Q21 Days Research Articles

Randomized phase III Trial of MEDI4736 (durvalumab) as concurrent and consolidative therapy or consolidative therapy alone for unresectable stage 3 NSCLC: A trial of the ECOG-ACRIN Cancer Research Group (EA5181).

TPS8584 Background: Platinum-based concurrent chemoradiation(CRT) followed by one year of the human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody, durvalumab, which blocks the interaction of PD-L1 with its receptors PD-1 and CD80, is the standard of care for locally advanced, unresectable non-small cell lung cancer (NSCLC). Early studies have noted the feasibility of concomitant administration of radiotherapy and immune checkpoint inhibition in NSCLC. EA5181 will evaluate the use of concomitant durvalumab with chemo-radiotherapy for locally advanced NSCLC. Methods: EA5181 is a randomized, multi-center, phase III study for patients with unresectable Stage III NSCLC comparing the efficacy of CRT with concomitant durvalumab to CRT, followed by one year of durvalumab. Eligibility criteria include: an ECOG PS of 0-1, adequate pulmonary function (FEV1 and DLCO both > 40%), no history of auto-immune disease and no past chemotherapy or RT for this lung cancer. Stratification factors include age, sex, stage, and planned concurrent chemotherapy type. Eligible patients with be randomized 1:1 to receive 60Gy RT (2Gy fractions) CRT and durvalumab (Arm A) or 60Gy CRT (Arm B). Investigators will be allowed to choose from three different chemotherapy options: cisplatin/etoposide q 28 days, Pemetrexed/cisplatin q 21 days, and weekly paclitaxel/Carboplatin. Arm A will use 750mg fixed of durvalumab (considered equivalent to 10mg/kg) on days 1, 11, and 21 of RT. Assuming no disease progression, patients in both arms will be followed by monthly (q28 days) fixed dose of 1500mg durvalumab for one year which will be given optimally within 14 days of radiation or when (non)hematologic toxicity is < Grade 2. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, incidence of local/distant progression and toxicity. The target sample size is 660 patients, anticipated to recruit over 55 months, with follow up for an additional 42 months. This provides approximately 82% power if the true hazard ratio for overall survival was 0.75 or less, with 2-sided alpha of 0.05, and assuming a median survival of 42.5 months in the control arm. The study was activated on 04/09/20 and has currently accrued 90 patients on 02/03/21. Clinical trial information: NCT04092283.

SGNTUC-019: Phase 2 basket study of tucatinib and trastuzumab in previously treated solid tumors with HER2 alterations (trial in progress).

TPS3151 Background: Tucatinib (TUC) is a highly selective HER2-directed TKI approved in combination with trastuzumab (Tras) and capecitabine (Cape) for HER2 overexpressed/amplified (HER2+) metastatic breast cancer (BC), based on a statistically significant and clinically meaningful PFS, OS, and ORR benefit over Tras and Cape. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and Tras showed superior activity to either agent alone. While various HER2-directed agents have been evaluated in HER2+ and HER2-mut tumors, there are no approved HER2 therapies outside of breast and gastric cancers. The SGNTUC-019 basket study is evaluating TUC combined with Tras in patients (pts) with HER2+ or HER2-mut locally-advanced unresectable or metastatic solid tumors. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase 2 study. Eligible pts must have progressed on or after the last systemic therapy for advanced disease. Metastatic cervical cancer: must have received platinum-based chemotherapy ± bevacizumab; hormone receptor positive (HR+) HER2-mut BC: must have received a prior CDK4/6 inhibitor. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulation, and cardiac function, and no prior HER2-directed therapy (except Tras for uterine serous carcinoma). For eligibility, HER2 alterations can be demonstrated by HER2+ in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. Pts with HER2+ disease will be enrolled in cohorts for cervical, uterine, biliary tract, and urothelial cancers, non-squamous NSCLC, and other solid tumors (except GEC, BC, and CRC). Pts with HER2-mut disease will be enrolled in cohorts for non-squamous NSCLC, BC, and other solid tumors. Except for solid tumor and BC cohorts, 12 RECIST 1.1 evaluable pts will be enrolled in each cohort. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Other solid tumor and BC cohorts will enroll 30 pts in a single stage. If justified, additional HER2+ or HER2-mut disease-specific cohorts may be opened. Approximately 162-270 pts are planned. The primary objective is antitumor activity in each cohort, with confirmed ORR per investigator as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. HR+ BC pts will also receive fulvestrant 500 mg IM every 4 weeks and C1 D15. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. TUC PK will be evaluated in all pts in Cycles 2-6. QoL is evaluated q2 cycle using EQ-5D-5L. Sites are open in the US; EU and Asia will be opened. Enrollment began in Dec 2020. Clinical trial information: NCT04579380.

PD1 inhibition in soft-tissue sarcomas with tertiary lymphoid structures: A multicenter phase II trial.

11507 Background: PD1 inhibition has shown limited activity in all comers clinical trials including patients with advanced soft-tissue sarcomas (STS). In the PEMBROSARC study, objective response rate, progression-free (PFS) and overall survival (OS) were respectively 2.1%, 1.4 and 7.1 months respectively (Toulmonde et al. Jama Oncol 2017). We have recently shown that the presence of tertiary lymphoid structures (TLS) may represent a biomarker to select patients who are more likely to benefit from immunotherapy (PetitPrez et al., Nature 2020). We report here the first clinical trial investigating the efficacy of PD1 inhibition in TLS-positive STS. Methods: PEMBROSARC is an open-label multicenter phase II study of pembrolizumab in combination with low-dose cyclophosphamide in pts with STS selected based on the presence of TLS. TLS status has been assessed centrally has previously described (PetitPrez et al., Nature 2020). Eligible patients received pembrolizumab 200mg IV q21 days and cyclophosphamide 50 mg BID 1week on, 1 week off. All patients had confirmed progressive disease at inclusion based on central review of two imaging performed at less than 6 months interval. The primary efficacy endpoint was 6-month non-progression (as per RECIST evaluation criteria v1.1). Based on the following hypotheses: 15% 6-month non-progression rate (H0), 40% acceptable 6-month non-progression rate (H1), 5% type I error rate, 90% power, a total of 29 assessable patients were necessary and 8 patients or more had to be progression-free at 6 months to reach the first endpoint. Results: 240 patients were screened for TLS status between September 2018 and January 2020 in 7 centers of the French Sarcoma Group. Among them, 48 were found to be TLS+ as per central review and 35 were included in the study. The three most frequent histological subtypes were: well-differentiated/dedifferentiated liposarcoma (n = 13); UPS (n = 6), and leiomyosarcoma (n = 4). 30 patients were eligible for efficacy. Of those, as per central imaging review, 13 patients (43.3%) had tumor shrinkage resulting in partial response in 8 patients (26.7%) and stable disease in 5 cases (16.7%). 10 patients had progressive disease. Twelve patients were progression-free at 6 months (40.0% 95%CI = [22.7 – 59.4]).Median PFS and OS were 4.1 months (95%CI, 1.4-9.6) and 14.5 months (95%CI, 8.5- 18.3 months), respectively. Conclusions: With an objective response and a 6-month non-progression rates of 26.7% and 40% respectively versus 2.1% and 4.2% in all comers, the PEMBROSARC study confirms that selection based on TLS status is an efficient approach to tailor immunotherapy in STS patients. Clinical trial information: NCT02406781.

A phase II trial of abemaciclib in patients with p16ink4a negative, relapsed mesothelioma.

8558 Background: Genetically stratified therapy for malignant mesothelioma (MM) is lacking. MMs frequently harbour loss of chromosome 9p21.3 locus (CDKN2A) associated with shorter survival. CDKN2A encodes the tumour suppressor p16ink4a, an endogenous suppressor of CDK4 and CDK6. Genetic reconstitution of p16ink4a into CDKN2A suppresses MM in preclinical models, underpinning the rationale for targeting of CDK4/6 in p16ink4a negative MM. We therefore developed a multi-centre molecularly stratified phase IIa trial to test this hypothesis as arm 2 of the Mesothelioma Stratified Therapy umbrella trial (NCT03654833, MiST2). Methods: Patients with histologically confirmed MM (pleural or peritoneal) were molecularly screened by immunohistochemistry for p16ink4a, BAP1, BRCA1, and PDL1 (Dako 22C3). Patients with p16ink4a negative MM were eligible. Key inclusion factors: histological confirmation of MM with an available archival tissue block, ECOG performance status 0-1, prior platinum-based 1st line chemotherapy (any line allowed), evidence of disease progression with measurable disease by CT (RECIST 1.1), and adequate haematological/organ function. Patients received Abemaciclib (Ab) 200mg bd po daily in q21 day cycles. Primary endpoint was disease control rate at 12 weeks (DCR12w). The null hypothesis was rejected if ≥ 11 patients had disease control (A’Hern design). Secondary endpoints: DCR at 24 weeks (DCR24w), best objective response rate and toxicity (NCI CTCAE 4.03). Patients could undergo an optional re-biopsy upon disease progression. Results: Between November 2019 and March 2020, 26 patients with p16ink4a negative MM received at least one dose of Ab. The median age of pts was 67 (range, 64-74) years, 89% were male, 80.8% epithelioid, 84.6% ECOG PS1, > 1 prior systemic therapy 62%. All patients received at least one cycle with 27% completing 6 cycles. No dose reductions occurred in 53.9% of pts. DCR12w: 54% (95% confidence limit (CI), 36% – 71%), DCR24w: 23% (95%CI, 9% – 44%). Best responses (within 24w): partial - 15% (95%CI, 4- 35%), one occurring after 18 weeks; stable disease - 53.8% (33.4 – 73.4%); progression - 7.7% (0.9 – 25.1%). Adverse events (any cause): ≥ grade 3 toxicities affected 5.7% of pts. Conclusions: MiST2 met its primary endpoint, warranting further clinical evaluation of Ab. Whole exome sequencing of the cohort is ongoing to explore genomic correlates of de novo and acquired resistance. Clinical trial information: NCT03654833.

A phase I study of mirvetuximab soravtansine (MIRV) and gemcitabine (G) in patients (Pts) with selected frα-positive solid tumors: Results in the ovarian cancer (EC) cohort.

5542 Background: Mirvetuximab soravtansine (MIRV) is an ADC comprising a FRα-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. MIRV has promising single agent activity in FRα-positive medium/high expression epithelial ovarian cancer (EOC), at 6 mg/kg, based on adjusted ideal body weight (AIBW) IV every (q) 21 days. This study evaluated MIRV and G in recurrent EOC, endometrial and triple negative breast cancer. The recommended phase 2 dose (RP2D) was established at MIRV 6 mg/kg AIBW IV, day 1 and G 800 mg/m2 IV, d1, 8 q21 days (J Clin Oncol 37, 2019, Abs. #3009). Here we report the results from the EOC cohort. Methods: Patients (pts) with FRα-positive platinum resistant EOC with ≤4 prior chemotherapy (CT) regimens, were eligible. FRα positivity was initially defined as ≥ 25% of cells with PS2+ staining intensity (low to high FRα expression) and was subsequently revised to require medium/high FRα expression (≥50%/ ≥75% of cells with PS2+ staining intensity). Results: From 10/2017 to 12/2020, 113 EOC pts underwent FRα screening, with 74 FRα-positive results. Thirty total EOC pts (with median 3 prior lines of therapy) were treated; 8 pts during dose escalation and 22 EOC pts at the RP2D (all evaluable for response). Fifteen (50%) pts had high FRα, 10 pts (33%) medium FRα, and 5 pts (17%) low FRα expression. Eleven (36%) of the 30 EOC pts achieved a partial response (PR), 15 pts (50%) had SD and 4 pts (13%) progressed. Among the 11 responders, 5 pts had high FRα, 4 pts medium FRα and 2 pts low FRα expression. Non-heme clinically significant adverse events (AEs) included: G2 sensory neuropathy (4 pts) G3 diarrhea (3 pts), G3 fatigue (2 pts), G3 pneumonitis (2 pts), and 1 pt with G5 respiratory failure (secondary to pneumonia but drug-induced pneumonitis could not be ruled out). Conclusions: MIRV in combination with G has promising clinical activity in late line platinum resistant FRα-positive EOC, with best responses observed in high FRα expression. The regimen is well tolerated with expected AEs based on the known toxicities of each agent. This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by ImmunoGen Corp and Cancer Center Support Grant P30CA033572. Clinical trial information: NCT02996825.

TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early stage breast cancer.

TPS603 Background: Although patients with hormone receptor-positive (HR+)/HER2-negative breast cancer (BC) frequently respond clinically to neoadjuvant treatment, fewer than 10% achieve a pathologic complete response (pCR) with standard chemotherapy or endocrine therapy, even in combination with targeted agents such as CDK4/6 inhibitors. Thus, finding more effective therapies for this disease remains an area of unmet need. HER2 amplification is a known driver of endocrine resistance and HER2 protein may be expressed at a low level (IHC 1+ or 2+) in up to 60% of HR+ BC. Trastuzumab deruxtecan (DS-8201a, T-DXd) is a novel HER2-targeting antibody drug conjugate (ADC) that is FDA approved for HER2-positive metastatic BC and has demonstrated promising clinical efficacy in HER2-low BC with an objective response rate of ̃37%. The aim of TALENT (TRIO-US B-12) is to evaluate the clinical activity and toxicity of neoadjuvant T-DXd either alone or in combination with endocrine therapy in patients with HR+/HER2-low early BC. Methods: TRIO-US B-12 TALENT (NCT04553770) is an ongoing randomized, multicenter, open-label, two-stage, phase II neoadjuvant trial for participants with early stage, HR+, HER2-low expressing (1+ or 2+ by IHC) BC. Eligible participants include men and women with previously untreated, operable invasive BC greater than 2.0 cm (cT2) in size. Pts with recurrent or metastatic BC, or inflammatory BC are excluded. Pts are randomized 1:1 to receive six cycles of T-DXd (5.4 mg/kg IV q21 days) either alone or in combination with anastrozole (1 mg PO QD). Men and pre/peri menopausal women randomized to the anastrozole arm also receive standard of care GnRH agonist. Stratification factors include HER2 expression (1+ or 2+) and menopausal status. Tumor tissue is taken at baseline, cycle 1 day 17-21, and at surgery. Blood samples are taken at four time points for biomarker analysis. The primary endpoint is pCR rate (breast and lymph node) at definitive surgery. In stage I, 58 participants will be randomized (29/arm). If >2 participants in an arm achieve pCR, that arm will expand (stage II) to enroll an additional 15 participants (total of 44/arm). A pCR rate of >10% (5/44) would be considered favorable, warranting further evaluation of the treatment in a larger trial. Other endpoints include safety, changes in Ki67 expression, Residual Cancer Burden index, biomarker analysis (including serial cfDNA analysis), and health-related quality of life. As of January 2021, four participants have enrolled. Conclusions: To our knowledge this is the only ongoing study evaluating T-DXd with or without endocrine therapy for HR+, HER2-low breast cancer in the neoadjuvant setting. The study will shed light on clinical activity and biomarkers, which may guide larger confirmatory studies for patients with HR+, HER2-low early breast cancer. Clinical trial information: NCT04553770.

Phase II study of atezolizumab in advanced alveolar soft part sarcoma (ASPS).

11519 Background: ASPS constitutes < 1% of soft tissue sarcomas and frequently presents in adolescents and young adults. There are no approved therapies for ASPS. We are currently evaluating the clinical activity of atezolizumab (atezo), an anti-PD-L1 antibody, in patients (pts) with advanced ASPS. Methods: This is a multicenter, open-label, single-arm phase II study where atezo is administered at a fixed dose of 1200 mg in adults or 15 mg/kg (1200 mg max) in pediatric pts age ≥2 once Q21 days. The primary objective is to determine the objective response rate (ORR) of atezo using RECIST 1.1. Secondary objectives include duration of response and correlating response with the immune effects of atezo in blood and paired tumor biopsies (pre- and post-treatment). Tumor specimens were analyzed with multiplex immunofluorescence immuno-oncology panels to quantify CD8+, PD-1+, and PD-L1+ cells/mm2 in the tumor microenvironment. CD8+ density was calculated as the total number of CD8+ cells divided by the entire area (mm2) of the tumor and invasive margins of the biopsy. Results: As of February 4, 2021, 44 pts have been enrolled. The median age in the study was 31 years (range, 12–70) with equal male: female distribution. 54.5% of pts were Caucasian. Baseline ECOG ≤1 was present in 97.7%. The median time on study was 11.5 months (range, 0.8–40.3 months). At data cutoff, response evaluation was available for 43 pts with an ORR of 37.2% (16/43). One pt experienced a complete response and 15 pts experienced a partial response (PR), of which 14 were confirmed. The median time to confirmed response was 3.5 months (range, 2.1–14.9 months). The median duration of confirmed response was 16.5 months (range, 4.9–38.1 months). Stable disease (SD) was present in 58.1% (25/43). One or more grade 3 adverse events potentially related to atezo were identified in 16.3% (7/43) pts. These include diarrhea, hypothyroidism, transaminitis, anemia, vertigo, extremity pain, myalgia, pneumonitis, rash, and stroke (n = 1 each). No grade 4 or 5 events have been reported. Among 8 cases with evaluable biopsy pairs, both baseline and C3D1 specimens in all cases demonstrated CD8+ T cell infiltration and PD-L1 expression. PD-1 expression was detected at baseline in 5 cases and at C3D1 in 7 cases. In 6 cases (3 SDs and 3 PRs), treatment did not change CD8+ cell density. In the other 2 cases (both PRs), CD8+ density increased > 3x above baseline by C3D1. Analysis of T cell activation using pharmacodynamic response biomarkers, along with whole exome and RNA-seq to evaluate the genomic and transcriptomic landscape of ASPS, are ongoing. Conclusions: Atezo is well tolerated and demonstrates promising single agent activity with durable responses in advanced ASPS. Preliminary tumor biomarker analysis confirms the presence of multiple PD-1/PD-L1 immune checkpoint (IC) components, indicating that advanced ASPS is an ideal candidate for therapeutic IC inhibition. Funded by NCI Contract No HHSN261200800001E. Clinical trial information: NCT03141684.

Anaplastic features (AnaF) and DNA-damage repair pathway (DDR) mutations in metastatic castration-resistant prostate cancer (mCRPC).

92 Background: Anaplastic prostate cancer displays features of small-cell carcinoma, a type of neuroendocrine tumor. Treatments for anaplastic prostate cancer are based on small cell lung cancer regimens. Both AnaF and mutations in DDR pathways, including BRCA2 confer an aggressive phenotype. For patients (pts) with certain DDR mutations, olaparib (O) was recently FDA approved, and an ongoing study is evaluating whether the addition of durvalumab (D) confers additional benefit in mCRPC (NCT02484404). We evaluate a potential preliminary relationship between DDR mutations, treatment with D and O, and AnaF. Methods: This is a phase II study of O plus D in pts with mCRPC with disease that is amenable to biopsy. On-study core biopsies undergo mutational analysis. Prior treatment with enzalutamide (enza) and/or abiraterone (abi) is required. D is given at 1500 mg iv q28 days + O 300 mg tablets po q12 hours. The primary endpoint is PFS. Pts were categorized into those with and without AnaF as defined by Aparicio et al. (2013). AnaF include small-cell histology; exclusively visceral metastases; predominantly lytic bone metastases; bulky lymphadenopathy (≥5 cm) or high-grade (Gleason ≥8) mass in prostate/pelvis; low PSA (≤10 ng/mL) at initial presentation with high volume (≥20) bone metastases; neuroendocrine markers in histology or serum plus elevated LDH, malignant hypercalcemia, or elevated serum CEA; or short interval (≤6 months) to androgen-independent progression. Results: Of 55 pts accrued, 24 had prior abi and enza; 19 pts had prior taxane. Common adverse events include anemia, fatigue, and nausea. Also, 11 pts (20.0%) displayed clear AnaF (Table) and 43 pts lacked AnaF, including 8 (14.5%) with partial AnaF that did not meet the full criteria, 4 (7.3%) who likely did not have AnaF due to difficulty in quantifying disease burden, 29 (52.7%) who did not have AnaF, and 2 (3.6%) had unknown status. Four pts (36.4%) with clear AnaF had DDR aberrations, including 3 (27.3%) with BRCA2, 1 (9.1%) with both BRCA2 and CHEK2, and 1 (9.1%) with ATM. Conclusions: Pts with mCRPC with DDR mutations can also have AnaF. This preliminary data demonstrates that pts with anaplastic prostate cancer and pts with DDR mutations are two distinct populations with some degree of overlap. O+D is well-tolerated, and future studies should focus on finding optimal treatments for pts with AnaF without and without DDR mutations. Clinical trial information: NCT02484404. [Table: see text]

SGNTUC-019: Phase II basket study of tucatinib (TUC) and trastuzumab (Tras) in previously treated solid tumors with HER2 alterations: Urothelial cancer cohort (trial in progress).

TPS499 Background: Tucatinib (TUC), a highly selective HER2-directed TKI recently approved for HER2 overexpressed/amplified (HER2+) metastatic breast cancer, is being developed as a novel therapy for patients (pts) with metastatic CRC, gastric cancer, and other GI tumors. In xenograft models of HER2+ and HER2-mutated (HER2-mut) tumors, dual targeting of HER2 with TUC and trastuzumab (Tras) showed superior activity to either agent alone. Despite the development of several new therapies for metastatic urothelial cancer, response durations generally remain short and the great majority of pts succumb to the disease, highlighting the need for therapeutic approaches. Given that 20-30% of urothelial cancers have molecular alterations of the ErbB family, TUC in combination with Tras warrants further evaluation in this population. The SGNTUC-019 basket study is evaluating TUC in combination with Tras in pts with HER2+ or HER2-mut solid tumors, including a cohort of pts with locally advanced or metastatic (LAUM) urothelial cancer. Methods: SGNTUC-019 (NCT04579380) is a multi-cohort, open-label, international phase II study evaluating pts with previously treated solid tumors displaying HER2 overexpression/amplification or activating mutations. Eligible pts must have HER2+ or HER2-mut LAUM solid tumors, with progression on or after the last systemic therapy for advanced disease. Pts must be ≥18 years old, with ECOG PS ≤1, adequate hepatic, hematological, renal, coagulatory, and cardiac function, and no prior exposure to HER2-directed therapy. For eligibility, HER2 alterations can be demonstrated by HER2 overexpression/amplification in tumor tissue by prior IHC/ISH (IHC 3+/signal ratio ≥2.0 or gene copy number >6), or by HER2 amplification/mutation in a prior or on-study NGS assay of ctDNA or prior tissue NGS assay. The HER2 overexpression/amplification urothelial cancer cohort will enroll 12 RECIST 1.1 response-evaluable pts. If ≥2 responses are observed, the cohort will be expanded to a total of 30 pts. Pts with HER2-mut urothelial cancer will be enrolled in a cohort of 30 pts for all solid tumor types except breast cancer and non-squamous NSCLC. If justified, a separate cohort for HER2-mut urothelial cancer may be opened. The primary objective is antitumor activity in each cohort, with confirmed ORR as primary endpoint, and disease control rate, duration of response, PFS, and OS as secondary endpoints. Pts will receive TUC 300 mg orally twice daily and Tras 8 mg/kg IV on Cycle 1 Day 1 and 6 mg/kg q21 days from Cycle 2 Day 1. Disease assessments per RECIST 1.1 will occur q6 weeks for 24 weeks, then q12 weeks. Trough concentrations of TUC will be evaluated in all pts in Cycles 2-6, with a peak concentration sampled in Cycle 3. Quality of life will be evaluated q2 cycle using EQ-5D-5L. Sites will open in the US, EU, and Asia; enrollment is anticipated to begin in Dec 2020. Clinical trial information: NCT04579380.

Abstract OT-28-02: Phase II randomized trial of neoadjuvant trastuzumab and pertuzumab with either palbociclib plus letrozole or paclitaxel for postmenopausal women with estrogen receptor-positive / HER2-positive breast cancer - The TOUCH trial

Abstract Background: HER2 blockade in combination with chemotherapy (CT) remains the treatment of choice for patients with HER2+ early breast cancer (BC), irrespective of estrogen receptor (ER) status. Patients with ER+/HER2+ early BC may benefit from HER2 blockade in combination with endocrine therapy (ET) and potentially also new targeted agents. Recent data have elucidated cyclin-dependent kinases 4 and 6 (CDK4/6) as key therapeutic targets acting downstream of both ER and HER2 pathways suggesting CDK4/6 inhibitors like palbociclib may be ideal partners for ET in this context. Pre-clinical and clinical data suggest that a gene signature of functional loss of retinoblastoma (RBsig) might predict sensitivity to CT versus CDK4/6 inhibition in ER+/HER2+ early BC. The TOUCH hypothesis is that neoadjuvant therapy with palbociclib + ET + dual HER2 blockade with trastuzumab and pertuzumab may be more active in postmenopausal patients with ER+/HER2+ RBsig LOW early BC while those with RBsig HIGH may require CT. This will be formally tested in the primary objective, exploring the interaction between the RBsig status (HIG or LOW) and treatment activity, assessed by pathological complete response (pCR), of palbociclib+letrozole versus paclitaxel when given with trastuzumab+pertuzumab for ER+/HER2+ primary breast cancer. The study was initially targeting older patients due to the particular appealing of CT de-escalation in this population. Due to the increasing interest for CT de-escalation and the mounting evidence of the potential benefit of such ET combination optimization, TOUCH has been recently amended to extend accrual to postmenopausal women. Trial design: TOUCH is an open-label, multicenter, randomized phase II neoadjuvant trial in postmenopausal patients with ER+/HER2+ primary BC. Eligible patients will be randomized (1:1) to dual HER2 blockade (5 doses trastuzumab + pertuzumab) plus either palbociclib (125 mg/d po; 21 of 28d x 4 cycles) and letrozole (daily x 16 weeks), or paclitaxel (80 mg/m2 iv, d1,8,15 q28 days x 4 cycles), before surgery. RBsig (HIGH vs LOW) will be determined centrally on mandatory pre-treatment biopsies. Patients ≥65 years will receive a baseline geriatric assessment including G8, Instrumental Activity of Daily Living (IADL) and Charlson Comorbidity Index. The primary objective is to explore the interaction between RBsig and treatment activity assessed by pathological complete response (pCR) at time of surgery. Exact logistic regression will test RBsig by treatment interaction (2-sided a=.05) and estimate odds ratios (OR) for treatment effect on pCR according to RBsig status. The sample size provides 86% power, assuming an overall pCR rate of 26%, 50% RBsig LOW, and OR=2.4 vs OR=0.11 for RBsig LOW vs HIGH. Accrual: The trial will recruit 144 patients from approximately 45 Centers in Belgium, France, Italy and Switzerland. The first patient was enrolled in April 2019. Accrual as of mid-June 2020 was 25 patients. The TOUCH trial (IBCSG 55-17) is sponsored and coordinated by IBCSG with financial support from Pfizer and Roche. The trial is conducted in collaboration with Unicancer GERICO and SAKK. NCT03644186 Citation Format: Laura Biganzoli, Etienne Brain, Luca Malorni, Andrea Gombos, Ursula Hasler-Strub, Claudio Zamagni, Camille Chakiba, Heidi Roschitzki-Voser, Meredith M Regan. Phase II randomized trial of neoadjuvant trastuzumab and pertuzumab with either palbociclib plus letrozole or paclitaxel for postmenopausal women with estrogen receptor-positive / HER2-positive breast cancer - The TOUCH trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-28-02.

Trial-in-progress: A pilot study of combined immune checkpoint inhibition in combination with ablative therapies in subjects with hepatocellular carcinoma (HCC).

TPS355 Background: Locoregional therapies for hepatocellular carcinoma, such as transcatheter arterial chemoembolization (TACE) or ablation, can induce a peripheral anti-tumor immune response. This may be amplified by immune checkpoint inhibitors (ICI). Early and higher anti-CTLA4 dosing could potentially lead to better priming and a stronger immune response. Recent data has suggested that early (day 1 only), increased doses of anti-CTLA4 therapy, was associated with encouraging clinical activity and a tolerable safety profile. This study will evaluate dual immune checkpoint, CTLA4 (tremelimumab, day 1-only dosing) and PD-L1 (durvalumab) blockade in combination with TACE in patients with advanced HCC. Intensive peripheral immune-monitoring and longitudinal on-treatment tumor biopsies will focus on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Methods: Patients with HCC (Childs Pugh A/B7; Barcelona Clinic Liver Cancer Stage B/C; ECOG 0/1; sorafenib-naïve or experienced) are being enrolled in a pilot study (Study Number UCDCRC/19/01) of tremelimumab at 2 dose levels (DL1 and DL2) in combination with durvalumab and TACE until disease progression (per irRECIST). DL1: tremelimumab (75mg q28 days for 4 doses) and durvalumab (1500mg q28 days). DL2: tremelimumab (300mg in a single dose on day 1) and durvalumab (1500mg q28 days). Subtotal TACE will be performed during study week 6 with the dose-limiting toxicity (DLT) evaluation period encompassing the first 8 weeks of the study. Primary endpoint is 6-month progression-free survival with secondary efficacy endpoints being safety, tolerability and overall survival. Exploratory objectives will evaluate changes in immune parameters in the tumor and peripheral blood of patients undergoing anti-CTLA4 therapy pre- and post-RFA or TACE. A major focus will be on the role of the innate immune system, particularly Natural Killer cells, in anti-tumor responses. Patients will be enrolled and treated at St Vincent’s University Hospital in Dublin, Ireland. This study is currently open and actively recruiting. Clinical trial information: EudraCT Number 2019-002767-98.

Cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) after platinum chemotherapy: safety and preliminary activity of the open-label, single-arm, phase 2 ARCADIA trial

Both DURVA and CABO, an inhibitor of MET, AXL, and VEGFR, have shown single-agent activity in pts with UC. ARCADIA is a phase 2 study evaluating the combination of CABO with DURVA in pts with advanced UC or non-UC histology (NCT03824691). Herein we report the results of the interim safety analysis and the preliminary activity. Pts receive CABO 40 mg daily, orally, and are administered DURVA 1500 mg, intravenously, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. Key inclusion criteria are: ECOG-PS 0-1, UC and non-UC histology, failure of 1 or 2 platinum-based regimen for metastatic disease. Response is evaluated by RECIST criteria v.1.1 q2 cycles by CT and PET/CT scans. The primary endpoint of the study is OS. Other endpoints include safety (CTCAE v.4.03), objective response-rate (ORR), duration of response, progression-free survival. PD-L1 expression is assessed using with the Ventana SP142 assay. Next-generation sequencing tests (FoundationOne) on pre-therapy tumor samples is also performed As of May 20, 2020, 14 pts were enrolled with a median follow-up of 5 mo (range 1-8). Median age was 66 yrs (range 44, 74), 21% were male, and 60% had ECOG PS 1. 2 pts had pure neuroendocrine (NE) histology. Four pts (28%) had received 2 prior systemic anticancer therapies. Median tumor mutational burden (TMB) was 6 mut/Mb. Treatment-related AEs (TRAEs) occurred in 9 pts (64.3%), including 2 (14.3%) Grade 3 TRAEs, within the first 2 cycles. 3 pts (21.4%) discontinued CABO due to toxicity, none DURVA. The most common of any grade AEs were increased transaminases (35.7%) asthenia and diarrhea (28.6%), and hypertension (21.4%). In 10 response-evaluable pts, partial response (PR) was obtained in 2 (20%), ongoing at 6+ mo in one case harboring a driver RET (F116L) mutation. 0/2 NE tumors responded. CABO in combination with DURVA demonstrated encouraging clinical activity in pts with advanced UC with an acceptable safety profile. More mature results according to CABO-response biomarkers and histology will be presented.

Consolidation with Nivolumab and Brentuximab Vedotin after Autologous Hematopoietic Cell Transplantation in Patients with High-Risk Hodgkin Lymphoma

Consolidation with Nivolumab and Brentuximab Vedotin after Autologous Hematopoietic Cell Transplantation in Patients with High-Risk Hodgkin Lymphoma

A Phase 2 Trial of Daratumumab and Pembrolizumab in Refractory Multiple Myeloma

A Phase 2 Trial of Daratumumab and Pembrolizumab in Refractory Multiple Myeloma

AML-140: Effect of Early Blood Counts on Response and Overall Survival Following Glasdegib Plus LDAC in Newly Diagnosed AML: BRIGHT AML 1003 Post Hoc Analysis

Context The BRIGHT AML 1003 randomized phase 2 study ( NCT01546038 ) compared glasdegib (GLAS) plus LDAC vs LDAC-alone in patients with newly diagnosed AML or high-risk MDS who were ineligible for intensive chemotherapy. Addition of GLAS to LDAC approximately doubled overall survival (OS) without significant worsening of myelosuppression-related complications ostensibly by targeting leukemic stem cells dependent on the hedgehog pathway, which is not involved in normal adult hematopoiesis. Objective Evaluate potential association of outcomes with early blood count recovery. Design Patients were randomized 2:1 to open-label GLAS+LDAC or LDAC-alone (first patient visit Jan-2014), and continued treatment to a maximum of 4 years (final data cutoff April 2019). Setting Multicenter (European and North American centers). Patients This analysis included patients with AML (78 GLAS+LDAC; 38 LDAC-alone). Interventions Glasdegib 100 mg QD; LDAC 20 mg BID × 10 days q28 days. Main outcome measures The study primary endpoint was OS (previously published: Cortes et al., 2019, HR 0.51; p=0.0004). This post hoc analysis compared outcomes with GLAS+LDAC vs LDAC-alone in subgroups according to cell counts at cycle 2 day 1 (C2D1), using thresholds for absolute neutrophil count (ANC) ≥ 1000 or 500/μL, hemoglobin ≥ 10 or 9 g/dL, and platelets ≥ 100,000 or 50,000/μL. Results Among all patients regardless of baseline ANC, hemoglobin or platelets, achievement of thresholds at C2D1 was associated with improved OS with GLAS+LDAC (all comparisons p Conclusions In these patients, improved OS was associated with various blood count thresholds after 1 cycle of GLAS+LDAC vs LDAC-alone. In patients with baseline measurements below threshold, recovery of hemoglobin and platelet thresholds was associated with improved OS. Platelet recovery correlated with response in the GLAS+LDAC group. These exploratory results are consistent with the hematopoiesis-sparing mechanism of GLAS, and merit further evaluation. Study sponsor Pfizer.

AML-043: Glasdegib Plus Low-Dose Cytarabine in Acute Myeloid Leukemia or Myelodysplastic Syndrome: BRIGHT AML 1003 Final Report and 4-Year Overall Survival Follow-Up

Context In newly diagnosed AML or high-risk MDS, the randomized phase 2 BRIGHT AML 1003 ( NCT01546038 ) primary analysis showed superior overall survival (OS) for glasdegib (GLAS) + low-dose cytarabine (LDAC) vs LDAC-alone. After the primary cutoff, the trial continued to predefined completion 4 years from randomization of all patients. Objective To assess outcomes at study completion (data cutoff April 2019). Design Beginning January 2014, patients with newly diagnosed AML or high-risk MDS and unsuitable for intensive chemotherapy were randomized 2:1 to open-label GLAS+LDAC or LDAC-alone. Setting Multicenter study at centers in Europe and North America. Patients For the randomized groups (88 GLAS+LDAC vs 44 LDAC-alone), median (range) treatment duration was 83 (3-1575) and 47 (6-239) days; 4/88 vs 1/44 completed ≥4 years' follow-up, and median follow-up was >45 months for both groups. Interventions Glasdegib 100-mg QD; LDAC 20-mg BID×10 days q28 days. Main outcome measures The prespecified primary endpoint was OS (Jan 2017 cutoff: HR 0.51; 80%CI 0.39-0.67 p=0.0004). We compared OS, complete remission (CR), and safety at the final data cutoff. Results Consistent with the primary findings, GLAS+LDAC prolonged OS vs LDAC-alone in the overall ITT population (median OS 8.8 [95%CI 5.0-11.7] vs 4.9 months [2.9-6.5] HR 0.53 [95%CI 0.35-0.80] p=0.001). Results were consistent in patients with AML (HR 0.53 [95%CI 0.35-0.80] p=0.001). Similarly, OS results were consistent for subgroups by cytogenetic risk, patient characteristics, and de novo/secondary AML. GLAS+LDAC induced higher CR rates in the ITT population (16/88 vs 1/44; RR 8.12, 95%CI 1.05-62.78, p=0.010) and across subgroups. Notably, fewer patients discontinued GLAS+LDAC due to AEs (38.1% and 46.3%) and there was no increased sepsis or bleeding vs LDAC-alone despite longer glasdegib treatment. With GLAS+LDAC, SMO-inhibitor-associated AEs included dysgeusia (25.0%), muscle spasms (22.6%), and alopecia (10.7%), with only 1 patient discontinuing due to dysgeusia. Conclusions This BRIGHT AML 1003 analysis showed primary results were maintained after >20 months' additional follow-up. Consistent with primary analyses, GLAS+LDAC continued to have an acceptable safety profile and improved OS vs LDAC-alone. HRs were consistent across cytogenetic risk subgroups and support use of GLAS+LDAC in de novo and secondary AML. Study sponsor Pfizer.

Abstract CT139: Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study

Abstract Introduction: Cer is an oral ALK/ROS1 inhibitor. Aberrancies in ALK and ROS1 have been observed in many cancer types and ALK inhibition has synergistic effects with chemotherapy in ALK or ROS1 rearranged tumors in preclinical models. We launched a Phase I study of Cer in combination with Gem-based chemotherapy in advanced solid tumors. Herein we present initial results of this study. Methods: Phase I, dose-escalation study of Cer in combination with A1: Gem 1000 mg IV D1/8/15 q28 days; A2: Gem 1000 mg IV + nanoparticle albumin-bound Paclitaxel 125 mg IV both D1/8/15 q28 days; A3: Gem 1000 mg IV + Cisplatin 60 mg IV D1/8 q21 days in pts with advanced, solid malignancies until disease progression, intolerable toxicity or withdrawal. A 3 + 3 dose-escalation design was used starting at Cer 450 mg once daily (DL1) in all arms; DL2 was 600 mg once daily. Primary objective was to determine the maximum tolerated dose (MTD) of Cer. Key inclusion criteria: diagnosis of advanced solid malignancy for which Gem-based treatment was appropriate, >18 years old, ECOG PS 0/1, adequate bone marrow/renal/liver function. Key exclusion criteria: interstitial lung fibrosis/disease, recent acute coronary event, CHF NYHA III/IV, corrected QTc > 450 ms. Pts in A3 could have up to 2 prior lines of therapy. Prior use of ALK inhibitors allowed. Plasma was collected for PK on C1D1, C2D1, and C1D15. Archival tumor tissue was tested for ALK/ROS1/JNK/MET by IHC. Results: Thirty-eight patients were enrolled with 21 evaluable for dose-limiting toxicity (DLT) in A1 and A3. A2 (n=4) closed to accrual for toxicity. Median age was 61 years. Seven pts (41%) had cholangiocarcinoma. A1 had one DLT (G3 ALT increase) in DL2; MTD was 600 mg. A3 had one DLT in DL1 (G3 acute renal failure) and two DLTs in DL2 (G3 thrombocytopenia and G3 dyspnea); MTD was 450 mg. G3-5 AEs in all pts: anemia (A1: 3/19, A3: 2/15), nausea (A1: 1/19, A3: 2/15), emesis (A1: 1/19, A3: 1/15), neutropenia (A1: 2/19, A3: 8/15), thrombocytopenia (A1: 1/19, A3: 4/15), hyperbilirubinemia (A3: 3/15), pneumonia (A1: 2/19), acute renal failure (A3: 1/15), fatigue (A3: 2/15). Fifteen patients were evaluable for response; the overall response rate was 20% with two PR (pt with head and neck carcinoma in A1 and pt with carcinoma of unknown primary in A3) - and one CR in a pt with cholangiocarcinoma (A3) lasting 10.3 months. Overall, disease control rate was 47%. Of 5 evaluable pts with cholangiocarcinoma 3 had clinical benefit. Median PFS 3.4 mo (A1)/4.8 mo (A3) and OS 13.7 mo (A1)/29.1 mo (A3). PK and IHC data will be presented at the conference. Conclusions: The MTD of Cer is 600 mg in combination with Gem and 450 mg in combination with Gem/Cisplatin. Further evaluation of Cer plus Gem-based chemotherapy is planned in ALK/ROS1 positive cholangiocarcinomas. Citation Format: Christos Fountzilas, Alex Adjei, Mateusz Opyrchal, Rachel Evans, Kristopher Attwood, Andrew Goey, John Wilton, Wen Wee Ma, Renuka Iyer. Ceritinib (Cer) in combination with gemcitabine (Gem)-based chemotherapy in patients (pts) with advanced solid tumors, a phase I study [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 CT139.

Results from the safety lead-in for a phase II study of pembrolizumab in combination with binimetinib and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC).

4031 Background: The majority of pts with mCRC have microsatellite stable (MSS) tumors with minimal response to PD-L1/PD-1 blockade. MEK inhibition and VEGF inhibition have immunomodulatory effects (upregulation of tumor major histocompatibility complex-I expression, enhanced T-cell infiltration, reduced MDSCs and Tregs in tumors) supporting clinical evaluation of combined MEKi (B), anti–PD-1 (P), and anti-VEGF (BV) in pts with mCRC. We hypothesize that the combination of binimetinib, pembrolizumab, and bevacizumab (BPBV) will result in greater clinical benefit than pembrolizumab alone. Methods: Patients with chemotherapy-refractory mCRC were evaluated (20 planned in the safety lead-in and 50 planned for total accrual). B was dosed at 45mg PO BID, P was administered at 200mg IV Q21 days, and BV was administered at 7.5mg/kg IV Q21 days. Primary objectives were safety, tolerability, and investigator-assessed ORR by RECIST 1.1. Clinical benefit rate (CR+PR+SD) and progression-free survival were secondary endpoints. Descriptive statistics were used to summarize safety and clinical activity. Results: As of January 9, 2020, 21 pts (10 KRAS/NRASmt, 11 RASwt, 21 MSS) were enrolled into the safety lead-in and were evaluable. The median number of prior therapies was 6. The BPBV combination was tolerable. Treatment-related Gr 1-2 and Gr 3-4 AEs occurred at 60% and 38%, respectively. The most frequent related Gr 3-4 AEs were aceniform rash, diarrhea, and hypertension (19%, 14%, 14% respectively). No treatment-related Gr 5 AEs occurred. A total of 17 patients were evaluable for response. Confirmed PR was observed in 2 pts (12%). SD was noted in 14 patients (82%) leading to a clinical benefit rate of 94%. 1 patient had PD as the best response to treatment. Median PFS was 6.4 months (95% CI 4.2-8.9). Molecular determinants, immune biomarkers, and updated tumor assessments of response will be presented. Conclusions: B + P + BV demonstrated a tolerable safety profile and improvements in ORR and clinical benefit rate compared to those reported with SOC in heavily pretreated pts with mCRC. Objective responses observed in pts were durable, suggesting benefit of this novel combination in a patient population refractory to immune therapies. Clinical trial information: NCT03475004 .

A phase Ib study of pembrolizumab (pembro) plus trastuzumab emtansine (T-DM1) for metastatic HER2+ breast cancer (MBC).

1046 Background: Preclinical evidence suggests treatment (tx) with T-DM1 plus an anti-PD1 antibody triggers antitumor immunity. We conducted a phase 1 trial to determine the safety and explore the efficacy of T-DM1 plus pembro. Methods: Eligible patients (pts) had MBC previously treated with trastuzumab (H) and taxane (T), were T-DM1-naïve, and received >1 prior line of tx for MBC or developed recurrence within 6 months (mo) of adjuvant tx. A dose de-escalation (esc) design was used with 6 pts in the dose-finding cohort, followed by an expansion (exp) cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies (bx). The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and clinical benefit rate (CBR: complete response + partial response + stable disease >24 weeks). Associations between immune biomarkers and tx response were explored. Results: 20 pts started protocol tx (6 in dose de-esc cohort; 14 in exp cohort). Median follow-up was 23.5 mo. Pts had median age 54 yrs and median 1 line of prior MBC tx (range 0-2); 100% had received prior T, H, and pertuzumab. There were no dose-limiting toxicities in the dose de-esc cohort; thus full doses of T-DM1 (3.6 mg/kg q21 days) and pembro (200 mg q21 days) were the RP2D. 85% of pts experienced tx-related adverse events (AEs) > grade (gr) 1; 20% of pts experienced gr3 AEs. There were no gr>4 AEs. Gr3 AEs were fatigue; AST increase; ALT increase; pneumonia; pneumonitis; oral mucositis; and vomiting, each in 1 pt. 17 pts had baseline bx; 6 pts had repeat bx after 1 tx cycle. Efficacy results, overall and by PD-L1 Combined Positive Score (CPS; 22C3 staining) and tumor-infiltrating lymphocyte (TIL) status, are shown in the table. Tumors’ antigen presentation will be explored through HLA/dendritic cell marker staining and immune signatures by RNA sequencing. Conclusions: T-DM1 plus pembro was safe and tolerable. The regimen demonstrated clinical activity. Further exploration of immune-related predictive biomarkers is warranted. Clinical trial information: NCT03032107 . [Table: see text]

SWOG S1400F (NCT03373760): A phase II study of durvalumab plus tremelimumab for previously treated patients with acquired resistance to PD-1 checkpoint inhibitor therapy and stage IV squamous cell lung cancer (Lung-MAP Sub-study).

9623 Background: The Lung Cancer Master Protocol (Lung-MAP) is designed to evaluate novel targeted therapies in patients with advanced squamous lung carcinoma. In the S1400F sub-study (non-match), we tested whether combined CTLA-4 and PD-1 inhibition with durvalumab plus tremelimumab (D+T) could overcome primary or acquired resistance to anti-PD-(L)1 therapy. Response, progression-free (PFS) and overall survival, and safety in the acquired resistance cohort are reported herein. Methods: Patients with previously treated squamous lung carcinoma, performance status (PS) 0-1, and adequate organ function that developed disease progression after ≥24 weeks of anti-PD-(L)1 monotherapy were eligible. Prior severe immune-related toxicities, intervening systemic therapy and combination chemo-immunotherapy were not permitted. Patients received D1500 mg + T75 mg IV q28 days for 4 cycles then D maintenance until disease progression. The primary endpoint was best objective response (RECIST 1.1). Interim analysis for futility was planned after 20 patients evaluable for response were enrolled. If no responses were observed, the cohort would stop enrolment. Results: 30 eligible patients were accrued to the acquired resistance cohort. Median age was 68 years, 60% of patients were male, 33% PS 0 and had received a median of 2 prior lines of therapy (maximum 4). Best response to prior anti-PD-(L)1 therapy was CR/PR/SD in 3/7/20 patients, with a median duration of anti-PD-(L)1 therapy of 8.6 months (5.2-30.4). No objective responses were seen with D+T; 47% had SD as best response. Median PFS was 2.0 months (95% CI 1.6-2.9) and survival 7.5 months (95% CI 5.3-8.7). Among the 14 patients with SD as best response, the median PFS calculated from first disease assessment is 2.8 months (95% CI: 1.4-3.9). Grade≥3 adverse events at least possibly related to protocol therapy were seen in 10/30 patients. These include 1 treatment-related death due to pneumonitis and 1 death not otherwise specified. Other adverse events include grade 3 confusion (1), dehydration (2), diarrhea (3), encephalopathy (1), weakness (1), hyperglycemia (1), hypoxia (1), lymphopenia (1), nausea, (1), neutropenia (1), thrombocytopenia (1), rash (1), vomiting (1), grade 4 dyspnea (1), leucopenia (1) and lymphopenia (1). Conclusions: D+T did not demonstrate activity in patients with acquired resistance to PD-1 checkpoint inhibitors and pretreated advanced squamous lung carcinoma. Clinical trial information: NCT03373760 .