Regorafenib enhances anti-PD1 immunotherapy efficacy in murine colorectal cancers and their combination prevents tumor regrowth

Background Patients with advanced colorectal cancer (CRC) have a poor prognosis. Combinations of immunotherapies and anti-angiogenic agents are currently being evaluated in clinical trials. In this study, the multikinase inhibitor regorafenib (REG) was combined with an anti-programmed cell death protein 1 (aPD1) antibody in syngeneic murine microsatellite-stable (MSS) CT26 and hypermutated MC38 colon cancer models to gain mechanistic insights into potential drug synergism. Methods Growth and progression of orthotopic CT26 and subcutaneous MC38 colon cancers were studied under treatment with varying doses of REG and aPD1 alone or in combination. Sustained effects were studied after treatment discontinuation. Changes in the tumor microenvironment were assessed by dynamic contrast-enhanced MRI, and histological and molecular analyses. Results In both models, REG and aPD1 combination therapy significantly improved anti-tumor activity compared with single agents. However, in the CT26 model, the additive benefit of aPD1 only became apparent after treatment cessation. The combination treatment efficiently prevented tumor regrowth and completely suppressed liver metastasis, whereas the anti-tumorigenic effects of REG alone were abrogated soon after drug discontinuation. During treatment, REG significantly reduced the infiltration of immunosuppressive macrophages and regulatory T (Treg) cells into the tumor microenvironment. aPD1 significantly enhanced intratumoral IFNγ levels. The drugs synergized to induce sustained M1 polarization and durable reduction of Treg cells, which can explain the sustained tumor suppression. Conclusions This study highlights the synergistic immunomodulatory effects of REG and aPD1 combination therapy in mediating a sustained inhibition of colon cancer regrowth, strongly warranting clinical evaluation in CRC, including MSS tumors.

Aggressive childhood-onset papillary craniopharyngioma managed with vemurafenib, a BRAF inhibitor

The papillary subtype of craniopharyngioma rarely occurs in children and commonly presents as a suprasellar lesion. Patients with papillary craniopharyngiomas frequently harbor the BRAF-V600E mutation and treatment with a BRAF inhibitor results in tumor shrinkage in several patients. Herein, we report a patient with childhood-onset papillary craniopharyngioma treated with vemurafenib for 40 months after multiple surgeries. At age 10, he presented with growth failure secondary to an intrasellar cystic lesions. He had three transsphenoidal surgeries before age 12 and a fourth surgery 25 years later for massive tumor recurrence. Pathology showed a papillary craniopharyngioma with positive BRAF-V600E mutation. Rapid tumor regrowth 4 months after surgery led to treatment with vemurafenib that resulted in tumor reduction within 6 weeks. Gradual tumor regrowth occurred after a dose reduction of vemurafenib because of elevated liver enzymes. He had further surgeries and within 7 weeks after stopping vemurafenib, there was massive tumor recurrence. He resumed treatment with vemurafenib before radiation therapy and similar tumor shrinkage occurred within 16 days. In this patient with childhood-onset papillary craniopharyngioma that was refractory to multiple surgeries, the use of vemurafenib resulted in significant tumor shrinkage that allowed for completion of radiation therapy and tumor control.

Characteristic of Tumor Regrowth After Gamma Knife Radiosurgery and Outcomes of Repeat Gamma Knife Radiosurgery in Nonfunctioning Pituitary Adenomas

ObjectiveThis study aimed to report the characteristic of tumor regrowth after gamma knife radiosurgery (GKRS) and outcomes of repeat GKRS in nonfunctioning pituitary adenomas (NFPAs).Design and MethodsThis retrospective study consisted of 369 NFPA patients treated with GKRS. The median age was 45.2 (range, 7.2–84.0) years. The median tumor volume was 3.5 (range, 0.1–44.3) cm3.ResultsTwenty-four patients (6.5%) were confirmed as regrowth after GKRS. The regrowth-free survivals were 100%, 98%, 97%, 86% and 77% at 1, 3, 5, 10 and 15 year, respectively. In multivariate analysis, parasellar invasion and margin dose (<12 Gy) were associated with tumor regrowth (hazard ratio [HR] = 3.125, 95% confidence interval [CI] = 1.318–7.410, p = 0.010 and HR = 3.359, 95% CI = 1.347–8.379, p = 0.009, respectively). The median time of regrowth was 86.1 (range, 23.2–236.0) months. Previous surgery was associated with tumor regrowth out of field (p = 0.033). Twelve patients underwent repeat GKRS, including regrowth in (n = 8) and out of field (n = 4). Tumor shrunk in seven patients (58.3%), remained stable in one (8.3%) and regrowth in four (33.3%) with a median repeat GKRS margin dose of 12 (range, 10.0–14.0) Gy. The actuarial tumor control rates were 100%, 90%, 90%, 68%, and 68% at 1, 3, 5, 10, and 15 years after repeat GKRS, respectively.ConclusionsParasellar invasion and tumor margin dose (<12 Gy) were independent risk factors for tumor regrowth after GKRS. Repeat GKRS might be effective on tumor control for selected patients. For regrowth in field due to relatively insufficient radiation dose, repeat GKRS might offer satisfactory tumor control. For regrowth out of field, preventing regrowth out of field was the key management. Sufficient target coverage and close follow-up might be helpful.

276 Prognostic value of tumor size varies by treatment in a meta-analysis of 15 randomized clinical trials in advanced non-small cell lung cancer across immunotherapy, TKI, and chemotherapy regimens

BackgroundRECIST1 is commonly used to characterize intermediate outcomes for clinical trials in the context of solid tumors, and it is largely based on a standardized measure of tumor size known as the sum of longest diameters (SLD). In recent years, the FDA has granted accelerated approvals for several new compounds based on improvements in RECIST-based surrogate outcomes like overall response rate and progression-free survival.2 However, there are concerns regarding the robustness of these surrogate endpoints relative to overall survival (OS),3 4 and it is not known whether their prognostic value is similar across TKI, chemotherapy, and immunotherapy regimens.MethodsWe have developed a Bayesian meta-analytic joint model for longitudinal SLD and OS in order to predict Phase III outcomes from early Phase II data. We validated this model in extensive simulation studies. The model utilizes a generalized Stein-Fojo equation5 to characterize SLD over time in terms of 3 parameters: f (proportion of tumor that is treatment-susceptible), ks (the decay rate among susceptible cells), and kg (the growth rate among resistant cells). Two quantities [tumor shrinkage (f * ks) and tumor regrowth ((1-f) * kg)] are then associated with survival in the context of a proportional-hazards survival model. We estimated this model using Stan6 on a dataset of >6,000 subjects in 15 randomized clinical trials in advanced non-small cell lung cancer.ResultsBoth tumor shrinkage and tumor regrowth were found to be associated with OS (HR for tumor shrinkage: median 0.51, 90% CrI 0.42 - 0.61; HR for tumor regrowth: median 1.24, 90% CrI 1.18 - 1.32). There is a stronger association between tumor shrinkage and OS among patients randomized to a PD-1/PD-L1 inhibitor, either as a monotherapy or in combination with a CTLA-4 inhibitor, than among patients in other trial arms (figure 1). By contrast, there were negligible differences across treatment classes in the association between tumor regrowth and OS.Abstract 276 Figure 1Hazard associated with SLD submodel parameters varies according to the class of treatment in a joint model for SLD and overall survival with varying association by assigned treatment regimen. The points represent posterior median values per treatment, with lines representing 90% posterior credible intervals (CrI). Two treatment classes demonstrated posterior probability greater than 90% of a non-zero treatment-specific effect for the response term: the combination PD-1/PD-L1 inhibitor + CTLA-4 inhibitor [interaction HR = 0.64 (90% CrI 0.39 - 1.00; posterior probability of HR<1: 95.2%)] and the PD-1/PD-L1 inhibitor alone [interaction HR = 0.62 (90% CrI 0.42 - 0.89; posterior probability of HR<1: 99.2%)].ConclusionsOur results suggest that not all reductions in tumor size are equal. A patient with a certain degree of tumor shrinkage on the PD-1/PD-L1 inhibitor will have lower mortality risk than a patient with a similar degree of shrinkage on the other regimens evaluated. More research is needed to determine whether the result is unique to this particular PD-1/PD-L1 inhibitor, to determine what mechanisms of action mediate these treatment-specific effects, and to develop improved surrogate measures of treatment efficacy.ReferencesEisenhauer EA, Therasse P, Bogaerts J, et al: New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–247.Of Health USD, Services H, Others: Clinical trial endpoints for the approval of non-small cell lung cancer drugs and biologics: guidance for Industry, 2015Mandrekar SJ, An M-W, Meyers J, et al: Evaluation of Alternate Categorical Tumor Metrics and Cut Points for Response Categorization Using the RECIST 1.1 Data Warehouse. J Clin Orthod32:841–850, 2014Blumenthal GM, Karuri SW, Zhang H, et al: Overall response rate, progression-free survival, and overall survival with targeted and standard therapies in advanced non-small-cell lung cancer: US Food and Drug Administration trial-level and patient-level analyses. J Clin Oncol33:1008–1014, 2015Stein WD, Figg WD, Dahut W, et al: Tumor growth rates derived from data for patients in a clinical trial correlate strongly with patient survival: a novel strategy for evaluation of clinical trial data. Oncologist13:1046–1054, 2008Carpenter B, Gelman A, Hoffman MD, et al: Stan: A probabilistic programming language [Internet]. jitc-2020-SITC2020.0277.pdf

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 &gt; 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&lt;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.

A two-step program preventing bone metastatic relapse

Treating bone metastatic prostate cancer with docetaxel nanoparticles and denosumab averts tumor regrowth.

SURG-05. LASER INTERSTITIAL THERMAL THERAPY FOR MELANOMA BRAIN METASTASIS: A CASE SERIES

Stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) have been established as non-invasive treatment modalities for intracranial metastasis from malignant melanoma, with SRS emerging as a safe and effective stand along therapy. However, either due to tumor regrowth or radiation necrosis, these radiation modalities can fail. MR-guided laser interstitial thermal therapy (LITT) has emerged as an option for these tumors. Clinical data for five patients at our institution was retrospectively reviewed. These were all the patients that had undergone LITT for intracranial metastatic melanoma after prior treatment failure that included a radiation modality. Demographics, prior treatments, surgical data, perioperative complications, adjuvant treatments, and follow imaging data were gathered. Of the five patients, one patient had received WBRT, three patients had received prior SRS to the area that underwent LITT, and one patient had a prior craniotomy with adjuvant SRS. Two of the tumors were located in the premotor area (frontal lobe), two tumors were located in the motor strip, and one tumor was located in the cerebellum. The average tumor volume was 4.32 cc (range 1.86 - 7.84 cc). Median time of hospital stay was 2 days (with a 2.6 day average). No perioperative complications were encountered. Three of the patients had received adjuvant therapy at our institution; these patients were not delayed in receiving adjuvant therapy. Of these three patients, only one patient had a BRAF mutation detected. Four patients received follow up imaging at our institution, with no patients demonstrating tumor regrowth in the site of LITT. Regrowth of intracranial metastasis of malignant melanoma is a known possibility of traditional radiation therapies. LITT should be considered as a safe, effective option for those that fail these traditional therapies, especially those located in areas difficult to access. The low complication rate allows patients to restart adjuvant therapies.