADCs for all three additional targets were well tolerated at doses of 18 mg/kg (single dose IV infusion) compared to their corresponding control ADCs that showed severe to life-threatening neutropenia at markedly lower doses.

Conclusions

The increase in tolerability and comparable efficacy of the NAcS-ADCs vs. the control ADCs against HER2 as well as three additional known clinical targets highlight the broad applicability of our novel NAcS-linked auristatin payload and its ability to expand the therapeutic window of ADC therapy.

Legal entity responsible for the study

Zymeworks Inc.

Disclosure

J. Babcook, R. Davies, S. Barnscher, J. Rich, K. Yin, V. Fung, G. Winters, G. Garnett, P. Kaminker, K. Hamblett: Employee of Zymeworks Inc. and have a financial interest in the company in the form of stock or stock-options.

Funding

Zymeworks Inc.

Background

The number of cytotoxic payload classes with different modes-of-action which have been successfully employed in antibody-drug conjugates (ADC) is still rather limited. So far, ADCs with microtubule inhibitors, DNA binding payloads, or topoisomerase I inhibitors have been advanced into clinical testing. To this end, the identification of ADC payload classes with a novel mode of action will increase therapeutic options. The kinesin spindle protein (KSP/Eg5/KIF11) is an ATP-dependent motor protein involved in the separation of centrosomes in G2/M phase which is an essential event in mitosis. KSP inhibitors (KSPi) have generated interest due to their high antitumor activity in preclinical models. However, transferring the preclinical potency of small molecule KSP inhibitors (SMOL KSPis) into highly efficient clinical regimens with a sufficient therapeutic window has remained challenging. Targeted delivery of payloads selectively to tumor cells while sparing normal cells may enlarge the therapeutic window of KSPis.

Methods

We have investigated a new pyrrole subclass of KSPis. The KSP inhibitor was profiled on a large panel of 370 cancer cell lines and showed sub-nM potency against cell lines originating from different cancer indications. ADCs were generated through the conjugation of the KSPi to antibodies targeting different cancer antigens and characterized in vitro and in vivo.

Results

KSPi-ADCs showed strong and specific internalization and displayed specific and potent anti-proliferative activity in vitro. The ADCs exhibited sub-nanomolar potency in antigen-positive cancer cell lines and more than 100-fold selectivity versus control-ADCs in cytotoxicity assays. Furthermore, selective anti-tumor efficacy of KSPi-ADCs was demonstrated in vivo using both cancer cell line-derived (CDX) as well as patient-derived (PDX) xenograft models. Specific accumulation of KSPi-ADC payload metabolites in the tumor versus other murine tissues was demonstrated in biodistribution studies.

Legal entity responsible for the study

Bayer AG

Disclosure

A. Sommer: Stock shareholder of Bayer AG. My husband is employed by Boehringer Ingelheim.

Funding

Has not received any funding

Background

D-type cyclins (D1, D2 and D3) together with their associated cyclin-dependent kinases CDK4 and CDK6 are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and CDK6 are currently in clinical trials for patients with several cancer types, with promising results. We demonstrated that cyclin D3-CDK6 phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumor cells reduces PPP and serine pathway flows, thereby depleting anti-oxidants NADPH and glutathione. This, in turn, elevates the levels of reactive oxygen species and causes tumor cell apoptosis. The pro-survival function of cyclin D-associated kinase operates in tumors expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumor subsets that undergo cell death and tumor regression upon CDK4/6-inhibition. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism represents a particularly powerful oncogene that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.

Targeting immune checkpoints such as the one mediated by programmed cell death protein 1 (PD-1) and its ligand PD-L1 have been approved for treating multiple types of human cancers with durable clinical benefit. However, many cancer patients fail to respond to anti-PD-1/PD-L1 treatment, and the underling mechanism(s) is not well understood. Recent studies revealed that response to PD-L1 blockade might correlate with PD-L1 expression levels on tumor cells. Hence, it is important to mechanistically understand the pathways controlling PD-L1 protein expression and stability, which can offer a molecular basis to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade in cancer patients. We found that PD-L1 protein abundance is regulated by cyclin D-CDK4, and that inhibition of CDK4/6 in vivo elevates PD-L1 protein levels. Combining CDK4/6 inhibitor treatment with anti-PD-1 immunotherapy enhanced tumor regression and dramatically improved overall survival rates in mouse tumor models. Our study uncovered a novel molecular mechanism for regulating PD-L1 protein stability by a cell cycle kinase and revealed the potential for using combination treatment with CDK4/6 inhibitors and PD-1/PD-L1 immune checkpoint blockade to enhance therapeutic efficacy for human cancers.

Legal entity responsible for the study

Dana-Farber Cancer Institute

Disclosure

P. Sicinski: Receive a research grant from Novartis.

Funding

NIH

Background

While immune checkpoint inhibitors (ICI) are efficacious and lead to durable responses in patients with various cancers, only a minority of patients respond. An approach to increase the efficacy of ICI is to combine them with chemotherapy, in order to enhance immunogenic cell death and “prime” the immune system. However, chemotherapy itself can cause damage to various cell types of the immune system, potentially diminishing the activity of the ICI combination. Using trilaciclib, a short-acting IV CDK4/6 inhibitor that preserves hematopoietic stem cells and enhances immune system function during chemotherapy, we have developed a novel approach to preserve immune system function during chemotherapy to allow optimal activity of ICI.

Methods

To evaluate the efficacy of trilaciclib added to chemotherapy/ICI combinations, tumor-bearing immunocompetent mice (MC38 or CT26) were treated with trilaciclib, chemotherapy (oxaliplatin or 5-FU), or ICIs (anti-PD-L1 or anti-PD-1) alone or in combination, and tumor size was measured for up to 100 days. To gain insight into the effect of transient exposure of trilaciclib on the tumor microenvironment, we are examining the cellular composition, proliferation status and gene expression of tumor immune infiltrates from MC38 tumor-bearing mice post-treatment.

Results

The addition of trilaciclib to chemotherapy/ICI significantly improved anti-tumor activity and prolonged overall survival. Potential mechanisms by which transient trilaciclib exposure enhances anti-tumor activity include: reduction of Treg populations, preservation of T lymphocyte function, and changes in gene expression leading to enhanced lymphocyte activation and a pro-inflammatory tumor microenvironment.

Conclusions

These findings suggest that transient trilaciclib-induced G1 cell-cycle arrest in tumor immune infiltrates prior to chemotherapy/ICI combination treatment creates a favorable tumor microenvironment resulting in increased antitumor activity. Based on these findings, a Phase 2 study to assess the safety and efficacy of trilaciclib or placebo with carboplatin, etoposide, and atezolizumab in first-line extensive stage SCLC patients is ongoing (NCT03041311).

Legal entity responsible for the study

G1 Therapeutics

Funding

G1 Therapeutics

Disclosure

P.J. Roberts, A.Y. Lai, J.A. Sorrentino, R.K. Malik: All authors are employees of G1 Therapeutics.

Background

CDK4/6 inhibitors are being used to treat a variety of human malignancies. In well-differentiated (WDLS) and dedifferentiated (DDLS) liposarcoma we had previously suggested that their clinical promise might be associated with their ability to down-regulate the MDM2 protein. In cultured cell lines, the down-regulation of MDM2, after cells left the cell cycle following CDK4 inhibition, induces them to progress from quiescence into senescence. Today, we will present further evidence supporting the idea that senescence after growth arrest is a mechanism that can account for the activity of CDK4 inhibitors, at least in WD/DDLS.

Results

We have found that PDLIM7 physically associates with MDM2 and prevents MDM2 turnover in quiescent cells induced by treatment with palbociclib (PD0332991). However, if PDLIM7 is sequestered by an intracellular cadherin, CDH18, MDM2 turnover occurs following treatment with PD0332991, driving the quiescent cell into the senescent state. CRISPR knockout of CDH18 can prevent both MDM2 degradation and senescence in cells challenged with CDK4 inhibitor. Establishing the clinical relevancy of this pathway, CDH18 expression is associated with clinical outcome and histologic subtype in patients with advanced WDLS and DDLS from our previous phase II trials. 92% of WDLS and 57% of DDLS had high CDH18 expression judged by immunohistochemistry. High expression of CDH18 in DDLS was associated with improved clinical outcomes.

Conclusions

This supports the hypothesis that the transition from quiescence to senescence has clinical relevance as a mechanism for this class of drugs.

Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center

Funding

National Cancer Institute, USA

Disclosure

All authors have declared no conflicts of interest.