Durable Stable Disease Research Articles

Pathology of durable stable disease in melanoma patients treated with ipilimumab, nivolumab, or ipilimumab, and nivolumab combination therapy.

9567 Background: As immunotherapy with checkpoint blockade becomes the backbone of melanoma treatment there is a need to better understand the biology associated with long term benefit. One particularly interesting set of patients are those with prolonged stable disease or response with residual findings on imaging. It is unknown if immunotherapy has led to scarring at the site of prior disease or if there are residual tumor cells being controlled by an ongoing immune response. Evaluating tissue from patients with prolonged responses provides a unique opportunity to determine the composition of residual lesions. Correlation with PET/CT helps determine if this is an accurate modality to reflect presence of residual viable tumor tissue. Methods: Metastatic melanoma patients that have attained long term stable disease after treatment with ipilimumab, nivolumab, or ipilimumab plus nivolumab were identified. Patients must have received ipilimumab, nivolumab or combination therapy 2+ years prior to enrollment and must have had stable disease for ≥ 6 months. Patients were consented and underwent PET/CT scans and biopsies of residual areas of stable disease. Pre- and post-treatment tissue samples underwent pathologic assessment to look at tumor cell content, fibrotic content, and inflammation. Results: Ten patients were consented for evaluation but only 7 met the screening criteria and underwent PET/CT and tissue biopsy. Six patients had FDG avid lesions on PET/CT which ranged in intensity from SUV 2.4-22. One patient had no FDG avidity in the areas of residual disease observed on CT. Biopsies from the residual stable lesions demonstrated predominantly necrosis and fibrosis with prominent pigment containing macrophages. One patient with an axillary nodal lesion with an SUV of 22 had active melanoma on pathology which was resected, and the patient has subsequently remained without progression of disease. Conclusions: Patients with durable stable disease after treatment with ipilimumab, nivolumab or ipilimumab and nivolumab combination therapy represent a unique population of melanoma patients treated with immune checkpoint inhibition. An examination of the residual lesions observed in these patients demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest some ongoing immune surveillance. One patient did demonstrate residual melanoma suggesting the need for ongoing monitoring of this patient population.

A phase 1/2 study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent glioblastoma.

TPS2071 Background: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor with a median overall survival (OS) of 15 months for patients with newly diagnosed GBM (ndGBM) and 5-7 months for patients with recurrent GBM (rGBM). To improve the prognosis of patients with GBM, novel therapies are urgently needed. Selinexor is a first-in class, oral, selective inhibitor of nuclear export that blocks exportin 1 (XPO1), forcing the nuclear retention and reactivation of tumor suppressor proteins, ultimately causing death of cancer cells. Selinexor is an FDA-approved treatment for patients with heavily pretreated multiple myeloma, for patients who received at least one prior therapy, and for patients with relapsed/refractory diffuse large B-cell lymphoma. Increased XPO1 expression in gliomas was associated with higher pathological stage and poorer prognosis. In a phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. In preclinical studies, selinexor showed synergy with radiation, temozolomide, or lomustine. The current trial tests the hypothesis that the addition of selinexor to standard therapy will improve clinical outcomes for patient with ndGBM or rGBM. Methods: This phase 1 dose finding study is followed by a 1:1 randomized phase 2 (n= 350) efficacy exploration trial to independently evaluate 3 regimens: Arm A – radiation +/- selinexor in unmethylated O6-methylguanine-DNA-methyltransferase (uMGMT) ndGBM; Arm B – radiation and temozolomide +/- selinexor in mMGMT ndGBM; Arm C – lomustine +/- selinexor in first relapsed rGBM following frontline radiation and temozolomide. The phase 1 primary endpoint is maximum tolerated dose/recommended phase 2 dose, with secondary endpoints of overall response rate (ORR) per modified Response Assessment in Neuro-Oncology (mRANO), duration of response (DOR), progression free survival (PFS), and OS. The phase 2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS at 6 months, ORR, and DOR. For Arm C, the phase 2 primary endpoint is OS, while key secondary endpoints are PFS, PFS at 6 months, ORR, and DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy in Arms A and B, and 80% power to detect a hazard ratio of 0.70 for Arm C. We are currently enrolling patients nationwide. Clinical trial information: NCT04421378.

Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors.

3005 Background: SHP2 transduces signals from activated receptor tyrosine kinases to downstream pathways including MAPK. TNO155 is a selective, allosteric, oral inhibitor of SHP2. Methods: CTNO155X2101 (NCT03114319) is an ongoing first-in-human, open-label dose escalation/expansion trial of TNO155 in adults with advanced solid tumors. The primary objective is to characterize the safety and tolerability of TNO155 and identify regimen(s) for future study. Secondary assessments included pharmacokinetics, pharmacodynamics, and preliminary clinical efficacy. Here we present data from TNO155 single agent escalation. Results: As of 10/26/2020, 118 patients received TNO155 in variable schedules: once (QD; 1.5–70 mg; n = 55) or twice daily (BID; 30–50 mg; n = 25) in a 2 weeks on/1 week off (2w/1w) cycle; or QD in a 3w/1w cycle (30–60 mg; n = 32), or continuously (40 or 50 mg QD; n = 6). The most common cancer diagnoses treated were colorectal (54%), gastrointestinal stromal tumor (16%), non-small cell lung (12%), and head & neck (8%). The median number of prior antineoplastic therapies was 4 (range 1–10). Overall 109 patients (92%) have discontinued study treatment, 94 (80%) for progressive disease and 6 (5%) for adverse events (AEs). TNO155 showed rapid absorption (median day 1 Tmax ̃1.1 hours), an effective median T½ of ̃34 hours, and near dose-proportional exposure at day 14 (power model: AUCτ beta = 1.09 [90% CI 1.02–1.16]). AEs were mostly Grade 1/2 and generally consistent with on-target effects of SHP2 inhibition. The most common treatment-related AEs (all grades) were increased blood creatine phosphokinase (n = 33, 28%), peripheral edema (n = 31, 26%), diarrhea (n = 31, 26%), and acneiform dermatitis (n = 27, 23%). The most common treatment-related Grade ≥3 AEs were decreased platelets (n = 5, 4%), increased aspartate aminotransferase, diarrhea, and decreased neutrophils (each n = 4, 3%). The best observed response was stable disease (SD) per RECIST 1.1, reported in 24 (20%) patients, with a median duration of SD of 4.9 months (range 1.7–29.3). Evidence of SHP2 inhibition, as measured by change in DUSP6 expression by qPCR in paired pre- vs. on-treatment tumor samples, was seen in the majority of patients treated with TNO155 doses ≥20 mg/day (≥25% reduction, 38/42 [90%]; ≥50% reduction, 25/42 [60%]). Analysis of tumor whole-transcriptome RNA sequencing data is ongoing. Conclusions: TNO155 shows favorable pharmacokinetic properties and promising early safety and tolerability data at doses with evidence of target inhibition. The optimal dose using several schedules is still under evaluation. Studies of TNO155 in combination with other agents, including nazartinib (mutant-selective EGFR inhibitor[i]), adagrasib (KRAS G12Ci), spartalizumab (anti-PD-1 antibody), ribociclib (CDK4/6i), and dabrafenib (BRAFi) with LTT462 (ERKi), are ongoing (NCT03114319, NCT04330664, NCT04000529, NCT04294160). Clinical trial information: NCT03114319.

Safety profile and disease stabilization in late stage, heavily pretreated, solid tumor patients in a first-in-human (FIH) study of ATX-101, a drug targeting proliferating cell nuclear antigen (PCNA).

3067 Background: PCNA is a conserved scaffold protein orchestrating DNA replication, repair or bypass pathways as well as cellular signaling and apoptosis. More than 500 protein-PCNA interactions have been identified which are mediated via two binding motifs, the PIP-box and APIM. Cellular stress, to which cancer cells and cells of tumor microenvironment are exposed, increases the affinity of the APIM motif. APIM-containing proteins bind to PCNA and mediate processes of escape mechanisms and survival of cancer cells. ATX-101 is a cell penetrating peptide containing APIM. It inhibits protein binding via APIM, resulting in cancer cell death and altered cellular signaling. Anticancer effects of ATX-101 have been demonstrated in vitro and in vivo. Methods: A FIH study using a 3+3 dose escalation design was conducted. Patients with late-stage solid tumors received weekly infusions of 20, 30, 45 and 60 mg/m² over 6 weeks. Primary objective was safety, secondary objectives were PK and efficacy. Patients with stable disease (SD) after 6 weeks could continue treatment in a long-term follow-up (LTFU) study. Results: As of January 2021, 22 patients have been treated. All patients received in average 3.8 [1-9] prior treatment lines, all but one had progressive disease at study entry and 80% were refractory to the last therapy. No dose limiting toxicity or death and no treatment related Grade 3/4 or serious adverse events were reported. The maximum tolerated dose was not reached. Mild to moderate infusion related reactions (IRR) were observed in 73% of patients. They were not dose dependent and resolved completely after treatment interruption and/or symptomatic treatment. IRRs occurred despite premedication and could cause infusion interruptions with extended infusion duration. Experiments in dogs indicate that transiently increased histamine levels may cause IRRs. However, elevated histamine and tryptase levels could not be measured in patients so far. ATX-101 exposure was dose-dependent. Cmax was reached either at the middle or at the end of infusion. ATX-101 disappeared quickly from plasma and was not detectable 5 - 60 minutes post infusion. 13 patients finished the FIH study, 10 had SD after 6 weeks. 9 of 10 patients moved into the LTFU study. The treatment duration in the LTFU study varied from 2.1 to 15.6 months (median 4.2 months). Conclusions: ATX-101 is well tolerated at all dose levels with IRRs being the most frequent AEs. Drug exposure is dose dependent with rapid plasma clearance, which confirms in vivo data demonstrating the quick uptake by cells of all organs. The observed duration of SD may be attributed to ATX-101 activity. Proof of concept combination studies are being initiated. Clinical trial information: 375262.

Phase IIa study of BVAC-C in HPV type 16 or 18 positive recurrent cervical carcinoma.

5512 Background: BVAC-C is a B cell- and monocyte-based immunotherapeutic vaccine transfected with recombinant HPV E6/E7, which was well tolerated in HPV positive recurrent cervical carcinoma in phase I study (J Clin Med. 2020 Jan 5;9(1):147). This phase IIa study sought to determine the antitumor activity of BVAC-C. Methods: Twenty-one patients with HPV 16 or 18 positive recurrent cervical cancer who had experienced recurrence after one prior platinum-based combination chemotherapy were enrolled. They were allocated to 3 arms; Arm 1, BVAC-C injection at 0, 4, 8 weeks (1x108 cells/dose); Arm 2, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose); Arm 3, BVAC-C injection at 0, 4, 8, 12 weeks (5x107 cells/dose) with topotecan at 2, 6, 10, 14 weeks (0.75 mg/m2 for 3 days). Results: The overall response rate was 21% (Arm 1: 29% (2/7), Arm 2: 25% (1/4), Arm 3 : 0 % (0/3)) among the evaluable patients (N = 14), and the median duration of response was 18 months (range, 9 – 26 months). The disease control rate was 43% (Arm 1: 29% (2/7), Arm 2: 50% (2/4), Arm 3 : 67 % (2/3)) and the median duration of stable disease were 12 months (range, 6 - 26 months). The median progression-free survival in all patients was 4 months (95% CI, 2 to Infinite months). Immune responses of patients after vaccination were shown to be correlated with clinical responses of them. Consistent with Phase I study, all evaluated patients showed not only inflammatory cytokine responses (IFN-γ or TNF-α), which might be mediated by the activation of natural killer cells and natural killer T cells, but also potent E6/E7-specific T cell responses upon vaccinations. Conclusions: BVAC-C demonstrated a durable antitumor activity with an immune response in HPV 16- or 18-positive recurrent cervical carcinoma patients who failed 1st line platinum based chemotherapy. Clinical trial information: NCT02866006.

AdvanTIG-105: Phase 1 dose-escalation study of anti-TIGIT monoclonal antibody ociperlimab (BGB-A1217) in combination with tislelizumab in patients with advanced solid tumors.

2583 Background: Anti-programmed death 1 (PD-1) therapy has improved clinical outcomes for patients (pts) with advanced solid tumors but unmet needs remain. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) is a co-inhibitory, immune checkpoint receptor. Ociperlimab (OCI; BGB-A1217) is a novel, humanized, monoclonal antibody that binds to TIGIT with high affinity and specificity. OCI has demonstrated competent binding with C1q and all Fcγ receptors and induces antibody-dependent cellular cytotoxicity. Preclinical studies demonstrated dual targeting with OCI and tislelizumab (TIS), an anti-PD-1 antibody, produces synergistic immune cell activation and enhanced antitumor activity. Methods: AdvanTIG-105 is a phase 1, open label, multicenter, dose-escalation study (NCT04047862) that assessed the safety and preliminary antitumor activity of OCI plus TIS in pts with advanced, metastatic, unresectable solid tumors, for which standard therapy was ineffective or unavailable. Eligible pts had an Eastern Cooperative Oncology Group performance score ≤1 and no prior therapy targeting TIGIT. Pts received OCI intravenously (IV) on Day 1 of Cycle 1 and TIS 200 mg IV on Day 8. Pts were monitored for dose-limiting toxicities (DLTs) until Day 28. If tolerated, OCI and TIS were administered sequentially on Day 29 and every 3 weeks (Q3W) thereafter. Pts received escalating doses of OCI (50-900 mg) plus TIS 200 mg. The study objective was determination of recommended phase 2 dose (RP2D) of OCI plus TIS. Study endpoints included assessment of adverse events (AEs), pharmacokinetics and antitumor activity. Data cut-off was October 12 2020. Results: 24 pts with various advanced solid tumors received OCI plus TIS. At baseline, pts had undergone a median of 2 prior treatment regimens; 9/24 (37.5%) pts had received prior immunotherapy. Median follow-up time was 17 weeks. No DLTs were observed. 20 pts had ≥1 treatment emergent AE (TEAE) and most TEAEs were grade ≤2; fatigue (6 pts) and diarrhea (4 pts) were most commonly reported. No pts had grade ≥4 TEAEs or TEAEs leading to death. There were 2 grade 3 immune related AEs (colitis and low cortisol). One pt on OCI 450 mg achieved partial response and 9 pts had stable disease. The longest duration of stable disease was 36 weeks (1 pt on OCI 150 mg). After administration, serum concentration of OCI decreased in a biphasic manner. Exposure to OCI increased proportionally with dose, and TIGIT receptor occupancy was sustained at ≥50 mg doses. Conclusions: OCI in combination with TIS was well tolerated across all doses in pts with advanced solid tumors. The RP2D was OCI 900 mg plus TIS 200 mg Q3W. Clinical trial information: NCT04047862.

Trial in progress: A phase 1b study of sotorasib, a specific and irreversible KRASG12C inhibitor, as monotherapy in non-small cell lung cancer (NSCLC) with brain metastasis and in combination with other anticancer therapies in advanced solid tumors (CodeBreaK 101).

TPS2669 Background: Kirsten rat sarcoma viral oncogene homolog ( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRASG12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. The combination of sotorasib with other anticancer therapies may enhance antitumor efficacy. This master protocol is designed to evaluate safety, tolerability, pharmacokinetics (PK), and efficacy of multiple sotorasib combinations in patients (pts) with KRASp.G12C mutated solid tumors. Herein, we overview 1 monotherapy and 11 combination cohorts. Methods: This is a phase 1b, open-label study evaluating sotorasib alone and in combination regimens (Table) in pts with advanced KRAS p.G12C mutated solid tumors. Dose exploration will evaluate the safety and tolerability of sotorasib alone and in combination regimens; dose expansion will then verify the safety and tolerability profile of sotorasib regimens and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic solid tumor with KRAS p.G12C mutation identified through molecular testing in pts who have received ≥1 lines of prior systemic therapy. Primary endpoints include dose-limiting toxicities and treatment-emergent or treatment-related adverse events. Secondary endpoints include PK profile of combination regimens and efficacy (eg, objective response, disease control, duration of response, progression-free survival, and duration of stable disease assessed per RECIST 1.1). Enrollment began in December 2019 and is ongoing. Clinical trial information: NCT04185883. [Table: see text]

Bosutinib in combination with pemetrexed in patients with selected metastatic solid tumors: A phase I study (NCT03023319).

3022 Background: Activation of the Src kinase pathway has been observed in about 50% of cancers of the colon, liver, lung, breast and pancreas. Ceppi, et al, explored that Src inhibitors might be synergistic in combination with pemetrexed. Bosutinib is an approved oral ATP-competitive Bcr-Abl tyrosine-kinase inhibitor with an inhibitory effect on Src kinases. Methods: In this phase 1, dose-escalation study, we enrolled 10 patients with advanced metastatic solid tumors who progressed on standard of care chemotherapy, 9 of whom were evaluable, to receive bosutinib and pemetrexed. Bosutinib was administered once daily in a 3 + 3 dose-escalation study design where the first cohort started at an oral dose of 200 mg daily with I.V. pemetrexed 500 mg/m2 on a three weekly schedule. The primary objective was to determine the dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of bosutinib with pemetrexed, and the type and frequency of adverse events. Secondary objective(s) were to estimate tumor response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: All patients had progressed on prior chemotherapy and included 9 patients with adenocarcinoma of the lung, and 1 patient with metastatic adenocarcinoma of the appendix. Two patients (22%) had prior pemetrexed exposure. Median age was 62 years (range, 58-44). The median number of bosutinib and pemetrexed cycles received was 2 (range, 1-4). Nine patients were evaluable. The MTD of bosutinib was 300 mg daily in this combination as 2 out of the 3 patients who received 400 mg experienced elevated liver transaminases (>CTCAE Grade 3) and one patient experienced grade 3 fatigue. Two patients (22%) had a partial response, and 6 patients (67%) had stable disease, including 2 patients with prior pemetrexed exposure, and 1 patient had disease progression. The two responders and the subject with the longest stable disease duration demonstrated Src overexpression on immunohistochemical staining of their tumor. Two patients died of sepsis; both had stable disease. Median PFS was 4.1 months (range, 1.2-11.6), and the median OS was 11.9 months (range, 4-36.7). Adverse events included pneumonia/sepsis, diarrhea, fatigue, rash, weakness, transaminitis, hypertension, and thrombocytopenia. Conclusions: The MTD of oral bosutinib was 300 mg daily in combination with pemetrexed 500 mg/m2 every 3 weeks. Despite the limitations of this phase I study there appears potential efficacy of this combination in pretreated patients. We are currently enrolling patients in the expansion cohort. Clinical trial information: NCT03023319.

Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation.

Lessons Learned Cediranib and olaparib combination did not result in clinically meaningful activity in patients with metastatic pancreatic ductal adenocarcinoma without known BRCA mutation. BackgroundCediranib, a vascular endothelial growth factor receptor inhibitor, suppresses expression of BRCA1/2 and RAD51 inducing homologous recombination DNA repair deficiency (HRD) in several cancer cell lines and xenograft models [1]. Olaparib provides a clinical benefit in patients with metastatic pancreatic adenocarcinoma (mPDAC) with germline BRCA mutation (gBRCAmt) [2]. We hypothesized that cediranib induces HRD in the absence of gBRCAmt and synergizes with olaparib, resulting in an objective response in patients with mPDAC.MethodsPatients with mPDAC with at least one prior systemic chemotherapy were enrolled. Patients with known gBRCAmt were excluded. Patients took cediranib 30 mg daily and olaparib 200 mg twice daily, orally. The primary endpoint was objective response (OR) rate.ResultsNineteen patients received the study drugs. Seven patients came off treatment before the first restaging scan: six because of clinical progression and one because of an adverse event. No OR was observed. Six patients had stable disease (SD) as a best overall response. The median duration of SD was 3.1 months. The median overall survival was 3.4 months. Common treatment‐related adverse events were fatigue, hypertension, and diarrhea.ConclusionCediranib and olaparib combination did not result in clinically meaningful activity in patients with mPDAC without gBRCAmt.

Brief Report: Heterogeneity of Acquired Resistance Mechanisms to Osimertinib and Savolitinib

IntroductionMET amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis. MethodsWhole-exome sequencing was performed in EGFR-mutant, MET-amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy. All patients achieved partial response or durable stable disease to osimertinib and savolitinib before developing acquired resistance. ResultsAfter progression on osimertinib and savolitinib, whole-exome analysis revealed MET-dependent mechanisms of resistance, such as acquired MET p.D1246H mutation, MET p.Y1230C mutation, and MET copy number gain. As for MET-independent mechanisms, development of ERBB2 mutation and amplification and copy number gains in amplifications in CCNE, CCND1, CDK6, and EGFR were observed. Patient 2 harbored an acquired PIK3CA p.H1047R mutation in which resistance could be overcome with combination of PI3K inhibitor and osimertinib in the patient-derived xenograft model. ConclusionsOur study reveals that acquired resistance to savolitinib plus osimertinib can occur from both MET-dependent and MET-independent mechanisms.

The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+\u2009and androgen receptor-positive metastatic or locally advanced breast cancer

PurposeAndrogen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab.MethodsEligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety.ResultsOverall, 103 women were enrolled [median age 60 years (range 34–83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0–3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs.ConclusionsEnzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination.ClinicalTrials.gov numberNCT02091960

Outcome of Patients with NSCLC and Brain Metastases Treated with Immune Checkpoint Inhibitors in a 'Real-Life' Setting.

Simple SummaryWe identified non-small cell lung cancer (NSCLC) patients with brain metastases who were treated with immune checkpoint inhibitors at Karolinska University Hospital, Sweden and University Hospital of Heraklion, Greece from 2016 to 2019. We analyzed intracranial efficacies in the patients who had not received local treatment for their brain metastases less than three months prior to the initiation of immune checkpoint inhibitors and had adequate radiological evaluation. We demonstrated that immune checkpoint inhibitors are active in NSCLC patients with brain metastases regardless of the presence of neurological symptoms. This is a novel finding since, until now, this patient group has irrefutably been underrepresented in clinical studies and there is a clear scarcity of data. The results of our analyses suggest that symptomatic patients with active brain metastases (BM) may be considered for immunotherapy in routine clinical practice as well as clinical trials.There is lack of data addressing the intracranial (IC) efficacy of immune checkpoint inhibitors (ICIs) on brain metastases (BM) in non-small cell lung cancer (NSCLC). This patient category is underrepresented in randomized clinical trials. We retrospectively collected clinical data on patients with non-oncogenic driven NSCLC with BM who were treated with ICIs at two medical oncology institutes in Sweden and Greece from 2016 to 2019. IC efficacy was assessed in patients who had not received local treatment for BM less than three months prior to the initiation of ICIs and had adequate radiological evaluation. We screened 280 patients, of which 51 had BM. BM was an independent predictor for inferior PFS (HR = 2.27; 95% CI, 1.53–3.36) but not OS (HR = 1.58; 95% CI, 0.97–2.60) for the whole patient population. IC response assessment was done on 33 patients. IC objective response rate (ORR) was 24.2%. The presence of neurological symptoms related to BM did not affect IC ORR (p = 0.48). High PD-L1 levels from extracranial biopsies were not a predictive factor for IC ORR (p = 0.13). ICIs are active in NSCLC patients with BM regardless of the presence of neurological symptoms and can achieve durable IC disease stabilization in a subgroup of patients.

RTID-08. A PHASE 1/2 STUDY OF SELINEXOR IN COMBINATION WITH STANDARD OF CARE THERAPY FOR NEWLY DIAGNOSED OR RECURRENT GLIOBLASTOMA (ndGBM OR rGBM)

Abstract BACKGROUND GBM is the most common and most aggressive primary brain tumor with poor prognosis and median overall survival (mOS) of patients with ndGBM and rGBM being 15 vs 5-7 months, respectively. Selinexor is a first-in class, oral, selective nuclear export inhibitor which forces nuclear retention and reactivation of many tumor suppressor proteins. Selinexor with low dose dexamethasone was recently approved for patients with triple-class refractory multiple myeloma. Additionally, selinexor monotherapy has demonstrated broad activity in other hematologic and solid malignancies. In a Phase 2 study in rGBM (NCT01986348), selinexor demonstrated encouraging intratumoral penetration and single-agent efficacy at 80 mg once weekly with durable response and disease stabilization in heavily pretreated patients. Preclinical GBM studies showed synergy when combining selinexor with radiation, temozolomide and lomustine. METHOD This is a phase 1 (PH-1) dose finding study followed by a 1:1 randomized phase 2 (PH-2; n= 350) efficacy exploration trial to independently evaluate 3 different combination regimens: Arm A: radiation +/- selinexor in uMGMT ndGBM; Arm B: radiation and temozolomide +/- selinexor in MGMT ndGBM; Arm C:omustine +/- selinexor in first relapse rGBM following frontline radiation and temozolomide. The PH-1 primary endpoint is MTD/RP2D, with secondary endpoints of ORR per modified RANO, duration of response (DOR), PFS, and OS. The PH-2 primary endpoint for Arms A and B in ndGBM is PFS, with key secondary endpoints being OS, PFS6, ORR, DOR. For Arm C, the PH-2 primary endpoint is OS while key secondary endpoints are PFS, PFS6, ORR, DOR. The study has 70% power to detect a hazard ratio of 0.67 between selinexor and control for primary efficacy for arms A & B, and 80% power to detect a hazard ratio of 0.70 for arm C. We are currently enrolling patients nationwide. Clinical trial identifier: NCT04421378

Azacitidine (AZA) with Nivolumab (Nivo), and AZA with Nivo + Ipilimumab (Ipi) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia: Clinical and Immune Biomarkers of Response

Azacitidine (AZA) with Nivolumab (Nivo), and AZA with Nivo + Ipilimumab (Ipi) in Relapsed/Refractory (R/R) Acute Myeloid Leukemia: Clinical and Immune Biomarkers of Response

ZUMA-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) With Relapsed or Refractory Large B Cell Lymphoma (R/R LBCL)

ZUMA-19: A Phase 1/2 Multicenter Study of Lenzilumab Use With Axicabtagene Ciloleucel (Axi-Cel) in Patients (Pts) With Relapsed or Refractory Large B Cell Lymphoma (R/R LBCL)

Abstract 4241: Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer

Abstract Introduction: Patients with microsatellite stable (MSS) metastatic colorectal cancer (MCRC) are considered resistant to immunotherapy with PD-1 and PD-L1 inhibitors. However, a recent study of regorafenib and nivolumab (REGONIVO) reported high response rates and a median progression free survival (PFS) of more than 6 months (mo) in a cohort of 24 Japanese patients (pts) with MSS chemo-resistant MCRC. Methods: We evaluated the outcome of advanced MSS MCRC pts who were treated on a compassionate basis with PD-1 inhibitors in combination with regorafenib 80 mg PO QD x 21 days every 28 days in a single US center. We report their response rate (RR), PFS, and overall survival (OS). Results: 16 pts (15 males) were treated with a combination of regorafenib + PD-1 inhibitors and were evaluable for response. 14 pts received regorafenib + nivolumab (5 with prior anti-PD-1 treatment) and 2 pts received regorafenib + pembrolizumab (both following pembrolizumab treatment). No treatment-related G3 or above toxicities were attributed to the combination therapy. No objective responses were noted on treatment. 11 pts had progressive disease (PD) and 5 pts experienced stable disease (SD) as best response at 2 mo. The duration of SD was 4 mo in 2 pts (1 pt with prior anti-PD1 exposure), 6 mo in 1 pt (prior anti-PD1 exposure), 5 mo+ in 2 pt (1 with prior anti-PD1 exposure). When limiting the analysis to the 9 regorafenib and checkpoint-inhibitor naïve patients, 2 pts were noted to have SD (4 months and 5 mo+). ctDNA assays were evaluated at baseline and at 4 weeks of treatment in 11 patients. All 9 patients with a rise in ctDNA at 4 weeks had PD at the 2-mo imaging point. 2 patients with declining ctDNA at 4 weeks experienced SD for 4 mo 5 mo+, each. OS analysis remains immature as the median follow-up is only 5 mo. Conclusions: Regorafenib and nivolumab combination was associated with modest clinical activity in patients with MSS chemotherapy-resistant MCRC. This US-based small retrospective trial is at odds with the Japanese REGONIVO trial. ctDNA may represent a powerful tool for predicting progression prior to radiographic staging. Citation Format: Marwan Fakih, Dawnyel Chevalier, Janelle Saluja, Cecilia Lau, Chongkai Wang. Regorafenib and nivolumab or pembrolizumab combination and ctDNA response assessment in refractory colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4241.

Difficulty in differential diagnosis for renal cancer with microscopic papillary architecture: overlapped pathological features among papillary renal cell carcinoma (RCC), mutinous tubular and spindle cell carcinoma, and unclassified RCC. Lessons from a Japanese multicenter study.

In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC. We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features. All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3years. Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs.

First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor

BackgroundThis phase 1 study examined the safety, maximum-tolerated dose (MTD) and antitumour activity of E7449, a novel PARP 1/2 and tankyrase 1/2 inhibitor.MethodsE7449 was orally administered once daily in 28-day cycles to patients with advanced solid tumours (50–800-mg doses). Archival tumour samples from consenting patients were evaluated for the expression of 414 genes in a biomarker panel (2X-121 drug-response predictor [DRP]) found to be predictive of the response to E7449 in cell lines.ResultsForty-one patients were enrolled (13 pancreatic, 5 ovarian, 4 each with breast, lung or colorectal cancer and 11 with other tumour types). The most common grade ≥3 treatment-related adverse event was fatigue (n = 7, 17.1%). Five patients experienced a dose-limiting toxicity (fatigue, n = 4, 800 mg; anaphylaxis, n = 1, 600 mg) for an MTD of 600 mg. E7449 exhibited antitumour activity in solid tumours, including 2 partial responses (PRs), and stable disease (SD) in 13 patients, which was durable (>23 weeks) for 8 patients. In 13 patients, the 2X-121 DRP identified those achieving PR and durable SD. E7449 showed good tolerability, promising antitumour activity and significant concentration-dependent PARP inhibition following 50–800-mg oral dosing.ConclusionThe results support further clinical investigation of E7449 and its associated biomarker 2X-121 DRP.Clinical trial registrationwww.ClinicalTrials.gov code: NCT01618136.

Trial in progress: A phase Ib study of AMG 510, a specific and irreversible KRASG12C inhibitor, in combination with other anticancer therapies in patients with advanced solid tumors harboring KRAS p.G12C mutation (CodeBreak 101).

TPS3661 Background: Kirsten rat sarcoma viral oncogene homolog (KRAS) p.G12C mutation has been identified as a driver oncogenic mutation in several solid tumors (eg, non-small cell lung cancer [NSCLC], colorectal cancer [CRC]). Development of therapies targeting KRASG12C has been unsuccessful. AMG 510 is a specific and irreversible small molecule inhibitor of KRASG12C. A first-in-human clinical trial of AMG 510 monotherapy in patients with KRAS p.G12C mutant solid tumors is currently ongoing. AMG 510 in combination with additional anticancer therapies may lead to enhanced antitumor efficacy. This study is a master protocol designed to evaluate multiple investigational regimens of AMG 510 in patients with KRAS p.G12C mutant solid tumors. Here, we present two combination cohorts of AMG 510 with a mitogen-activated protein kinase kinase (MEK) inhibitor and an investigational anti-programmed cell death protein-1 (PD-1) therapy, respectively. Additional combination cohorts will be presented at the meeting. Methods: This is a phase 1b, open-label study evaluating AMG 510 in combination with a MEK inhibitor or an investigational anti-PD-1 therapy in pts with KRAS p.G12C mutant solid tumors. The dose exploration phase (part 1; n=20) will evaluate the safety and tolerability of AMG 510 in combination with the MEK inhibitor or anti-PD-1 therapy; this will be followed by a dose expansion phase (part 2; n=40) to verify the safety and tolerability profile of AMG 510 combination therapies and assess antitumor efficacy. Key eligibility criteria include locally-advanced or metastatic malignancy with KRAS p.G12C mutation identified through molecular testing and at least one or multiple lines of prior systemic therapy (eg, ≥2 for advanced/metastatic colorectal cancer). Primary endpoints include dose-limiting toxicities, treatment-emergent or -related adverse events. Secondary endpoints include pharmacokinetic parameters of combination regimens, disease control rate, duration of response, progression-free survival, and duration of stable disease (measured by computed tomography or magnetic resonance imaging and assessed per RECIST 1.1). The study began enrolling pts in December 2019 and is ongoing. For more information, please contact Amgen Medical Information: medinfo@amgen.com . Clinical trial information: NCT04185883 .

Phase II study of gedatolisib for small-cell lung cancer (SCLC) patients (pts) with genetic alterations in PI3K/AKT/mTOR pathway based on a large-scale nationwide genomic screening network in Japan (EAGLE-PAT/LC-SCRUM-Japan).

9064 Background: Development of targeted therapy for SCLC based on a large-scale genomic screening is an innovative challenge. Gedatolisib is a highly potent dual inhibitor of PI3K/mTOR and is expected to have an effect for tumors with PI3K/AKT/mTOR pathway alterations. SCLC harboring this pathway alterations is rare. Thus, we conducted a phase II study based on a nationwide genomic screening network in Japan (LC-SCRUM-Japan) to develop novel targeted therapies. Methods: SCLC pts with targetable genetic alterations were screened at 154 institutions in Japan. A multicenter, single-arm phase II study was conducted to evaluate the efficacy and safety of gedatolisib in advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The primary endpoint was objective response rate (ORR). The planned sample size was 19 (threshold and expected ORR of 20% and 50%, one-sided alpha of 5%, and power of 80%). Results: 930 SCLC pts were screened from July 2015 to January 2020. Targetable genetic alterations were identified in 148 pts (16%), including 53 PI3K/AKT/mTOR (6%), 81 MYC family (9%), 10 EGFR (1%) and 15 KRAS (2%). A total of 12 pts with genetic alterations in the PI3K/AKT/mTOR pathway (5 PIK3CA, 6 PTEN, and 1 AKT1 mutation) were enrolled in the phase II study. The median age was 67 years (range 58-79), 7 pts were male and 5 pts received 2 or more prior chemotherapy (range 1-4). The ORR was 0% and disease control rate was 25%. The median progression-free survival (PFS) was 0.9 months (95% CI, 0.4 to 3.0). The median overall survival was 5.8 months (95% CI, 1.1 to NR). Treatment-related G3 adverse events (hypertension, hypoalbuminemia, oral mucositis, ALT increased and creatinine increased) were observed in 4 pts. One patient with PTEN I8fs mutation had a long duration of stable disease (PFS; 6.7 months). Conclusions: This Large-scale nationwide genomic screening network was effective to identify rare targetable genetic alterations and had a potential role to develop targeted therapies in SCLC. This phase II study didn’t show promising clinical benefit of gedatolisib for advanced SCLC pts with genetic alterations in the PI3K/AKT/mTOR pathway. The safety profile of gedatolisib was similar to that reported previously. Clinical trial information: UMIN000020585.