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Supplementary Figure Legends

Supplementary Figure 1. "Phase 2-Eligible" Population. Supplementary Figure 2. ALKA-372-001 and STARTRK-1 Dosing Regimens.

Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.Experimental Design: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg.Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non–small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962.Conclusions: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146–54. ©2015 AACR.

Purpose:To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study.Experimental Design:Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (n = 183) and testing (n = 246) sets. RT-PCR–based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan–Meier method and Cox regression model.Results:In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73–0.98 and 0.71 (0.55–0.86)], respectively; trastuzumab at T1 (0.81; 0.70–0.92); lapatinib + trastuzumab at T1 (0.67; 0.51–0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22–0.84).Conclusions:ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.

Suppl figures without legends modified on feb 20th

Including legends of Suppl Figures introduced on Feb 20th

Additional Methods; Tables and Figure [1]Supplementary Methods: Contrast-enhanced ultrasound (CE-US) [2]Supplementary Table S1. Pharmacokinetic characteristics of PF-03446962 following single-dose administration in cycle 1 [3]Supplementary Table S2. Best overall tumor response in patients treated with PF-03446962 [4]Supplementary Figure S1. Telangiectasia observed in patients treated with PF-03446962.

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]

TPS754 Background: Collecting duct carcinoma (CDC) is a rare type of non-clear cell renal cell carcinoma with an aggressive course and poor prognosis. The treatment of metastatic disease remains unsatisfactory as no standard-of-care has been established yet. The gap in the clinical management is certainly linked to the poor molecular characterization. To date, a comprehensive biological characterization of CDC and the identification of predictive biomarker is still lacking. Our previous studies proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signalling, metabolic and immune-related alterations and featured by a prognostic signature associating T cell immunity and angiogenesis with good clinical outcome and sensitivity to cabozantinib (Gargiuli et al, Cancers 2021 Jun 10;13(12):2903; Todoerti et al, J Clin Oncol 40, no. 16_suppl (June 01, 2022) e16507-e16507; Verzoni et al, Ann Oncol 33:S1218-S121). The aim of CICERONE trial is to change the paradigm of CDC management providing therapies in a biologically informed manner starting from our previous findings. Methods: First, we will define a molecular taxonomy of CDC through comprehensive transcriptomic profiling of 100 CDC samples retrospectively collected within 12 months from the Italian Group of Uropathology Network and the European Union Hub Center. Pathologic review by genitourinary pathologist was required. RNA-Seq will be performed. Results will be merged to that already obtained by the same methodology from the BONSAI dataset (NCT03354884) and evaluated by unsupervised clustering analysis. We will identify differentially expressed genes and pathways. The immune and angiogenic signatures will be searched validating our preliminary results to identify predictive signatures for the subsequent prospective phase II trial. RNA-seq data will be also explored to detect fusion transcripts, as potential source of novel CDC oncogenic drivers, and study immune tumor content through Cybersort deconvolution. RT-qPCR on RNA derived from tumor and normal tissue will be performed to determine tumor specific origin of the fusion transcripts. Immune infiltrate will be also characterized by IHC, together with PDL-1 scoring. Subsequently we will conduct a prospective phase II trial in order to optimize treatment choice and validate prospectively the biological data. In this phase, previously untreated patients with metastatic CDC will be treated according to baseline tumor signature. Moreover, we will assess whether a new concept of immune liquid biopsy that includes the assessment of immunosuppressive vs antitumor immune cells may represent an accessible and compliant tool to test systemic immunity and its implications in response to treatment. This study was supported by the Italian Ministry of health (RF-2019-12369602). Clinical trial information: NCT05372302 .

590 Background: Biliary Tract Cancers (BTC) have poor prognosis and limited therapeutic options. There is mounting evidence for biomarker-directed therapy for BTC, with several potentially actionable molecular targets reported in up to ~50% of patients and significant biological differences between intrahepatic (ICC) and extrahepatic (ECC) cholangiocarcinoma and Gallbladder cancer (GBC). ESMO and ASCO recommends the use of tumour multigene next generation sequencing (NGS) for CCA. Methods: This was a monocentric study assessing real-life clinical actionability of molecular alterations identified with expanded NGS for patients (pts) affected by advanced BTCs treated at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan from January 2016 to July 2022. NGS was performed either via the “Hotspot Cancer Panel, Ion Torrent”, the “Oncomine Comprehensive Assay Plus” or the FoundationOne CDx panel; FGFR2 testing was also performed via fluorescence in situ hybridisation. Molecular alterations were classified according to ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) and correlated with targeted treatments administered and efficacy endpoints. Benefit from targeted treatment was evaluated by means of progression-free survival (PFS) ratio, as defined as the ratio of each patient’s PFS2 (i.e. PFS on molecularly informed therapy) to the PFS1 (PFS on his/her most recent previous treatment), with d for efficacy equal to 1. Results: Out of 340 pts with adequate tissue for NGS, 231 (68%) were affected by ICC, 61 (32%) by ECC and 48 (14%) by GBC. Actionable alterations as per ESCAT I-III were found in 33 % of pts (N= 113, including IDH1 mutation, FGFR2 fusions/rearrangement/mutations, MSI-H, BRAFV600E mutations, ERBB2 mutations/amplifications, BRCA1/2 mutations); 88% of these alterations were found in pts with ICC. Targeted therapy was actually started for 48 pts (14 %), with 9 pts treated with ivosidenib, 32 with FGFR2 inhibitors, 2 with PD-L1 inhibitor, 6 with BRAF+MEK inhibitor and 1 with an HER2 inhibitor). Overall response rate and disease control rate were 18% and 62%, respectively.Median PFS was 5.4 months(95% CI 3.0 - 6.4) overall and 10.12 months on BRAF+MEK inhibitors, 5.55 months on FGFR2 inhibitors, 2.92 months on ivosidenib and 6.23 months on PD-L1 inhibitors. Median PFS ratio was 1.1 (95%CI 0.7 - 1.4), with benefit rate of 51%. Of note, 5 (10%) received targeted therapy as > III line. Median overall survival of targeted therapy was 10 months. Conclusions: Expanded sequencing for BTCs is feasible in real-life and can improve treatment strategy. Analysis of PFS ratio and of treatment outcomes shows clinically meaningful benefit of targeted treatment in pretreated patients.

9033 Background: In advanced NSCLC (aNSCLC) with PD-L1 < 50% chemo-immunotherapy is the standard of care. Although the activity of single agent pembrolizumab was reported, no biomarkers have been identified able to select patients who mostly benefit. The trial aimed to identify immune biomarkers associated with PFS in aNSCLC patients with PD-L1 levels < 50% treated with first-line pembrolizumab. Here we reported for the first time the clinical outcomes of the trial and circulating immune profiling (CIP) biomarkers correlated to PFS. Methods: This phase II trial was conducted at Fondazione IRCCS Istituto Nazionale dei Tumori of Milan. Eligible patients were previously untreated stage IIIB-IV NSCLC, EGFR and ALK wild type with PD-L1 < 50%, PS 0-2. PD-L1 was assessed with 22-C3 antibody (Dako). Patients received pembrolizumab 200 mg every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. The primary endpoint was the association of immune biomarkers with PFS. OS, ORR, DCR, DoR and safety were secondary endpoints. CIP was performed by determination of absolute cell counts for 36 innate and adaptive immunity subsets through multiparametric flow cytometry on freshly isolated whole blood samples at baseline. An orthoblique principal components-based clustering approach and multivariable Cox regression model adjusted for clinical variables were used to analyse CIP variables and their correlation with clinical endpoints. Results: From May 2018 to October 2020, of 87 screened, 65 patients were enrolled. The median age was 70.9 years, most patients were male (67.7%), smoker (87.7%), non-squamous (83.1%), PDL1 + (70.8%). 12 patients (18.5%) had PS 2. During a median follow-up of 26.4 months (mo), 51 radiological progressions, 46 deaths and 60 PFS events were observed. The median PFS was 2.9 mo (95%CI 1.8 - 5.6) and the median OS was 12.1 mo (95%CI 8.7 - 17.1). The ORR was 24.1% (2 complete and 12 partial responses), DCR was 53.4% and median DoR was 14.5 mo (95%CI 6.4 - 24.9). Drug related G3-G4 adverse events were: 2 hyponatremia, 2 lipase increased, 1 pneumonitis. Out of 7 CIP clusters identified, 2 were statistically significant at multivariable analysis on 57 patients. Higher baseline counts of 8 subsets within these two clusters were associated with better PFS (HR values range: 0.88-0.98; p values range: 0.001- 0.016). The significant subsets included lymphocytes (cells expressing CD3, or CD19 or CD56, but lacking granulocyte and monocyte markers) and main NK subsets (including CD56dim CD16+, CD56dim CD16- and HLA-DR+ NK cells). Conclusions: This trial confirmed that pembrolizumab as first-line single agent is safe and active also in a subgroup of aNSCLC patients with PD-L1 < 50%. CIP biomarkers can be useful to identify patients with a favourable outcome, thus avoiding the adding toxicity of chemotherapy. Clinical trial information: NTC03447678.

e16179 Background: Biliary tract cancers (BTCs) are a group of rare tumors with a dismal prognosis and a complex molecular landscape. In this setting, the incidence and clinical relevance of cancer-associated thrombosis (CAT) is unknown, thus BTCs are not included in common thrombotic risk scores (e.g. Khorana Score). Moreover, retrospective studies highlighted associations between thromboembolic events and some genetic alterations, such as KRAS in lung and colorectal cancer, ALK/ROS1 in lung cancer and IDH1 mutations in glioma. Nevertheless, the impact of different genomic alterations on CAT risk in BTCs patients has never been investigated. The aim of this study was to investigate for the first time the incidence and the clinical relevance of CAT in a cohort of BTC patients. In addition, we investigated the association between tumor genomics and CAT in this patients’ population. Methods: Clinical and genomic data of consecutive BTC patients who underwent extensive molecular profiling with the FoundationOneCDx panel at Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Italy, were collected. The association between genomic alterations and CAT incidence was investigated with the Fisher exact test, considering alterations occurring in at least 5% of patients. Cox regression was used to analyze the impact of CAT, considered as a time-dependent covariate, on overall survival (OS). Results: 140 patients were included in the analysis, mostly represented by cases of intrahepatic cholangiocarcinoma (77%). CAT occurred in 18 (13%) patients, the majority being pulmonary embolism (28%) and visceral thrombosis (44%). Pathogenic KRAS and BRCA1 mutations were found in 33% and 11% of patients with CAT, resulting significantly associated with an increased risk of thrombosis ( p = 0.041 for both). Patients who experienced CAT showed a significantly poorer OS (HR 3.29, p = < 0.001). Conclusions: This is the first report describing a non-negligible incidence and significant prognostic impact of CAT in BTC patients. Future studies investigating the clinical and molecular risk factors for CAT in this population are needed to tailor thromboprophylaxis in this rare population.

TPS8594 Background: Despite definitive surgery and perioperative chemotherapy, many patients with locoregional non-small cell lung cancer (NSCLC) continue to experience recurrent disease and limited survival. Although targeted therapies are standard treatment for metastatic NSCLC with genomic alterations, their use in the early-stage setting is still being characterized. Initial studies examining targeted therapy in neoadjuvant setting for early-stage epidermal growth factor receptor positive NSCLC has shown promise. Selpercatinib is a highly selective, potent, and central nervous system active rearranged during transfection (RET) inhibitor with demonstrated robust and sustained antitumor activity and manageable toxicity in patients with RET fusion-positive advanced NSCLC. Cohort 7 of the Phase 2, open-label, single arm LIBRETTO-001 study evaluates efficacy and safety of neoadjuvant selpercatinib in patients with resectable stage IB-IIIA RET fusion-positive NSCLC (NCT03157128). Methods: Key eligibility criteria include age ≥18 years; histologically confirmed stage IB–IIIA NSCLC (AJCC, version 8); presence of RET fusion in tumor (by PCR or NGS) or blood (by NGS) (pre-treatment biopsy confirmed); resectable and operable tumor; measurable disease (RECIST 1.1); and ECOG performance status 0-1. Key exclusion criteria include presence of other known oncogenic drivers; and concurrent investigational anticancer therapy. Eligible patients will undergo full staging including radiographic tumor measurements using CT, PET, and brain MRI at baseline and after two 28-day cycles of neoadjuvant selpercatinib, followed by surgery. Dosing regimen is 160 mg twice daily. Resected tumor specimens will be sent to an Independent Pathology Review Committee (IPRC) for evaluation. Patients may then be treated with stage-appropriate adjuvant therapy/surveillance, based on the treating physician’s decision, followed by selpercatinib until disease recurrence, unacceptable toxicity, withdrawal, or death, for a maximum treatment duration of 3 years. The primary endpoint is to determine the rate of major pathologic response (MPR) by IPRC, defined as ≤ 10% residual viable tumor cells in the surgically resected specimen. Efficacy based on the MPR will be assessed using the Simon's 2-stage design. In Stage I, 9 patients will be enrolled; if ≤1 patient achieves an MPR, the study will be stopped. Otherwise, at least 10 additional patients will be enrolled, with a total of 19 patients undergoing surgery. The rate of pathologic complete response (pCR) by IPRC, disease-free survival, and overall survival will be assessed as secondary endpoints. pCR rate will be determined at the time of surgery, indicating no remaining viable tumor cells. Safety of peri-operative treatment will be assessed, including 30- and 90-day post-operative readmission and mortality rates. Clinical trial information: NCT03157128.

9051 Background: Chemo-immunotherapy is the standard of care for patients with advanced NSCLC and PD-L1 < 50%. Efficacy has been reported in this setting with single agent pembrolizumab, but no reliable biomarkers yet exist for selecting patients likely to respond to single agent immunotherapy. The aim of this trial was to identify potential new immune biomarkers associated with PFS in NSCLC patients with PD-L1 < 50% treated with first line pembrolizumab. Methods: Advanced EGFR and ALK wild type treatment-naïve NSCLC patients with PD-L1 < 50% were enrolled. Gene expression profile was performed using nCounter PanCancer IO 360 Panel (Nanostring) on baseline tissue. Circulating immune profiling was performed by determination of absolute cell counts with multiparametric flow cytometry on freshly isolated whole blood samples at baseline and at first radiological evaluation. Gut bacterial taxonomic abundance was obtained by shotgun metagenomic sequencing of stool sample at baseline. Pembrolizumab was administered at 200 mg flat dose every 3 weeks until 35 cycles, disease progression or unacceptable toxicity. Omics data was analyzed with sequential univariate Cox Proportional Hazards regression predicting PFS, with Benjamini-Hochberg multiple comparisons correction. Biological features significant with univariate analysis were analyzed with multivariate Least Absolute Shrinkage and Selection Operator (LASSO). Results: From May 2018 to October 2020 65 patients were enrolled. Main characteristics were: male 67.6%, smokers 87.7%, PD-L1 positive 70.8%. Median follow up and PFS were 26.4 and 2.9 months, respectively. Gene expression profile was performed in 48 patients, microbiome in 54 patients and circulating immune profiling in 56 patients at baseline and in 46 patients at first radiologic evaluation. LASSO multivariate analysis with optimal lambda of 0.28 showed high expression levels of IRF9 and COMP genes was associated with an unfavorable PFS (HR 3.03, 1.52 – 6.02, p = 0.08 and HR 1.22, 1.08 – 1.37, corrected p = 0.06, respectively). High expression levels of CD244 (HR 0.74, 0.62- 0.67, p = 0.05), PTPRC (HR 0.55, 0.38 – 0.81, p = 0.098), KLRB1 (HR 0.76, 0.66 – 0.89, p = 0.05) in tissue samples and NK cells/CD56dimCD16+ (HR 0.56, 0.41 – 0.76, p = 0.006) in peripheral blood at baseline and non classical CD14dim CD16+ monocytes (HR 0.52, 0.36 – 0.75, p = 0.004), eosinophils (CD 15+CD16-) (HR 0.62, 0.44 – 0.89, p = 0.003) lymphocytes (HR 0.28, 0.15 – 0.5, p < 0.001) in peripheral blood after first radiologic evaluation were associated to a favorable PFS. No microbiome features were selected by LASSO. Conclusions: To the best of our knowledge, this is the first prospective trial in NSCLC with PD-L1 < 50% performed with a multi-omic approach able to identify immune cell subsets and expression levels of genes associated to PFS under first line treatment with pembrolizumab. Clinical trial information: NTC03447678.

438 Background: HER2 overexpression has been found in invasive UC, suggesting a role for HER2 in disease progression and prognosis (Kruger Int J Oncol 2002). T-DXd is an antibody-drug conjugate comprising an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor payload. Preclinical models showed that T-DXd combined with an anti-PD-1 antibody had greater efficacy versus either agent alone (Iwata Mol Cancer Ther 2018). We conducted a phase 1b, 2-part, open-label, multicenter study of T-DXd in combination with nivo in pts with HER2-expressing advanced/metastatic UC (NCT03523572). Methods: Pts aged ≥18 y had pathologically documented advanced/metastatic UC with centrally confirmed HER2 expression by immunohistochemistry (IHC) 2+/3+ (cohort 3; high expression) or IHC 1+ (cohort 4; low expression) who received prior platinum-based therapy with documented progression. Pts received T-DXd at 5.4 mg/kg and nivo 360 mg IV every 3 weeks (recommended dose for expansion). The primary endpoint was confirmed objective response rate (ORR) assessed by independent central review (ICR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints (assessed by ICR) included duration of response (DOR), progression-free survival (PFS), time to response (TTR), and overall survival (OS), and safety. Results: At the primary analysis data cutoff (July 22, 2021), 34 pts (cohort 3, n = 30; cohort 4, n = 4) received T-DXd and nivo. Median age was 70.9 y (range, 41.4-80.5), 88.2% were male, 61.8% received ≥1 prior regimens for locally advanced/metastatic disease, and 26.5% had a history of liver metastases. Median treatment duration (all pts) was 3.2 mo (range, 1-21) for T-DXd and 4.1 mo (range, 1-20) for nivo. In cohort 3, ORR by ICR was 36.7% (95% CI, 19.9-56.1; complete response, 13.3%; partial response, 23.3%), median DOR was 13.1 mo (95% CI, 4.1- NE), median PFS was 6.9 mo (95% CI, 2.7-14.4), median TTR was 1.9 mo (range 1.2-6.9), and median OS was 11.0 mo (95% CI, 7.2-NE). Grade (G) ≥3 treatment-emergent adverse events (TEAEs) occurred in 73.5% of all pts (44.1% related to T-DXd; 26.5% related to nivo). TEAEs leading to drug discontinuation occurred in 32.4% of all pts (17.6% related to T-DXd; 23.5% related to nivo). The most common any-grade TEAEs were nausea (73.5%), fatigue (52.9%), and vomiting (44.1%). Adjudicated drug-related interstitial lung disease (ILD)/pneumonitis occurred in 23.5% of all pts (2 G1; 4 G2; 1 G3; 1 G5). Conclusions: T-DXd combined with nivo showed antitumor activity in pts with high-expressing HER2 UC. The safety profile was consistent with prior studies for T-DXd in other indications and nivo monotherapy in UC pts. Adjudicated ILD/pneumonitis was within the range observed in other T-DXd monotherapy studies. Ongoing clinical trials are further exploring T-DXd in this population. Clinical trial information: NCT03523572.

95 Background: mCRPC remains an incurable disease with unmet need for improved therapies. PARP inhibition has demonstrated antitumor activity, and preclinical studies suggest synergy between PARP and AKT inhibition. This phase Ib trial (NCT03840200) sought to determine the maximum tolerated dose of PARP inhibitor rucaparib (ruca) with AKT inhibitor ipatasertib (ipat) and explore early safety and efficacy in patients (pts) with mCRPC. Methods: The study had 2 parts: a part 1 dose-escalation phase (cohort [C]1: ipat 300 mg QD + ruca 400 mg BID; C2a: ipat 300 mg QD + ruca 600 mg BID; C2b ipat 400 mg QD + ruca 400 mg BID; C3: ipat 400 mg QD + ruca 600 mg BID) in unselected pts with mCRPC or advanced breast or ovarian cancer, and a Part 2 dose-expansion phase in pts with mCRPC whose previous androgen deprivation therapy failed. The primary safety endpoints were AEs and dose-limiting toxicities, with the goal of identifying a recommended phase II dose (RP2D). The primary efficacy endpoint was prostate-specific antigen (PSA) response (PSA reduction of ≥ 50%) in pts with mCRPC. Secondary efficacy endpoints included ORR per RECIST 1.1, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 and OS in pts with mCRPC. We assessed homologous recombination deficiency (HRD), PIK3CA/ AKT1/ PTEN status and other alterations by next-generation sequencing. Results: Part 1 enrolled 21 pts: 17 with mCRPC, 3 with ovarian cancer and 1 with breast cancer (C1 [n=8], C2a [n=6] and C2b [n=7], C3 [not opened]). Ipat 400 mg QD + ruca 400 mg BID was the selected RP2D. 30 pts enrolled in Part 2, so 37 pts with mCRPC (C2b + Part 2) received the RP2D (median follow-up 93 days). All grade AEs occurred in 37 pts (100%), serious AEs in 8 pts (22%) and AEs leading to treatment modification in 26 pts (70%). The most frequent AEs (all grade and grade 3, respectively) were diarrhea (35 [95%] and 2 [5%]); asthenia (24 [65%] and 4 [11%]); and nausea (24 [65%] and 2 [5%]). There was 1 grade 4 AE (anemia) and no grade 5 AEs. See the table for efficacy data. In biomarker subgroups, the PSA response rate was 50% (3/6) in pts with HRD tumors vs 25% (4/16) in pts with HR-proficient tumors, and 14% (1/7) vs 40% (6/15) in pts with PIK3CA/ AKT1/ PTEN–altered or intact tumors, respectively. Conclusions: The combination of ipat and ruca was well tolerated but did not show clinically relevant antitumor activity in pts with mCRPC, including in predefined biomarker subpopulations. Clinical trial information: NCT03840200. [Table: see text]

Background - Physical distancing for COVID-19 led to decreased in-person patient follow up assessments and delayed imaging appointments. Herein we describe for the first time the impact of delays in diagnostic investigations of patients with an history of early-stage breast cancer (BC) in the largest public cancer center of Lombardy, the Italian region most affected by the pandemic. Methods - This single-institution retrospective study included three observational periods. The first pandemic peak period (March-April 2020) corresponding to the interruption of follow up imaging; the post-peak period (May-December 2020); the pre-pandemic period represented by the five previous years (January 2015- December 2019) as control. The flow of diagnostic activities was compared among the different years. Moreover, the number and characteristics of recurrent BC cases (rBC) diagnosed in the post-peak period were compared to the figures observed in pre-pandemic years, when imaging was regularly carried out, using descriptive statistics. A further comparison was performed between the characteristics of scheduled and delayed rBC diagnosed after the first peak. Results - During the first pandemic peak, diagnostic investigations declined by 81.2% (from 1032 in January-February to 194 in March-April), a drop which was not identified in the same period of the pre-pandemic years, before rebounding to 1065 in May-June, 832 July-August (reflecting the summer physiological drop), 1334 September-October, and 879 November-December. The average number of rBC cases of 16 (range 12-25) in March-April of the pre-pandemic period declined to a value as low as 4 during the first pandemic peak. Thereafter, the number of rBC cases began a steady increase, until reaching a total of 27 in September-October 2020, almost doubling the mean of 14.8 (range 11-21) achieved in the corresponding months of 2015-2019. As a result, the absolute number of rBC cases was 76 in 2020 and on average 78.4 (range 70 - 95) in pre-pandemic years, and the rBC proportion of 1.42% (76/5336; 95% exact confidence interval, CI: 1.12-1.78%) in 2020 was slightly higher than the average proportion of 1.26% of the five previous years, though the latter being well included in the CI of the 2020 proportion. No difference in primary tumor presentation and age at initial diagnosis was found among recurrent patients before and after the pandemic. Of the rBC cases reported during 2020, 10 were from 513 patients with postponed follow up who were finally diagnosed between September-December. As compared to patients on schedule, delayed rBC cases did not present with ductal carcinoma in situ, and reported a median tumor size of 18 mm (range 4.3-90 mm), which was 20% higher than the median of 15 mm (3.1-34) observed for scheduled patients. Distribution of luminal-like, triple negative and HER2-overexpressing BC subtypes among evaluable rBC cases was 75%, 12.5%, 12.5% in scheduled and 66%, 11% and 22% in delayed cases, respectively. Conclusions - Our data showed a slight decrease in the absolute number of rBC during 2020 despite a rebound of examinations, and an increased size of invasive recurrence following the 2-month stop of the first pandemic peak. The full impact of the COVID-19 pandemic on recurrent cancer diagnosis will be known when national population-based data become available in the coming years. Citation Format: Serena Di Cosimo, Catherine Depretto, Rosalba Miceli, Paolo Baili, Silva Ljevar, Milena Sant, Claudio Ferranti, Secondo Folli, Massimiliano Gennaro, Filippo G de Braud, Claudio Vernieri, Maria Carmen De Santis, Laura Lozza, Andrea Vingiani, Giancarlo Pruneri, Giovanni Apolone, Alfonso Marchianò, Gianfranco P Scaperrotta. The impact of COVID-19 on diagnosis of recurrent breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-01-12.

201 Background: Dostarlimab is a programmed death receptor-1 (PD-1) blocking antibody that is approved in the US as a monotherapy in adult patients (pts) with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen or dMMR recurrent or advanced solid tumors that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. Here, we report on the antitumor activity and safety of dostarlimab monotherapy in pts with dMMR colorectal cancer (CRC), a post-hoc subgroup analysis of cohort F of the GARNET trial. Methods: GARNET is a phase 1, multicenter, open-label, single-arm study of dostarlimab monotherapy in pts with advanced or recurrent solid tumors. Cohort F of the GARNET expansion cohorts enrolled pts with dMMR/MSI-H or POLε mutated non-endometrial solid tumors, including pts with CRC. Pts must have progressed per blinded independent central review (BICR) following prior systemic therapy for advanced disease. Pts with CRC were required to have progressive disease after or been intolerant to fluoropyrimidine, oxaliplatin, and irinotecan. Pts received 500 mg intravenous dostarlimab every 3 weeks for 4 cycles, followed by 1000 mg every 6 weeks until discontinuation. Primary endpoints were objective response rate (ORR) and duration of response by BICR per RECIST v1.1. Pts were included in the efficacy analysis if they received ≥1 dose of dostarlimab, had measurable disease at baseline, and had ≥24 weeks of follow-up. All pts who received ≥1 dose of dostarlimab were included in the safety analysis. Results: As of the March 01, 2020 interim analysis data cut, 141 pts with dMMR non-endometrial solid tumors were included in the safety analysis, with 106 in the efficacy analysis. Of the pts in the efficacy analysis, 69 (65.1%) had CRC. Confirmed ORR by BICR per RECIST v1.1 in pts with dMMR CRC was 36.2% (95% CI, 25.0%–48.7%). There were 3 complete responses and 22 partial responses. At the data cut, 23 pts (92%) were still on treatment. Median duration of response had not been reached for pts with CRC. In the overall dMMR non-endometrial solid tumor population, treatment-related adverse events (TRAEs) were reported in 68.1% of pts, with 8.5% of pts experiencing at least 1 grade ≥3 TRAE. The most common grade ≥3 TRAE was lipase increased in 2 (1.4%) of pts. Only 5 pts (3.5%) discontinued dostarlimab due to at TRAE. Treatment-related serious AEs were reported in 9 (6.4%) pts. Conclusions: Dostarlimab demonstrated durable clinically meaningful antitumor activity in pts with dMMR CRC, which was consistent with that seen in patients with dMMR non-CRC solid tumors. No new safety signals were detected in patients with dMMR non-endometrial solid tumors. Clinical trial information: NCT02715284.

358 Background: Nivo (anti–PD-1) has shown durable responses and manageable safety (ORR, 19.6%; grade 3‒4 treatment-related AEs [TRAEs], 18%) in advBC (Sharma et al. Lancet Oncol 2017), but prolonging survival in more pts requires additional approaches to overcome tumor evasion mechanisms. IDO1 allows tumor escape through kynurenine (KYN) production, which stimulates regulatory T cells and suppresses effector T-cell proliferation. Anti─PD-1 can upregulate IDO1, supporting the rationale for combining nivo with an IDO1i. BMS-986205 is a selective, potent, once-daily (QD) oral IDO1i that works early in the IDO1 pathway to reduce KYN production. BMS-986205 + nivo showed favorable safety and efficacy in heavily pretreated pts with select solid tumors (Luke et al. SITC 2017; NCT02658890). Updated safety across all tumor cohorts and efficacy in the immuno-oncology (I-O)–naive advBC cohort are reported. Methods: Dose-escalation methods in this phase 1/2a, open-label study were previously described; during expansion, pts received BMS-986205 100 or 200 mg QD + nivo 240 mg IV Q2W or 480 mg IV Q4W. Objectives included safety and ORR by RECIST v1.1 (includes unconfirmed responses). Results: As of Mar 2018, 516 pts received BMS-986205 + nivo; 45% had ≥2 prior regimens. TRAEs occurred in 57% of pts (grade 3‒4, 12%), the most common being fatigue (15%) and nausea (12%); 19 pts (4%) discontinued due to TRAEs, and 3 pts ( < 1%) died due to a TRAE (myocarditis, Stevens-Johnson syndrome, and hepatic failure). In all treated pts and within the advBC cohort (n = 30), the frequency and severity of TRAEs and rate of discontinuation due to TRAEs was lower with the 100- vs 200-mg BMS-986205 dose. Among the 27 pts with I-O–naive advBC, with a median duration of follow-up of 24 wk, ORR was 37% (3 CRs, 7 PRs), and the DCR was 56%; ORR in pts with tumor PD-L1 ≥1% (Dako PD-L1 IHC 28-8 pharmDx assay; n = 14) vs < 1% (n = 10) was 50% vs 30%. Conclusions: BMS-986205 + nivo was well tolerated in heavily pretreated pts, and tolerability was improved with the 100-mg BMS-986205 dose. Preliminary evidence of efficacy was observed in advBC, supporting further evaluation of BMS-986205 + nivo. Clinical trial information: NCT02658890.

e16064 Background: In recent years, several new agents have been introduced into clinical practice for patients (pts) with metastatic renal cell carcinoma (mRCC). The aim of this study was to describe the difference in terms of exposure to multiple lines of treatment and overall survival (OS) between two groups of pts who started therapy for mRCC in two different periods of time (period 1: 2005-2010 and period 2: 2011-2016). Methods: Data were retrospectively collected from the database of the Istituto Nazionale Tumori of Milan. The proportion of pts who received subsequent lines of treatment after first disease progression (PD) was compared between the two groups of pts. OS was defined as time from the start of first-line treatment to death or last follow-up. Unadjusted and adjusted analyses for Heng risk groups were done. Results: Overall,457 pts with mRCC were evaluated: 274 pts (60%) started treatment in period 1 and 183 (40%) in period 2. Most pts in both groups had intermediate risk (65.7% and 86.3% respectively). The proportion of poor-risk pts was significantly higher in period 1 (21.2% vs 7.7%). Among pts who stopped first-line treatment due to PD, pts in period 2 had a higher chance of receiving second-line treatment as compared to pts of period 1 (80.8% vs 64.7%, 95% CI 1.31-4.04, p = 0.003). Similarly, among those who stopped second-line treatment due to PD, pts in period 2 had a higher chance of receiving a third-line treatment compared to pts in period 1 (71.2% vs 49.3%, 95% CI 1.32-4.87, p = 0.004). In the whole study population, median OS (mOS) was 24.9 months (95% CI 21.6-31.1): 21.7 months (95% CI 18.8-26.3) in pts of period 1 and 38.2 months (95% CI 27.7-49.0) in pts of period 2 (Hazard Ratio [HR] 0.65,95% CI 0.49-0.84, p = 0.001) respectively. When adjusted for Heng groups, OS remained significantly longer for pts of period 2 (HR 0.76, 95% CI 0.57-1.00, p = 0.05). Conclusions: mRCC pts who started a treatment over the last 5 years have been exposed to a higher number of treatment lines as compared to those treated before 2011. Our data suggest that the increase of treatment options as well as a better clinicians’ expertise is associated with a better outcome.