Supplementary Figure 1 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Supplementary Data from GSK690693 Delays Tumor Onset and Progression in Genetically Defined Mouse Models Expressing Activated Akt

Supplementary Figure 1: Study design

Supplementary Figure 2 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Supplementary Figure 4. Effects of GSK1838705A on animal weights.

Supplementary Table 7: Next-generation sequencing of tumor biopsy samples (see separate Excel file) Supplementary Table 8: Copy number variations for patients with tumor biopsy samples available (see separate Excel file) Supplementary Table 9: Summary of copy number variations as assessed by polymerase chain reaction (see separate Excel file)

Supplementary Fig. S1 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

Supplementary Fig. S2 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

Supplementary Methods and Figure Legends 1-2 from Characterization of an Akt Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity

Supplementary Table S4 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

Supplementary Figures 1-3 PDF file - 245K, Supplementary Figure 1: Dose-dependent pharmacodynamic effect of GSK2656157 on PERK in mouse pancreas. Supplementary Figure 2: Specificity of phospho-PERK antibody in mouse cells. Supplementary Figure 3: Effect of PERK inhibitor on RNA expression in tumor xenografts.

Supplementary Figure 5. Anti-tumor activity of GSK1838705A in additional xenografts.

Supplementary Fig. S1 from Pharmacokinetic-pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity

Supplementary Figure 6. Glucose metabolism after 8-day treatment of GSK1838705A.

Supplementary Data from Antitumor Activity of GSK1904529A, a Small-molecule Inhibitor of the Insulin-like Growth Factor-I Receptor Tyrosine Kinase

Supplementary Figure 2. Representative cell cycle histograms from MCF-7 and NCIH929 cells treated with 1 μM of GSK1838705A for 48 h.

Supplementary Material PDF file - 147K, Supplementary Methods: Immunohistochemistry and magnetic resonance imaging. Supplementary Table 1: Kinase selectivity profiling of GSK2656157. Supplementary Table 2: Gene list for Human UPR array

Neoadjuvant therapy with PD-(L)1 inhibitors, both as monotherapy and in combination, leads to pathological responses in resectable, early-stage NSCLC. NeoCOAST (NCT03794544) is a phase 2 study of the anti-PD-L1 monoclonal antibody (mAb) D alone or combined with the anti-CD73 mAb oleclumab (O), the anti-NKG2A mAb monalizumab (M), or the anti-STAT3 antisense oligonucleotide danvatirsen (Da) as neoadjuvant therapy. Pts with untreated, stage I [>2 cm]–IIIA NSCLC were randomized to receive 1 cycle of D alone or in combination. The primary endpoint was investigator-assessed major pathological response (MPR) rate. In a subset of pts, treatment-induced transcriptomic changes were assessed by RNA sequencing from tumor tissue collected pre-treatment and at surgery. Using a tumor-informed method, ctDNA was analyzed pre-treatment, after treatment, and post-surgery. Molecular response (MR) is defined as ≥50% reduction in variant allelic fraction from pre-treatment. As previously reported, MPR was numerically higher in all combination arms [D+O (n=4/21, 19%), D+M (n=6/20, 30%), and D+Da (n=5/16, 31%)], compared with D monotherapy [n=3/27, 11%]. Among pts with an MPR, 2 had EGFR driver mutations (both D+O arm); KRAS, STK11, RET and ALK alterations were observed in pts without an MPR. Expression of genes associated with NK cells (KLRC1, GNLY) and CD8 T cells (CD8A, GZMK) increased after treatment in all arms; with a greater increase with D+O and D+M (1–5 log2FC, adj p < 0.1) than D alone (0–1 log2FC, n.s.). Tertiary lymphoid structure, interferon, and inflammatory signatures were significantly upregulated after treatment in the D+O and D+M arms. Analysis of ctDNA identified pts who had MR (25–60% per arm after treatment, and 75–100% post-surgery), including pts without an MPR. Association of tumor mutational burden and additional biomarkers with clinical outcomes will be reported. Single cycle of D+O and D+M resulted in greater intra-tumoral immunomodulation than D alone.

PACIFIC established consolidation durvalumab (D) as SoC for unresectable Stage III NSCLC with no progression after cCRT. Combination therapy may improve outcomes. CD73 is involved in RT resistance. RT induces NKG2A ligand and shows additive antitumour effects with PD-1 blockade preclinically. COAST (NCT03822351) is a global phase 2 study of D alone or combined with the anti-CD73 mAb oleclumab (O) or anti-NKG2A mAb monalizumab (M) as consolidation therapy. Pts with histologically/cytologically documented unresectable Stage III NSCLC, ECOG PS 0/1 and no progression after cCRT were randomised 1:1:1 ≤42 days post cCRT to receive D 1500 mg IV Q4W alone or combined with O 3000 mg IV Q2W (first 2 cycles, then Q4W) or M 750 mg IV Q2W for up to 12 months, stratified by histology. The primary endpoint was investigator-assessed post cCRT ORR per RECIST v1.1. Key secondary endpoints included PFS and safety. Between Jan 2019 and Jul 2020, 189 pts were randomised, of whom 186 received D (n=66), D+O (n=59) or D+M (n=61). As of 17 May 2021, median follow-up was 11.5 months (range, 0.4–23.4; all pts). D+O and D+M numerically increased ORR (odds ratio [95% CI] 1.83 [0.80, 4.20] and 1.77 [0.77, 4.11] respectively) and significantly improved PFS versus D alone. Grade ≥3 treatment-emergent AE (TEAE, all-cause) incidence was 39.4%, 40.7% and 27.9% with D, D+O and D+M respectively. Overall, the most common grade 3/4 TEAEs were pneumonia (5.9%) and decreased lymphocyte count (3.2%); both were more common with D and D+O than with D+M. Combined rates of pneumonitis and radiation pneumonitis of any grade were 21.2% with D, 28.8% with D+O and 21.3% with D+M, with grade ≥3 events in 3.0%, 3.4% and 1.6%. Biomarker data will be presented. Addition of both novel agents improved ORR, PFS and 10-month PFS rate over D alone. Safety was similar across arms with no new safety signals identified.Table: LBA42ITTDD+OD+MN676062ORR (95% CI), %a,b25.4 (15.5, 37.5)38.3 (26.1, 51.8)37.1 (25.2, 50.3)Objective responses, na172323CR, n (%)2 (3.0)1 (1.7)3 (4.8)PR, n (%)15 (22.4)22 (36.7)20 (32.3)Median PFS (95% CI), moc6.3 (3.7, 11.2)NR (10.4, NE)15.1 (13.6, NE)PFS HR (95% CI)d,e-0.44 (0.26, 0.75)0.65 (0.49, 0.85)10-month PFS rate (95% CI), %c39.2 (26.1, 52.0)64.8 (50.4, 76.0)72.7 (58.8, 82.6)aConfirmed and unconfirmed b95% CI by Clopper-Pearson exact method c10-month minimum follow-up for all pts; Kaplan-Meier estimates for PFS, PFS rate and 95% CIsdPFS HR and 95% CI estimated by Cox regression model, stratified by histology eCompared to 67 D+O pts and 64 D+M pts enrolled concurrently with D pts Open table in a new tab

Immunotherapy targeting programmed death protein 1 (PD-1) or its ligand (PD-L1) offers clinical benefit in HNSCC, but combination treatments are needed to improve outcomes. Here we report initial safety and efficacy of the anti-PD-L1 durvalumab plus MEDI0457, a DNA immunotherapeutic vaccine expressing HPV 16/18 E6/E7 proteins and IL-12, in pts with HPV+ R/M HNSCC. This phase Ib/IIa, open-label, multicenter study (NCT03162224) enrolled pts with incurable, histologically/cytologically confirmed R/M HPV+ HNSCC, who had ≥1 prior platinum-containing regimen or other approved therapy if platinum-ineligible. MEDI0457 at a dose of 7 mg IM (weeks 1, 3, 7, then Q8W after week 12) and durvalumab 1500 mg IV Q4W were given until disease progression or unacceptable toxicity. Primary objectives included safety and efficacy by objective response rate (ORR; RECIST v1.1). Exploratory endpoints included induction of antibodies and HPV-specific T cells peripherally. Tumor-infiltrating T cells were measured. In July 2017 to Aug 2019, 35 pts were enrolled. Most were male (97.1%) with oropharyngeal primary (82.9%); 31.4% had PD-L1 ≥25%. At the interim data cutoff (DCO; 22 Nov 2019), therapy was ongoing in 13 pts (37.1%) and 27 were response-evaluable. Treatment-related adverse events (TRAEs) occurred in 77.1% of pts, mostly of Grade 1–2 severity. Fatigue (37.1%) and injection site pain (34.3%) were most common. Five pts (14.3%) had Grade 3 TRAEs and 1 pt (2.9%) had 3 serious Grade 3 TRAEs (AST and ALT increased and myocarditis causing discontinuation). No pts had Grade 4/5 TRAEs. ORR was 22.2% with 3 complete responses (all ongoing at DCO) and 3 partial responses (2 ongoing at DCO). Peripheral HPV-specific T cells and tumoral CD8+ T cells were increased.Table: 916MO1 prior line of platinum tx for R/M HNSCC (non-refractory) n=121 prior line of platinum tx for R/M HNSCC (refractory) n=6≥2 prior lines of platinum tx for R/M HNSCC n=9TotalN=27Best overall response, nCR3003PR1023SD2136PD54413NE1102ORR (CR or PR), %33.30.022.222.2 Open table in a new tab MEDI0457 plus durvalumab was well tolerated and showed clinical benefit. The study is active but not recruiting.