Tumor Regrowth Rate Research Articles

8801 Towards Safe and Efficacious Medical Therapy for Patients with Clinically Non-Functioning Pituitary Tumors

Abstract Disclosure: D. Zhang: None. M. Bergsneider: None. W. Kim: None. M.B. Wang: None. H. Vinters: None. A.P. Heaney: None. Clinically non-functioning pituitary tumors (CNFTs) account for one-third of all pituitary adenomas. They do not cause clinical and/or biochemical evidence of tumor-related hormone hypersecretion, grow insidiously and typically present with mass effect symptoms such as headache and visual field deficits. Surgical resection is the current standard of care for CNFTs but complete resection is infrequently achieved due to their size and invariable invasion of locally adjacent structures. CNFT remnant tumor regrowth rates approach 50% and these patients may need repeat surgery and/or radiotherapy (RT). The latter is quite effective in achieving tumor control, but carries a risk of hypopituitarism of ∼ 40% at 10 years. Although dopamine agonists and somatostatin receptor ligands have been explored as medical therapy, there are currently no consistently effective medical treatments for CNFTs. There is a clear unmet need for novel safe and effective medical therapies for these comparatively common tumors. In a highly innovative approach we have used patient-derived ex vivo 3D tumoroid human CNFTs in an automated high throughput compound screen (HTS) to identify novel tumoricidal and growth inhibitory compounds for CNFTs. To date, we have screened ∼4,000 compounds and have identified 13 potential hits that inhibited tumor cell proliferation (a reduction of 76±15%) and induced apoptosis (induction rate of 8.2 ± 6.6) in the CNFT tumoroids respectively. The hit compounds to date fall into 3 categories based on their targets, namely Na+/K+-ATPase inhibitors (n=6), reactive oxygen species (ROS) regulators (n=4), and cell cycle inhibitors (n=3). Representative “hit” compounds from each group identified in our primary screen were rescreened in triplicate in 20 concentrations from 25µM to 50pM at 2-fold dilutions. Dose-response curves characterized compound doses that inhibited cell viability by 50% (IC50) and ranged from 13nM to 103nM. Two of these 3 compounds also induced 2-3-fold apoptosis at 0.1uM with the final compound displaying a potent 5-10-fold pro-apoptotic effect at 0.15uM concentration. In parallel, we used single cell RNA sequencing to validate targets that emerged from our HTS and to characterize the mechanism of action (MOA) of these hit compounds. As proof of concept, several of the known drug targets were noted to be amongst the highest differentially expressed genes in the CNFT tumor cell population. This approach validating a candidate target in conjunction with demonstrable activity of a drug for that same target in CNFTs may simultaneously provide us with a back-bone molecule to further develop with structural activity relationship analysis and/or allow us to individualize drug choice in patients based on immunocytochemical tumor target expression. Presentation: 6/1/2024

Genome-Wide DNA Methylation Profiling as a Prognostic Marker in Pituitary Adenomas-A Pilot Study.

The prediction of the regrowth potential of pituitary adenomas after surgery is challenging. The genome-wide DNA methylation profiling of pituitary adenomas may separate adenomas into distinct methylation classes corresponding to histology-based subtypes. Specific genes and differentially methylated probes involving regrowth have been proposed, but no study has linked this epigenetic variance with regrowth potential and the clinical heterogeneity of nonfunctioning pituitary adenomas. This study aimed to investigate whether DNA methylation profiling can be useful as a clinical prognostic marker. A DNA methylation analysis by Illumina's MethylationEPIC array was performed on 54 pituitary macroadenomas from patients who underwent transsphenoidal surgery during 2007-2017. Twelve patients were excluded due to an incomplete postoperative follow-up, degenerated biobank-stored tissue, or low DNA methylation quality. For the quantitative measurement of the tumor regrowth rate, we conducted a 3D volumetric analysis of tumor remnant volume via annual magnetic resonance imaging. A linear mixed effects model was used to examine whether different DNA methylation clusters had different regrowth patterns. The DNA methylation profiling of 42 tissue samples showed robust DNA methylation clusters, comparable with previous findings. The subgroup of 33 nonfunctioning pituitary adenomas of an SF1-lineage showed five subclusters with an approximately unbiased score of 86%. There were no overall statistically significant differences when comparing hazard ratios for regrowth of 100%, 50%, or 0%. Despite this, plots of correlated survival estimates suggested higher regrowth rates for some clusters. The mixed effects model of accumulated regrowth similarly showed tendencies toward an association between specific DNA methylation clusters and regrowth potential. The DNA methylation profiling of nonfunctioning pituitary adenomas may potentially identify adenomas with increased growth and recurrence potential. Larger validation studies are needed to confirm the findings from this explorative pilot study.

Predicting overall survival from tumor dynamics metrics using parametric statistical and machine learning models: application to patients with RET-altered solid tumors.

In oncology drug development, tumor dynamics modeling is widely applied to predict patients' overall survival (OS) via parametric models. However, the current modeling paradigm, which assumes a disease-specific link between tumor dynamics and survival, has its limitations. This is particularly evident in drug development scenarios where the clinical trial under consideration contains patients with tumor types for which there is little to no prior institutional data. In this work, we propose the use of a pan-indication solid tumor machine learning (ML) approach whereby all three tumor metrics (tumor shrinkage rate, tumor regrowth rate and time to tumor growth) are simultaneously used to predict patients' OS in a tumor type independent manner. We demonstrate the utility of this approach in a clinical trial of cancer patients treated with the tyrosine kinase inhibitor, pralsetinib. We compared the parametric and ML models and the results showed that the proposed ML approach is able to adequately predict patient OS across RET-altered solid tumors, including non-small cell lung cancer, medullary thyroid cancer as well as other solid tumors. While the findings of this study are promising, further research is needed for evaluating the generalizability of the ML model to other solid tumor types.

Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure-Tumor Growth Inhibition Model: Apitolisib (Dual PI3K/mTORC1/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor).

Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size-time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.

Shielding against breast tumor relapse with an autologous chemo-photo-immune active Nano-Micro-Sera based fibrin implant.

Local recurrence post-surgery in early-stage triple-negative breast cancer is a major challenge. To control the regrowth of a residual tumor, we have developed an autologous therapeutic hybrid fibrin glue for intra-operative implantation. Using autologous serum proteins as stabilizers, we have optimized high drug-loaded lapatinib-NanoSera (Lap-NS; ∼66% L.C.) and imiquimod-MicroSera (IMQ-MS; ∼92% L.C). Additionally, plasmonic nanosera (PNS) with an ∼67% photothermal conversion efficiency under 980 nm laser irradiation was also developed. While localized monotherapy with either Lap-NS or PNS reduced the tumor regrowth rate, their combination with IMQ-MS amplified the effect of immunogenic cell death with a high level of tumor infiltration by immune cells at the surgical site. The localized combination immunotherapy with a Nano-MicroSera based hybrid fibrin implant showed superior tumor inhibition and survival with significant promise for clinical translation.

Depth of radiographic response (DpR) and time to tumor regrowth (TTG) to predict overall survival following anti-VEGF therapy in recurrent glioblastoma.

2063 Background: Anti-angiogenic therapies, anti-VEGF agents, cause high radiographic response rates due to reduction in vascular permeability. However, we theorized the degree of tumor shrinkage combined with the duration of response might be a more meaningful measure of tumor control and may better reflect real patient benefit. In the current study, we investigate the association between model-derived parameters describing enhancing tumor volumetric dynamics and overall survival (OS) in recurrent glioblastoma treated with anti-VEGF therapy from multiple clinical trials. Methods: N=134 patients treated with bevacizumab +/- irinotecan (BRAIN Trial; NCT00345163) and N=121 patients treated with cabozantinib (XL184-201; NCT00704288) were used to identify potential imaging biomarkers, and N=63 patients in the bevacizumab control arm in a phase III trial (GLOBE Trial; NCT02511405) were used as a validation dataset. Enhancing tumor volumes were estimated using T1 subtraction maps, and a biexponential model was used to model tumor response ( d) and regrowth ( g) rates, as well as time to tumor regrowth ( TTG), the inflection point where the tumor stops shrinking and starts to regrow, and the depth of response ( DpR) after initiation of anti-VEGF therapy for each patient. Log-rank, univariate, and multivariable Cox regression were used to quantify the relationship of these parameters and OS. Results: Optimized thresholds based on maximum hazard ratio occurred at d =0.11 months-1 ( P=5x10-9 training; P=0.0082 validation); g=0.07 months-1 ( P=5x10-20 training; P<0.0001 validation); TTG of 3.8 months ( P=6x10-17training; P<0.0001 validation); and DpR of 11.3% ( P=0.0026 training; P=0.0177 validation). Univariate and multivariable Cox regression using these thresholds and controlling for age and baseline tumor volume confirmed that d, g, TTG, and DpR were all significant and independent predictors of OS in both phase II training and phase III validation datasets ( P<0.01). Additionally, patients exhibiting combinations of a high DpR and/or long TTG showed differential median OS, while patients with favorable diffusion MR phenotypes exhibited a longer OS and significantly longer TTG. Conclusions: Volumetric response and regrowth rates, TTG, and DpR using a biexponential model are significant and independent predictors of OS in recurrent glioblastoma treated with anti-VEGF therapy. Clinical trial information: NCT00345163 ; NCT00704288 ; NCT02511405 .

Preclinical InVivo Data Integrated in a Modeling Network Informs a Refined Clinical Strategy for a CD3 T-Cell Bispecific in Combination with Anti-PD-L1.

TYRP1-TCB is a CD3 T-cell bispecific (CD3-TCB) antibody for the treatment of advanced melanoma. A tumor growth inhibition (TGI) model was developed using mouse xenograft data with TYRP1-TCB monotherapy or TYRP1-TCB plus anti-PD-L1 combination. The model was translated to humans to inform a refined clinical strategy. From xenograft mouse data, we estimated an EC50 of 0.345 mg/L for TYRP1-TCB, close to what was observed in vitro using the same tumor cell line. The model showed that, though increasing the dose of TYRP1-TCB in monotherapy delays the time to tumor regrowth and promotes higher tumor cell killing, it also induces a faster rate of tumor regrowth. Combination with anti-PD-L1 extended the time to tumor regrowth by 25% while also decreasing the tumor regrowth rate by 69% compared to the same dose of TYRP1-TCB alone. The model translation to humans predicts that if patients' tumors were scanned every 6 weeks, only 46% of the monotherapy responders would be detected even at a TYRP1-TCB dose resulting in exposures above the EC90. However, combination of TYRP1-TCB and anti-PD-L1 in the clinic is predicted to more than double the overall response rate (ORR), duration of response (DoR) and progression-free survival (PFS) compared to TYRP1-TCB monotherapy. As a result, it is highly recommended to consider development of CD3-TCBs as part of a combination therapy from the outset, without the need to escalate the CD3-TCB up to the Maximum Tolerated Dose (MTD) in monotherapy and without gating the combination only on RECIST-derived efficacy metrics.

Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy.

It is controversial whether patients who achieve clinical complete remission (cCR) of rectal cancer should be treated with the “watch and wait” (W&W) or radical resection (RR) strategy. Our study aimed to compare the survival outcomes and ostomy rate of the W&W and RR strategies. Between January 2008 and December 2015, we investigated 26 patients who achieved pathologic complete remission after undergoing RR and 36 patients who adopted the W&W strategy because of cCR. The tumor regrowth, salvage surgery, recurrence, disease-free, and overall survival (OS) rates were assessed. In our study, recurrences occurred in nine and two patients from the W&W and RR groups, respectively. Each patient in the RR group had a temporary or permanent ostomy, but only three (8.3%) had an ostomy in the W&W group. The 5-year recurrence rate was 25.0% in the W&W group and 7.7% in the RR group. Six patients (16.7%) had tumor regrowth in the W&W group, and all were resectable when regrowth. The 5-year OS rates between the two groups were nonsignificant. There is no specific risk factor for recurrence and OS. Under close surveillance, the W&W group achieved similar OS to the RR group and benefited from a lower ostomy rate.

Microsurgical resection of foramen magnum meningioma: multi-institutional retrospective case series and proposed surgical risk scoring system.

Foramen magnum meningiomas (FMMs) are a major surgical challenge, due to relevant surgical morbidity and mortality. The paper aims to review the clinical (symptomatic improvement, complication rate, length of hospital stay) and radiological outcome (completeness of resection) of microsurgical resection of FMMs, and to identify predictors of complications. A multi-institutional retrospective review of prospectively maintained database of FMMs included 51 patients (74.5% females) with a median tumor volume of 8.18cm3 (range, 1.77-57.9cm3) and median follow-up of 36months (range, 0.30-180.0months). Tumors were resected though suboccipital approach (58.8%) or posterior-lateral approaches (39.3%), including far-lateral, extreme lateral and transcondylar approaches. Gross-total resection (GTR) was achieved in 80.4% and 98% of cases did not present tumor regrowth or recurrence. Clinical symptoms improved in 34 patients (66.7%) and worsened in 5 (9.8%). The median length of hospital stay was 5days. Mortality was null. Postoperative complications developed in 15 patients (29.4%), with cerebrospinal fluid leak (7.8%) and lower cranial nerves deficits (7.8%) as the most frequent. Craniospinal location (p = 0.03), location anterior to the dentate ligament (DL) (p = 0.02), involvement of vertebral artery (VA) (p = 0.03) were significantly associated with complication rate. These three elements allow calculating the Foramen Magnum Meningioma Risk Score (FRMMRS), to estimate the risk of post-operative complications. Microsurgical resection allows for high GTR rate and low rate of tumor regrowth or recurrence, despite complications in one third of the patients. The FMMRS allows classifying FMMs and estimating the risk of post-operative complications.

Imaging Characteristics and Surgical Outcomes in Patients With Intraspinal Solitary Fibrous Tumor/Hemangiopericytoma: A Retrospective Cohort Study.

Retrospective cohort study. Intraspinal solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) is often misdiagnosed preoperatively as schwannoma or meningioma because its imaging characteristics are not well understood. As postoperative prognosis differs among the 3 lesions, predicting the probability of SFT/HPC preoperatively is essential. Thus, this study investigates the imaging characteristics of SFT/HPC compared with those of schwannoma or meningioma and evaluates surgical outcomes. The preoperative imaging findings, tumor resection extent, recurrence and regrowth rates, and neurological improvement were compared between 10 patients with SFT/HPC and 42 patients with schwannoma or 40 patients with meningioma. Most patients with SFT/HPC showed isointensity on both T1- and T2-weighted images compared with patients with schwannoma (P = 0.011 and 0.029, respectively) and no significant difference compared with patients with meningioma (P = 0.575 and 0.845, respectively). Almost all patients with SFT/HPC showed highly uniformizing enhancement patterns, similar to those with meningioma (P = 0.496). Compared with meningioma, SFT/HPC lacked the dural tail sign and intratumoral calcification and exhibited irregular shape. Of the 5 patients who underwent partial resection, 60% exhibited tumor recurrence and regrowth following surgery. Complete en bloc surgical resection should be attempted in patients with intraspinal SFT/HPC to prevent postoperative recurrence or regrowth. As this tumor is often preoperatively misdiagnosed, we recommend that the imaging findings exhibited in this study should be used to positively suspect SFT/HPC. This will enhance patient outcomes by enabling more appropriate preoperative surgical planning.

Longitudinal analysis of organ-specific tumor lesion sizes in metastatic colorectal cancer patients receiving first line standard chemotherapy in combination with anti-angiogenic treatment.

The purpose of this work is to assess the heterogeneity across organs of response to treatment in metastatic colorectal patient based on longitudinal individual target lesion diameters (ILD) in comparison to sum of tumor lesion diameters (SLD). Data were from the McCAVE trial, in which 189 previously untreated patients with metastatic colorectal carcinoma (mCRC) received either bevacizumab (control, C) or vanucizumab (experimental, E), on top of standard chemotherapy. Bayesian hierarchical longitudinal non-linear mixed effect models were fitted to the data using Hamilton Monte Carlo algorithm to characterize the time dynamics of the tumor burden, and to obtain estimates of the tumor shrinkage and regrowth rates. The ILD model brought more nuanced results than to the SLD model. Besides substantial differences in tumor size at baseline (with lesions located in liver more than twice as large as the ones in lungs), it revealed a more durable response in lesions located in lymph nodes and 'other organs' compared to liver and lungs. Specifically, in lymph nodes and 'other organs', the projected time to nadir was doubled in group E (2.12 and 2.44years respectively) compared to group C (1.07 and 1.20years respectively). This long period of tumor shrinkage associated with a slightly larger change from baseline at nadir (-51.4% in lymph nodes and -62.6% in 'other organs' in the group E, compared to -46.2% and -46.9% in group C) resulted in a clinically meaningful difference in the tumor dynamics of patients in group E compared to the group C. The proportion of variance explained by the inter-lesion variability for each model parameter was large (ranging between 10 and 56%), reflecting the heterogeneity in tumor dynamics across organs. These findings suggest that there is value in understanding both within- and between-patient variability in tumor size's time dynamics using an appropriate modeling framework, as this information may help in pairing the right treatment with individual patient profile.

Reactive oxygen species explicit dosimetry to predict local tumor growth for Photofrin-mediated photodynamic therapy.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to calculate reactive oxygen species concentration ([ROS]rx) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Singlet oxygen is the primary cytotoxic species for ROS, which is responsible for cell death in type II PDT, although other type I ROS is included in the parameters used in our model. Using a combination of fluences (50-250 J∕cm2) and ϕ (75 or 150 mW∕cm2), tumor regrowth rate, k, was determined for each condition by fitting the tumor volume versus time to V0 *exp(k*t). Treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Explicit dosimetry of light fluence rate on tissue surface, tissue oxygen concentration, tissue optical properties, and Photofrin concentration were performed. Light fluence rate at 3 mm depth (ϕ 3mm) was determined for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Initial tissue oxygenation [3 O 2]0 was measured by an Oxylite oxygen probe before PDT and used to calculate [ROS]rx,calc. This value was compared to [ROS]rx,meas as calculated with the entire tissue oxygen spectrum [3 O 2](t), measured over the duration of light delivery for PDT. Cure index, CI = 1-k/kctr , for tumor growth up to 14 days after PDT was predicted by four dose metrics: light fluence, PDT dose, and [ROS]rx,calc, and [ROS]rx,meas. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. These studies show that [ROS]rx,meas best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome.

Evaluation of natural growth rate and recommended age for shaving procedure by volumetric analysis of craniofacial fibrous dysplasia.

We evaluated the preoperative natural growth pattern of craniofacial fibrous dysplasia and postoperative volume changes in patients undergoing shaving procedures. Thirty-three patients who underwent serial computed tomography (CT) preoperatively and/or postoperatively were identified. The natural tumor growth rate was assessed using preoperative CT scans. The postoperative tumor regrowth rates and relevant variables were analyzed. The preoperative tumor growth rates were significantly lower in patients aged ≥ 16 years than in those aged < 16 years (P < .001). The postoperative tumor regrowth rates were significantly greater when a shaving operation was performed at age < 16 years than at age ≥ 16 years (P = .04). In patients with clinical recurrence, the postoperative remnant tumor volume was inversely correlated with the tumor regrowth rate. The tumor growth rate of craniofacial fibrous dysplasia significantly decreased after age 16. This should be considered when conducting functional and aesthetic assessments in planning for the shaving of craniofacial fibrous dysplasia.

MON-326 Non Functioning Pituitary Adenomas (NFPA): Sex Related Differences in Presentation, Clinical Features and Outcomes

INTRODUCTION: NFPA are characterized as tumors without a typical hormonal hypersecretion syndrome. They are frequently diagnosed in the sixth decade, by visual field defects, hypopituitarism or incidentally. PATIENTS AND METHODS: retrospective and observational study that included 103 patients with NFPA (60 females) who were seen between 1999 and 2019 in our hospital. We compared and analyzed patients characteristics by sex: reason for consultation, hormonal status at diagnosis, invasiveness of the tumor through MRI, treatments and outcomeRESULTS: out of 103 patients, 58,2% were women (W). Men (M) were significantly older than women (56 vs. 45 yold. p=0,002). The presence of a macroadenoma was similar in both sexes (93%W vs. 94,7% M), however tumor invasiveness was more frequent in men (50% vs. 24,6%). Most men consulted for incidental finding (47,4% vs. 29,8%); most women consulted for symptoms related to the tumor(70% vs 52%): hypogonadism 31,6% W, 13% M; galactorrhea 17% W; visual field defects 21,7% W, 23,7%M, pituitary apoplexy 11,6% M. At baseline hormonal assessment hyperprolactinemia was more frequent (50,9% vs 42%) and higher in women (mean PRL levels 75 ng/ml vs. 37 ng/ml). Hypogonadism was more frequent in men (54% vs 42%) as well as hypopituitarism (15% vs. 10,5%). Surgery was the most used therapy in both sexes (69% M vs. 73%W) but males required more frequently second surgery and radiotherapy than females (15% vs. 5% and 10% vs. 5% respectively). Gonadotropin secreting adenoma was diagnosed in 62% of men and 37,5% by tumor immunohistochemistry, in the 45% of women who presented negative immunostaining the presence of a gonadotrophic lineage is not ruled out, median Ki-67 labeling was low in both sexes (2%). After surgery 66% of men and 37% of women showed tumor remnant > 1cm (p=0,001), tumor regrowth was seen in 38,4% men and 10,4% women (p=0,03). Hypogonadism was greater in men than in women (56% vs 39%). Ninety two percent of men and 60,9% of women developed some degree of pituitary deficiency after surgery (P<0,001). Men showed a higher degree of complete hypopituitarism compared to women (pretreatment 15% vs 10,5%, post treatment 32% vs 13%). CONCLUSION: NFPA in men are usually diagnosed incidentally at an older age, are more invasive at presentation with a higher incidence of pituitary dysfunction. Moreover, they presented with greater rate of tumor regrowth and hypopituitarism after surgery. NFPA in women are diagnosed earlier due to endocrine symptoms, had lower degree of invasiveness with better outcomes after treatment. Sex related differences in NFPA may be associated with the delay in diagnosis, although a more aggressive biology cannot be discarded.

Abstract LB-C07: Preclinical evaluation of MCLA-129: A bispecific antibody targeting c-MET and EGFR

Abstract NSCLC is the most common form of cancer. Approximately 20% of NSCLC patients have mutations in the growth factor (GF) receptor EGFR. These patients respond to tyrosine kinase inhibitors (TKIs) that target mutant EGFR; however relapse eventually occurs. c-MET is one of the most common GF pathways upregulated in resistant patients. Met amplification is found in 5-10% of tumors that acquire resistance to EGFR TKIs in the first line of treatment and this frequency becomes higher in later lines of treatment. Preclinical studies have shown that co-inhibition of c-MET and EGFR inhibits growth and survival in these resistant tumors. We describe here an unbiased functional screen of bispecific antibodies (bAbs) targeting EGFR and c-MET to select MCLA-129 and its evaluation in an in vivo xenograft NSCLC model. Large collections of common light chain Fab binding ‘arms’ against EGFR and c-MET were derived from immunized MeMo® mice and used in different combinations (based on epitope and sequence diversity) to generate IgG1 Biclonics® bAbs. The panel of &amp;gt; 400 bAbs was screened for proliferation inhibition of the N87 cell line stimulated with EGF and/or HGF. Five bAbs inhibited N87 growth comparable to the combination of cetuximab and a MetMab analog (C+M). Two of the most potent Biclonics® bAbs were selected for further characterization and screened for inhibitory activity in NSCLC cell lines PC-9 and HCC827 that harbour an EGFR exon 19 deletion. The addition of HGF reversed the inhibitory effect of the EGFR TKI erlotinib and gefitinib in both cell lines. Combination of bAbs or C+M with erlotinib or gefinitinib resulted in inhibition of growth and downstream phosphorylation similar to erlotinib treatment without GF addition in both HGF alone or HGF + EGF culture conditions. The best bAb was as potent (PC-9) or more potent (HCC827) than C+M. The lead bAb, MCLA-129 was ADCC enhanced and shown to effectively mediate ADCC against NSCLC cell lines with both high and low affinity FcR bearing effector cells. MCLA-129 was then tested in an genetically engineered immunodeficient xenograft mouse model where endogenous mouse HGF promoter drives the expression of human HGF bypassing the problem of the low affinity binding of mouse HGF for human c-MET. Mice engrafted with HCC827 cells and treated with MCLA-129 (25 mg/kg) displayed significant tumor regression (below baseline) and a much slower tumor regrowth rate upon drug cessation and this activity was enhanced when combined with erlotinib (6mg/kg). This potent therapeutic activity was achieved without the contribution of ADCC and was not observed in mice that received only erlotinib, a bivalent c-MET antagonizing antibody or their combination. To model acquired resistance to EGFR TKI treatment, animals were treated with erlotinib until tumors were &amp;gt;500mm3, MCLA-129 was added to erlotinib in one randomized group. In this group, immediate tumor inhibition was observed, which persisted over the treatment period. In summary, MCLA-129 was synergistic with EGFR targeting TKI’s to reverse c-MET mediated resistance in NSCLC cell lines both in vitro and in vivo. The activity of MCLA-129 was superior to relevant comparator biologics that were combined to inhibit EGFR and c-MET signaling in the absence of functional immunity. These preclinical data suggest MCLA-129 could benefit NSCLC patients that become resistant to EGFR targeted therapies and warrants clinical evaluation. Citation Format: Cecile Geuijen, Mario di Matteo, Tristan Gallenne, Sarah Trusso Cafarello, Roy Nijhuis, Therese Visser, Willem Bartelink, Carina Bartelink-Clements, Berina Eppink, Rinse Klooster, John dekruif, Massimiliano Mazzone, Mark Throsby. Preclinical evaluation of MCLA-129: A bispecific antibody targeting c-MET and EGFR [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-C07. doi:10.1158/1535-7163.TARG-19-LB-C07

Residual Tumor Confers a 10-Fold Increased Risk of Regrowth in Clinically Nonfunctioning Pituitary Tumors.

ObjectiveWe evaluated tumor recurrence and regrowth rates following endoscopic transnasal transsphenoidal (TNTS) surgical removal in a consecutive series of clinically nonfunctioning pituitary adenomas (CNFTs).DesignRetrospective chart review of clinical, biochemical, and sellar MRI findings in all TNTS surgeries in patients with CNFT, performed by a single surgeon, between 2008 and 2015 (n = 280).PatientsNinety-three patients met eligibility criteria, with complete clinical, biochemical, and imaging follow-up for a 3-year minimum.ResultsOf 85 patients who were not irradiated, 3-month postsurgical MRI demonstrated no residual tumor in 58 of 85 (68.2%), equivocal findings in 12 of 85 (14.1%), and definite residual tumor in 15 of 85 (17.6%) patients. Six of 85 (7.1%) demonstrated tumor regrowth by 3 years, and 2 further patients demonstrated true tumor recurrence at 3 and 6 years after surgery, respectively, for a total recurrence rate of 9.4% (8 of 85). Eight of the 93 patients were irradiated between 3 months and 4 years after pituitary surgery. In 3 patients with tumor regrowth, 2 exhibited residual tumor and 1 had no residual findings at the 3-month postoperative imaging. Overall, Ki-67 labeling index or Knosp grading did not predict recurrence.ConclusionTumor recurrence at 3 years was low (1 of 58; 1.7%) if the 3-month postoperative MRI showed no residual tumor. The findings support a less frequent imaging schedule for this group. Patients with definite residual tumor visible at 3 months harbor the greatest risk for tumor growth, but regrowth does not occur in all patients (6 of 15; 40%).

Reactive oxygen species explicit dosimetry to predict local tumor control for Photofrin-mediated photodynamic therapy.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to calculate reactive oxygen species concentration ([ROS]rx) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma (RIF) tumors. Singlet oxygen is the primary cytotoxic species for ROS, which is responsible for cell death in type II PDT, although other type I ROS is included in the parameters used in our model. Using a combination of fluences (50-250 J/cm2) and ϕ (50 - 150 mW/cm2), tumor regrowth rate, k, was determined for each condition by fitting the tumor volume vs. time to V0*exp(k*t). Treatment was delivered with a collimated laser beam of 1 cm diameter at 630 nm. Explicit dosimetry of initial tissue oxygen concentration, tissue optical properties, and Photofrin concentration was used to calculate [ROS]rx,cal. ϕ was determined for the treatment volume based on Monte-Carlo simulations and measured tissue optical properties. Tissue oxygenation is measured using an oxylite oxygen probe to throughout the treatment to calculate the measured [ROS]rx,mea. Cure index, CI = 1-k/k ctr , for tumor gowth up to 14 days were determined as an endpoint using five dose metrics: light fluence, PDT dose, and [ROS]rx,cal, and [ROS]rx,mea. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ at a 3 mm tumor depth. Preliminary studies show that [ROS]rx,mea best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome.

Reactive Oxygen Species Explicit Dosimetry (ROSED) of a Type 1 Photosensitizer.

Type I photodynamic therapy (PDT) is based on the use of photochemical reactions mediated through an interaction between a tumor-selective photosensitizer, photoexcitation with a specific wavelength of light, and production of reactive oxygen species (ROS). The goal of this study is to develop a model to calculate reactive oxygen species concentration ([ROS]rx) after Tookad®-mediated vascular PDT. Mice with radiation-induced fibrosarcoma (RIF) tumors were treated with different light fluence and fluence rate conditions. Explicit measurements of photosensitizer drug concentration were made via diffuse reflective absorption spectrum using a contact probe before and after PDT. Blood flow and tissue oxygen concentration over time were measured during PDT as a mean to validate the photochemical parameters for the ROSED calculation. Cure index was computed from the rate of tumor regrowth after treatment and was compared against three calculated dose metrics: total light fluence, PDT dose, reacted [ROS]rx. The tumor growth study demonstrates that [ROS]rx serves as a better dosimetric quantity for predicting treatment outcome, as a clinically relevant tumor growth endpoint.

Baseline T Classification Predicts Early Tumor Regrowth After Nonoperative Management in Distal Rectal Cancer After Extended Neoadjuvant Chemoradiation and Initial Complete Clinical Response.

Selected patients with rectal cancer and complete clinical response after neoadjuvant chemoradiation have been managed nonoperatively with acceptable outcomes. However, ≈20% of these patients will develop early tumor regrowth. Identification of these patients could select candidates for more intensive follow-up. The purpose of this study was to investigate the influence of baseline radiological T classification on recurrences after a complete clinical response managed nonoperatively after chemoradiation. This was a retrospective review of a prospective collected database. The study was conducted at a single center. Patients with distal rectal cancer (cT2-4N0-2M0) undergoing extended chemoradiation (54 Gy + 5-fluorouracil-based chemotherapy) were eligible. Patients were reassessed for tumor response at 10 weeks after radiation completion. Patients with complete clinical response (clinical, radiological, and endoscopic) were managed nonoperatively and strictly followed. Complete clinical response rates, early tumor regrowth rates (<12 mo), local recurrence-free survival, and distant metastases-free survival were measured. A total of 91 consecutive patients with rectal cancer underwent extended chemoradiation. Sixty-one patients developed initial complete clinical response (67%). cT2 patients developed similar initial complete clinical response rates compared with cT3/T4 (72% vs 63%; p = 0.403). Early tumor regrowths were more frequent among baseline cT3/4 when compared with cT2 patients (30% vs 3%; p = 0.007). There were no differences in late local recurrences (p = 0.593) or systemic recurrences (p = 0.387). Local recurrence-free survival was significantly better for cT2 patients at 1 year (96% vs 69%; p = 0.009). After Cox regression analysis, baseline T stage was an independent predictor of improved local recurrence-free survival at 1 year (p = 0.03; OR = 0.09 (95% CI, 0.01-0.81)). This study was limited by its small sample size, retrospective nature, and short follow-up. cT2 patients who develop complete clinical response after extended chemoradiation managed nonoperatively are less likely to develop early tumor regrowths when compared with cT3/4 patients. cT3/4 patients should undergo more intensive follow-up after a complete clinical response to allow for early detection of early regrowths.

Erratum: Macroscopic singlet oxygen modeling for dosimetry of Photofrin-mediated photodynamic therapy: an in-vivo study.

Although photodynamic therapy (PDT) is an established modality for cancer treatment, current dosimetric quantities, such as light fluence and PDT dose, do not account for the differences in PDT oxygen consumption for different fluence rates (ϕ). A macroscopic model was adopted to evaluate using calculated reacted singlet oxygen concentration ([O21]rx) to predict Photofrin-PDT outcome in mice bearing radiation-induced fibrosarcoma tumors, as singlet oxygen is the primary cytotoxic species responsible for cell death in type II PDT. Using a combination of fluences (50, 135, 200, and 250 J/cm2) and ϕ (50, 75, and 150 mW/cm2), tumor regrowth rate, k, was determined for each condition. A tumor cure index, CI=1−k/kcontrol, was calculated based on the k between PDT-treated groups and that of the control, kcontrol. The measured Photofrin concentration and light dose for each mouse were used to calculate PDT dose and [O21]rx, while mean optical properties (μa=0.9 cm−1, μs′=8.4 cm−1) were used to calculate ϕ for all mice. CI was correlated to the fluence, PDT dose, and [O21]rx with R2=0.35, 0.79, and 0.93, respectively. These results suggest that [O21]rx serves as a better dosimetric quantity for predicting PDT outcome.