Chmielowski, Bartosz

Over the past few years, the NCCN Guidelines for Melanoma: Cutaneous have been expanded to include pathways for treatment of microscopic satellitosis (added in v2.2020), and the following Principles sections: Molecular Testing (added in v2.2019), Systemic Therapy Considerations (added in v2.2020), and Brain Metastases Management (added in v3.2020). The v1.2021 update included additional modifications of these sections and notable revisions to Principles of: Pathology, Surgical Margins for Wide Excision of Primary Melanoma, Sentinel Lymph Node Biopsy, Completion/Therapeutic Lymph Node Dissection, and Radiation Therapy. These NCCN Guidelines Insights discuss the important changes to pathology and surgery recommendations, as well as additions to systemic therapy options for patients with advanced disease.

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

TPS10099 Background: PDGFRα is a receptor commonly overexpressed in STS. Olaratumab is a fully human IgG1 MAb which specifically binds to human PDGFRα and blocks PDGFR-mediated signaling pathways. Olaratumab demonstrated significant tumor inhibition as a monotherapy and in combination with standard chemotherapy in preclinical human sarcoma xenograft models. A Phase 1b/2 clinical trial for patients with advanced or metastatic STS is currently enrolling patients in 9 sites across the United States; approximately 45 patients have been randomized. Methods: In Phase 1b, patients received olaratumab (15 mg/kg) via intravenous infusion on Days 1 and 8 of each 21-day cycle and D (75 mg/m²) 1 hour after olaratumab on Day 1. Phase 1b was completed without encountering dose-limiting toxicities; enrollment into Phase 2 has begun. The primary endpoint of the Phase 2 portion is to compare progression-free survival in patients with advanced STS when treated with D plus olaratumab versus D alone. Planned enrollment goal for Phase 2 is 130 patients. Patients are required to be ≥ 18 years old with ECOG 0-2, have appropriate organ function and histologically confirmed, measurable, and advanced STS. There is no restriction on the number of prior therapies. Patients are randomized 1:1 to either D plus olaratumab (Arm A) at same dose/schedule as in Phase 1b or D alone (Arm B). All patients can receive dexrazoxane. Upon completion of 8 cycles, patients in Arm A continue with olaratumab monotherapy. Patients in Arm B who develop disease progression during or after treatment can subsequently receive olaratumab monotherapy. Patients are stratified to treatment arms according to PDGFRα expression (positive vs. negative), number of previous lines of treatment, sarcoma subtype, and ECOG performance status. Response assessment occurs every 6 weeks. Exploratory analyses include biomarkers of olaratumab pharmacodynamic activity including PDGF ligands, PDGFR downstream molecules, VEGF, and changes in vascularity of tumor specimens.

10003 Background: Preclinical studies demonstrate synergistic anti-tumor activity by inhibiting mTOR and IGF-1R. This study evaluated the safety and efficacy of A12 and TEM in 3 chemo-refractory cohorts: IGF-1R (+) STS (Arm A), IGF-1R (+) bone (Arm B), and IGF-1R (-) bone and STS (Arm C). Methods: An optimal Simon 2 stage design was used for each arm. The primary end-point was progression free survival (PFS) at 12 weeks. Based on historical data, a 40% PFS rate was considered promising and a 20% PFS non-promising (type I/ II error, 0.05/0.10). ≥5 PFSs at 12 weeks were required in the first 19 and ≥16 PFSs were required in a total of 54 pts to consider each arm positive. Key eligibility: measurable disease (RECIST 1.1), age ≥18, 1- 4 priors, ECOG status 0-1. A12 (6 mg/kg) and TEM (25 mg) were administered IV weekly. Pre and post treatment tumor biopsies and plasma for IGF-1 and IGFBP3 were obtained. 20 Sarcoma Centers participated. Results: Starting in 02/2010, 383 pts were tested for IGF-1R by immunohistochemistry (IHC; 54% +) and 171 were treated: mean age 47 (range: 18-80), mean # priors 2.2 (range: 1-4). Grade 3/4 toxicities ≥10%: lymphopenia (12%), mucositis (10%). By intent to treat (ITT) analysis, each arm of the study achieved its primary 12 week PFS end-point (≥16 PFSs): Arm A: 18/56 (32%), Arm B: 19/50 (38%) (4 too early), Arm C: 27/63 (43%). The one-sided 95% CI for 12-week PFS is (0.22, 1), (0.27, 1), and (0.32, 1), respectively. By ITT the median PFS (95% CI) in weeks for each arm is 6.3 (5.9, 12.0), 11.0 (8.0, 18.0) and 11.6 (9.0, 17.9), respectively, and for chondro (n=18), Ewing’s (n=24), and osteo (n=23) only it is 22.6 (5.7, 40.9), 10.4 (5.7, 17.9) and 6.0 (6.0, 18.0), respectively. Westerns on 32 matched pair tumor biopsies indicate inhibition of IGF-1R, pAKT and pS6. Of biopsies on 7 IGF-1R (-) IHC pts (Arm C), 5 were IGF-1R (+) by western. Plasma biomarkers did not correlate with PFS. Conclusions: A12 and TEM met its primary end-point of improved PFS in pts with metastatic sarcoma. This effect was independent of IGF-1R status by IHC. These results support further clinical development of this combination in bone and STS.

Background Ontuxizumab, a humanized monoclonal antibody, targets endosialin (tumor endothelial marker 1 [TEM‐1] or CD248), which is expressed on sarcoma cells and is believed to be involved in tumor angiogenesis. This is the first trial to evaluate ontuxizumab in patients with sarcoma. Methods Part 1 was an open‐label, dose‐finding, safety lead‐in: 4, 6, or 8 mg/kg with gemcitabine and docetaxel (G/D; 900 mg/m 2 gemcitabine on days 1 and 8 and 75 mg/m 2 docetaxel on day 8). In part 2, patients were randomized in a double‐blind fashion in 2:1 ratio to ontuxizumab (8 mg/kg) or a placebo with G/D. Randomization was stratified by 4 histological cohorts. Results In part 2 with 209 patients, no significant difference in progression‐free survival between ontuxizumab plus G/D (4.3 months; 95% confidence interval [CI], 2.7‐6.3 months) and the placebo plus G/D (5.6 months; 95% CI, 2.6‐8.3 months) was observed ( P = .67; hazard ratio [HR], 1.07; 95% CI, 0.77‐1.49). Similarly, there was no significant difference in median overall survival between the 2 groups: 18.3 months for the ontuxizumab plus G/D group (95% CI, 16.2‐21.1 months) and 21.1 months for the placebo plus G/D group (95% CI, 14.2 months to not reached; P = .32; HR, 1.23; 95% CI, 0.82‐1.82). No significant differences between the treatment groups occurred for any efficacy parameter by sarcoma cohort. The combination of ontuxizumab plus G/D was generally well tolerated. Conclusions Ontuxizumab plus G/D showed no enhanced activity over chemotherapy alone in soft‐tissue sarcomas, whereas the safety profile of the combination was consistent with G/D alone.

9558 Background: Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by a dense fibrous stroma, resistance to chemotherapy and no actionable driver mutation for targeted therapy. We investigated the efficacy of PD-1/L1 inhibitors and correlation with genetic landscape and tumor immune microenvironment in DM. Methods: Retrospective analysis of 1054 pts with melanoma treated with anti-PD-1/L1, resulting in 57 pts with unresectable or metastatic DM. Available baseline biopsies were analysed by digital quantitative immunohistochemistry (IHC) for CD8 and PD-L1 and by whole exome sequencing (WES), compared to available tissue from non-DM pts treated with anti-PD1/L1 at UCLA. Results: At a median follow up of 20 mo, 40 pts (70%, 95% CI 57-82) had an objective response by RECIST 1.1 criteria, including 18 (45%) CRs with no relapse observed to date. Responses were similar in DM subsets (23 pure, 29 mixed and 5 indeterminate). Kaplan-Meier estimated 1-year and 2-year overall survival were 85% (95% CI 78-98) and 74% (95% CI 64-89). WES revealed a median of 1282 (interquartile range 517-1692) non-synonymous somatic mutations per tumor in DM tumors (n = 17), significantly higher (p = 0.02) than the median of 462 (interquartile range 230-1150) in non-DM (n = 23). Mutations in NF-1 were the most common (13/17) followed by loss-of-function TP53 and ARID2, and > 82% of single nucleotide mutations were UV damage signatures. IHC analysis from 19 DM and 13 non-DM revealed a strikingly higher percentage of PD-L1 positive cells in the tumor parenchyma in DM (p = 0.04), highly associated with CD8 density and PD-L1 expression in the tumor invasive margins, indicating an active adaptive immune response. No genetic mechanisms known to cause constitutive PD-L1 expression were detected in these samples. Conclusions: Patients with advanced DM derive significant clinical benefit from PD-1/L1 inhibitors, likely related to the high mutational burden and a highly active adaptive immune response as the main mechanism of immune escape prior to therapy. Our results challenge the general conception that dense fibrous stroma around the malignant cells interferes with immune cell infiltration and efficacy of immunotherapy.