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Aim: This systematic literature review and network meta-analysis evaluated the efficacy and safety of sintilimab + pemetrexed + platinum versus US FDA-approved/National Comprehensive Cancer Network-recommended immune checkpoint inhibitor (ICI) combination therapies for untreated advanced/metastatic non-squamous non-small-cell lung cancer without EGFR/ ALK aberrations. Methods: Bayesian network meta-analysis was the base-case analysis and included assessment of fixed and random effects, and independent and simultaneous models, adjusting for baseline risk (placebo response). Chemotherapy was the common comparator. Results: Sintilimab + pemetrexed + platinum was associated with significantly longer progression-free survival than atezolizumab + platinum + nab-paclitaxel (hazard ratio [HR]: 0.57; 95% credible interval [CrI]: 0.40–0.82) and nivolumab + ipilimumab + pemetrexed + platinum (HR: 0.66; 95% CrI: 0.48–0.92). Sintilimab + pemetrexed + platinum and pembrolizumab + pemetrexed + platinum showed comparable progression-free survival (HR: 0.96; 95% CrI: 0.71–1.30). There was no significant difference in overall survival (HR range: 0.61–0.81) or overall response rates (odds ratio [OR] range: 0.29–0.75) between sintilimab + pemetrexed + platinum and the other ICI combinations. The incidence of high-grade adverse events was higher with sintilimab + pemetrexed + platinum than with nivolumab + ipilimumab (OR: 0.46; 95% CrI: 0.33–0.64) or without chemotherapy (OR: 0.25; 95% CrI: 0.19–0.34), with no significant difference between sintilimab + pemetrexed + platinum and the other ICI combinations. Conclusion: Sintilimab + pemetrexed + platinum showed comparable efficacy and safety versus US standard-of-care first-line ICI combinations for advanced/metastatic non-squamous non-small-cell lung cancer.

Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

Molecular modifiers of KRAS G12C inhibitor (KRAS G12Ci) efficacy in advanced KRAS G12C-mutant NSCLC are poorly defined. In a large unbiased clinico-genomic analysis of 424 NSCLC patients, we identified and validated co-alterations in KEAP1, SMARCA4 and CDKN2A as major independent determinants of inferior clinical outcomes with KRAS G12Ci monotherapy. Collectively, co-mutations in these three tumor suppressor genes segregated patients into distinct prognostic subgroups and captured ~50% of those with early disease progression (PFS≤3 months) with KRAS G12Ci. Pathway-level integration of less prevalent co-alterations in functionally related genes nominated PI3K/AKT/MTOR pathway and additional baseline RAS gene alterations, including amplifications, as candidate drivers of inferior outcomes with KRAS G12Ci, and revealed a possible association between defective DNA damage response/repair and improved KRAS G12Ci efficacy. Our findings propose a framework for patient stratification and clinical outcome prediction in KRAS G12C-mutant NSCLC that can inform rational selection and appropriate tailoring of emerging combination therapies.

Supplementary Tables 1-3 and Table A-1, Figure 1, Appendix and Information from The BATTLE Trial: Personalizing Therapy for Lung Cancer

PDF file - 167K, Different probes for the same gene vary within and across microarray platforms

Purpose: Epithelial–mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non–small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.Experimental Design: We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.Results: Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.Conclusion: We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype. Clin Cancer Res; 19(1); 279–90. ©2012 AACR.

PDF file - 66K, CDH1 probes vary in their accuracy and dynamic range

Purpose: This randomized phase II study was initially designed to test the activity of two dose schedules of lapatinib (GW572016H), an oral, reversible, dual tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2/neu; HER2), in chemotherapy-naive patients with non–small cell lung cancer (NSCLC); it was later amended to target patients with bronchioloalveolar carcinoma or no smoking history.Experimental Design: Patients with good performance status and recurrent or metastatic NSCLC were randomized to lapatinib (orally, 1,500 mg once daily or 500 mg twice daily) until progression or intolerance. Patients could have had a maximum of one prior systemic therapy (chemotherapy or biological therapy) for NSCLC. Safety and activity were assessed every 4 and 8 weeks, respectively. Tumors were analyzed for EGFR and HER2 mutations and/or amplifications.Results: Of 75 patients in the nontargeted population, 1 (1.3%) had partial response and 16 (21%) had stable disease of ≥24 weeks. No complete or partial responses were observed in 56 patients in the targeted population; 14 (25%) had stable disease of ≥24 weeks. No responses were seen in three patients with EGFR mutations and five with EGFR gene amplification. No mutations in HER2 were found. One of two patients with HER2 amplification had a 51% decrease in tumor size; however, this response was unconfirmed. The most common adverse events were grade 1 or 2 diarrhea, rash, fatigue, nausea, and anorexia. Adverse events were similar across dosing regimens.Conclusions: Lapatinib was well tolerated, with no notable difference in toxicity between treatment groups. Lapatinib monotherapy did not induce a significant number of tumor regressions in NSCLC. Further studies may be warranted to determine whether lapatinib is active in combination with other agents in the treatment of NSCLC. Clin Cancer Res; 16(6); 1938–49

Supplemental Methods

Supplemental Figure 1. Representative example from one patient showing the rash that was most frequently observed with ensartinib. The white arrow in the top figure points to the rash that is circled in the bottom figure.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

PDF file - 50K, Mesenchymal lines are sensitive to Axl inhibition by SGI-7079

PDF file - 175K

Ensartinib was tested against wild-type ALK and 17 ALK variants in the Reaction Biology panel. Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50s

PDF file - 214K, The EMT signature genes

Supplementary Figure 1: Heatmap of the 68 non-small cell lung cancer cell lines with EGFR wild-type used to train the Sorafenib Sensitivity Signature; Supplementary Figure 2: Heatmap of the 37 patients with EGFR mutant tumors using the Sorafenib Sensitivity signature; yes: disease control at 8 weeks; no: no disease control at 8 weeks.

PDF file - 71K, Percentage tumor volume compared to control, survival and therapeutic efficacy at days 17 and 38 post-treatment

PDF file - 51K, EMT status of commonly mutated genes in NSCLC

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

PDF file - 27K, SGI-7079 and erlotinib do not adversely affect animal body weight

Supplementary Data from Randomized Phase II Multicenter Trial of Two Schedules of Lapatinib as First- or Second-Line Monotherapy in Patients with Advanced or Metastatic Non–Small Cell Lung Cancer

PDF file - 96K, Structure of pyrrolopyrimidine AXL inhibitor SGI-7079

Supplemental Figure 2. Arithmetic mean concentration-time curves for fasted patients receiving 225 mg of ensartinib on Days 1 and 22 of Cycle 1.

Purpose: To report the clinical efficacy of sorafenib and to evaluate biomarkers associated with sorafenib clinical benefit in the BATTLE (Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination) program.Patients and Methods: Patients with previously treated non–small cell lung cancer (NSCLC) received sorafenib until progression or unacceptable toxicity. Eight-week disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Prespecified biomarkers included K-RAS, EGFR, and B-RAF mutations, and EGFR gene copy number. Gene expression profiles from NSCLC cell lines and patient tumor biopsies with wild-type EGFR were used to develop a sorafenib sensitivity signature (SSS).Results: A total of 105 patients were eligible and randomized to receive sorafenib. Among 98 patients evaluable for eight-week DCR, the observed DCR was 58.2%. The median PFS and OS were 2.83 [95% confidence interval (CI), 2.04–3.58] and 8.48 months (95% CI, 5.78–10.97), respectively. Eight-week DCR was higher in patients with wild-type EGFR than patients with EGFR mutation (P = 0.012), and in patients with EGFR gene copy number gain (FISH-positive) versus patients FISH-negative (P = 0.048). In wild-type EGFR tumors, the SSS was associated with improved PFS (median PFS 3.61 months in high SSS vs. 1.84 months in low SSS; P = 0.026) but not with eight-week DCR. Increased expression of fibroblast growth factor-1, NF-κB, and hypoxia pathways were identified potential drivers of sorafenib resistance.Conclusion: Sorafenib demonstrates clinical activity in NSCLC, especially with wild-type EGFR. SSS was associated with improved PFS. These data identify subgroups that may derive clinical benefit from sorafenib and merit investigation in future trials. Clin Cancer Res; 19(24); 6967–75. ©2013 AACR.

Supplemental Figure 3. Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at 200 mg who had received prior crizotinib and as second-generation ALK TKI. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 16 patients, four had partial responses and four had stable disease. The color scheme represents which second-generation ALK TKI that patient received after crizotinib. Of note, the primary lesion of one of the 16 patients was too small, and thus indeterminate, at the post-baseline assessment, therefore a change in tumor size is not available. This patient had received, in order, prior crizotinib, alectinib, and ceritinib, and developed progression on ensartinib in a non-target brain lesion prior to cycle 3. *Denotes those patients with progressive disease as the best response. >Denotes patients still on study at the time of data cutoff.

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

PURPOSE To compare clinical outcomes in a cohort of patients with advanced non–small-cell lung cancer (NSCLC) with targetable genomic alterations detected using plasma-based circulating tumor DNA (ctDNA) or tumor-based next-generation sequencing (NGS) assays treated with US Food and Drug Administration–approved therapies at a large academic research cancer center. METHODS A retrospective review from our MD Anderson GEMINI database identified 2,224 blood samples sent for ctDNA NGS testing from 1971 consecutive patients with a diagnosis of advanced NSCLC. Clinical, treatment, and outcome information were collected, reviewed, and analyzed. RESULTS Overall, 27% of the ctDNA tests identified at least one targetable mutation and 73% of targetable mutations were EGFR-sensitizing mutations. Among patients treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapies, there were no significant differences in progression-free survival of 379 days and 352 days ( P value = .41) with treatment based on tissue (n = 40) or ctDNA (n = 40), respectively. Additionally, there were no differences in progression-free survival or objective response rate among those with low (n = 8, 0.01%-0.99%) versus high (n = 16, ≥ 1%) levels of ctDNA of the targetable mutation as measured by variant allele frequency (VAF). Overall, there was excellent testing concordance (n = 217 tests) of > 97%, sensitivity of 91.7%, and specificity of 99.7% between blood-based ctDNA NGS and tissue-based NGS assays. CONCLUSION There were no significant differences in clinical outcomes among patients treated with approved EGFR-TKIs whose mutations were identified using either tumor- or plasma-based comprehensive profiling and those with very low VAF as compared with high VAF, supporting the use of plasma-based profiling to guide initial TKI use in patients with metastatic EGFR-mutant NSCLC.

To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.

Patients with advanced cutaneous squamous cell carcinoma (CSCC) have a poor prognosis. Blocking the PD-1–PD-L1 axis has shown promising activity in this patient population. We assessed the safety and antitumor activity of PD-1 inhibitor pembrolizumab in patients with refractory advanced CSCC. This was a prespecified subgroup analysis of patients with advanced CSCC who enrolled in an open-label, phase II clinical trial for pembrolizumab in patients with refractory rare cancers during 2016–2018. Patients received pembrolizumab 200 mg intravenously every 21 days until progressive disease, unacceptable adverse event, or completion of 24 months of treatment. The primary endpoint was nonprogression rate (NPR) at 27 weeks; secondary endpoints included safety, objective response rate (ORR) per irRECIST, clinical benefit rate (CBR), progression-free survival, and overall survival. Twenty patients with refractory CSCC enrolled; 19 were evaluable for efficacy. Median follow-up time was 44.1 months. The NPR at 27 weeks was 37% (95% CI 0.16–0.62). Three patients had a complete response (CR), three had a partial response, and one had stable disease, for an ORR of 32% and a CBR of 37%; median duration of response was 27.3 months. All three patients with a CR remained free of recurrence at the time of writing. Severe treatment-related adverse events (grade ≥ 3) occurred in 10% of patients (2/20). PD-L1 expression was not correlated with response to pembrolizumab. A long-term follow-up confirms pembrolizumab’s antitumor activity and safety profile in patients with refractory CSCC. Patients with a CR may experience cure. ClinicalTrials.gov, NCT02721732, Registered March 29, 2016.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC. Neoadjuvant treatment with nivolumab plus ipilimumab is well tolerated and demonstrates clinical efficacy in patients with early stage lung cancer.

Programmed death-ligand 1 (PD-L1) expression may vary in different disease sites and at different time points of the disease course. We aimed to investigate PD-L1 heterogeneity and its usefulness as a predictive value for immune checkpoint inhibitor (ICI) therapy in patients with NSCLC.PD-L1 expression was analyzed in 1398 patients with NSCLC. The predictive value of PD-L1 for ICIs in 398 patients with metastatic NSCLC was assessed.PD-L1 was significantly associated with biopsy sites (p = 0.004). Adrenal, liver, and lymph node (LN) metastases had the highest PD-L1 expression as a continuous variable and at 1% or 50% cutoff. PD-L1 expression was lower in bone and brain metastases. Among 112 patients with two specimens tested, 55 (49%) had major changes in PD-L1 falling into different clinically relevant categories (1%, 1%-49%, ≥50%) at different time points. Previous ICI therapy was associated with significant decrease in PD-L1 compared with treatment-naive counterparts (p = 0.015). Patients with metastatic NSCLC treated with ICI (n = 398) were divided into three cohorts on the basis of biopsy sites: lung (n = 252), LN (n = 85), and distant metastasis (n = 61). Higher PD-L1 in lung or distant metastasis specimens was associated with higher response rate, longer progression-free survival, and overall survival. However, PD-L1 in LN biopsies was not associated with either response or survival.PD-L1 varies substantially across different anatomical sites and changes during the clinical course. PD-L1 from different biopsy sites may have different predictive values for benefit from ICIs in NSCLC.

Introduction Consolidation durvalumab after chemoradiation (CRT) is the current standard of care for locally advanced NSCLC. We hypothesized that adding immunotherapy concurrently with CRT (cCRT) would increase efficacy without additive toxicity. Methods This phase II study was conducted in two parts. Part 1 (n = 10) involved administration of conventionally fractionated CRT followed by consolidation chemotherapy (atezolizumab [two cycles] and maintenance atezolizumab up to 1 y). Part 2 (n = 30) involved administration of cCRT with atezolizumab followed by the same consolidation and maintenance therapies as in part 1. Programmed cell death ligand-1 staining cutoffs (1% or 50%) using Dako 22C3 immunohistochemistry were correlated with clinical outcomes. Results The overall toxicities for part 1/2 were overall adverse events of grade 3 and above of 80%/80%; immune-related adverse events of grade 3 and above of 30%/20%; and pneumonitis of grade 2 and above of 10%/16%, respectively. In part 1, for preliminary efficacy results, with a median follow-up of 22.5 months, the median progression-free survival was 18.6 months, and the overall survival was 22.8 months. In part 2, with a median follow-up time of 15.1 months, the median progression-free survival was 13.2 months, and the overall survival was not reached. There was no difference in cancer recurrence regardless of programmed cell death ligand-1 status. Conclusions Atezolizumab with cCRT is safe and feasible and has no added toxicities compared with historical rates.

BackgroundADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10+ tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577).MethodsEligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08–0.12×109 (dose group 1), 0.5–1.2×109 (dose group 2), and 1.2–15×109 (dose group 3/expansion) transduced cells.ResultsEleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m2 on days –5 to –2 and cyclophosphamide 1800 mg/m2 on days −5 to −4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10.ConclusionsADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing.

OBJECTIVE: This phase I trial (NCT01912625) evaluated the safety and pharmacokinetics of definitive concurrent chemoradiotherapy (cCRT) and the radiosensitizer trametinib (MEK1/2 inhibitor) for KRAS-mutated nonmetastatic non-small cell lung cancer (NSCLC). METHODS: Patients received cCRT (carboplatin/paclitaxel and 60 Gy/30 fractions radiotherapy); oral trametinib (7 days/week) commenced on day 1 and completed on the final day of radiotherapy. Dose-finding of trametinib was done using the time-to-event continual reassessment method (TiTE-CRM); dose levels were 0.5mg (level -1), 1mg (initial, level 1), 1.5mg (level 2), and 2mg (level 3). Progression-free (PFS) and overall survival (OS) times were also recorded. RESULTS: Fifteen patients (stage III, variety of KRAS mutations) were treated, with 1/5/4/5 at dose levels -1/1/2/3, respectively. Five patients received dose reductions (n=2, levels 2 and 3; n=1, level 1). Twelve patients completed the full cCRT course. One patient (following 12d trametinib) was taken off protocol for an unrelated/unresolved grade 1 event and later experienced grade 5 sepsis/respiratory failure. There was one grade 4 retinal detachment; grade 3 events included skin rash (n=2) and ventricular dysfunction, pneumonitis, pain, fatigue, and diarrhea (n=1 each). The final dose selected by the TiTE-CRM of trametinib was 1.5 mg. Pharmacokinetic profiles were elucidated and extensively described. At median follow-up of 70 months, median PFS was 11 months and median OS was 38 months. CONCLUSIONS: The MTD for trametinib when combined with cCRT is 1.5 mg, with encouraging preliminary outcomes. This combination merits further study to combine with consolidation durvalumab in non-metastatic KRAS mutant NSCLC.

Author(s): Munster, Pamela; Mita, Monica; Mahipal, Amit; Nemunaitis, John; Massard, Christophe; Mikkelsen, Tom; Cruz, Cristina; Paz-Ares, Luis; Hidalgo, Manuel; Rathkopf, Dana; Blumenschein, George; Smith, David C; Eichhorst, Barbara; Cloughesy, Tim; Filvaroff, Ellen H; Li, Shaoyi; Raymon, Heather; de Haan, Hans; Hege, Kristen; Bendell, Johanna C | Abstract: PurposeThis first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase.Patients and methodsPatients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5-40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy.ResultsForty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission g4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD.ConclusionCC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment.Clinical trial registrationNCT01353625.

BackgroundSAR444245 (THOR-707) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, SAR444245 showed anti-tumor benefits, but with no severe side effects, both as single agent and when combined with anti-PD1 comparing with historical data from aldeslukin. Preclinical study demonstrated SAR444245 enhances ADCC function of cetuximab. The HAMMER trial, which is the FIH study shows preliminary encouraging clinical results: initial efficacy and safety profile with SAR444245 monotherapy and in combination with pembrolizumab or with cetuximab support a non-alpha preferential activity, validating preclinical models. The Pegasus Head and Neck Ph 2 study will evaluate the clinical benefit of SAR444245 in combination with other anticancer therapies for the treatment of patients with R/M HNSCC.MethodsThe Pegasus Head and Neck will enroll approximately 272 patients in 4 separate cohorts concurrently. In cohorts A1 & A2, 1L R/M HNSCC patients will receive SAR444245 + pembrolizumab, or SAR444245+ pembrolizumab+ cetuximab respectively. In cohort B1 & B2 patients with 2/3L R/M HNSCC failed a checkpoint based regimen & a platinum containing regimen will receive SAR444245 + pembrolizumab, or SAR444245 + cetuximab. Patients to be enrolled in cohort B2 need to be cetuximab-naïve in R/M setting. SAR444245 is administered intravenously IV at a dose of 24 ug/kg Q3W until disease progression (PD) or completion of 35 cycles. Pembrolizumab is administered at a dose of 200 mg Q3W until PD or completion of 35 cycles. Cetuximab is administered at a dose of 400/250 mg/m2 QW until PD. The study primary objective is to determine the antitumor activity of SAR444245 in combination with other anticancer therapies. Secondary objectives include confirmation of dose and safety profile, assess other indicators of antitumor activity, and assess the pharmacokinetic profile and immunogenicity of SAR444245. The study will be conducted in the US, Canada, France, Germany, Italy, Netherlands, Poland, South Korea, Spain and Taiwan.AcknowledgementsThe Pegasus Head and Neck study is sponsored by Sanofi.

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with HER2 exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study. PATIENTS AND METHODS Patients with advanced HER2 exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response. RESULTS Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across HER2 exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis. CONCLUSION Poziotinib showed promising antitumor activity in patients with HER2 exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy.

Purpose: Cetuximab, which modulates immune responses, may affect the efficacy of subsequent immunotherapy. Here, we assessed outcomes with nivolumab, by prior cetuximab exposure, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) who had experienced progression within 6 months of platinum-containing chemotherapy. Patients and Methods: In the randomized, open-label, phase III CheckMate 141 trial, patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks or investigator's choice (IC) of single-agent chemotherapy, with stratification by prior cetuximab exposure. The primary endpoint was overall survival (OS); additional endpoints were progression-free survival, objective response rate, and safety. Results: In patients with prior cetuximab exposure, the median OS was 7.1 months with nivolumab versus 5.1 months with IC (HR, 0.84; 95% CI, 0.62–1.15); OS benefit with nivolumab was maintained across most demographic subgroups. In patients without prior cetuximab exposure, the median OS was 8.2 months with nivolumab versus 4.9 months with IC (HR, 0.52; 95% CI, 0.35–0.77); OS benefit with nivolumab was maintained across patient baseline subgroups including tumor programmed death ligand 1 (PD-L1) expression ( Conclusions: Nivolumab appeared to improve efficacy versus IC regardless of prior cetuximab use, supporting its use in patients with R/M SCCHN with or without prior cetuximab exposure. The reduction in risk of death with nivolumab compared with IC was greater in patients without prior cetuximab exposure versus with prior cetuximab exposure.

Objectives: Many patients with squamous cell carcinoma of the head and neck (SCCHN) are ≥65 years old; comorbidities and other age-related factors may affect their ability to tolerate traditional chemotherapy. Nivolumab is the only immunotherapy to significantly improve overall survival (OS) versus investigator’s choice (IC) of single-agent chemotherapy at primary analysis in a phase 3 trial (CheckMate 141) in patients with recurrent/metastatic SCCHN post-platinum therapy. In this post hoc analysis, we report efficacy and safety by age. Patients and methods: Eligible patients were randomized 2:1 to nivolumab 3 mg/kg every 2 weeks (n = 240) or IC (methotrexate, docetaxel, or cetuximab n = 121). The primary endpoint of the trial was OS. For this analysis, outcomes were analyzed by age < 65 and ≥65 years. The data cut-off date was September 2017 (minimum follow-up 24.2 months). Results: At baseline, 68 patients (28.3%) receiving nivolumab and 45 patients (37.2%) receiving IC were ≥65 years. Baseline characteristics were generally similar across age groups. OS and tumor response benefits with nivolumab versus IC were maintained regardless of age. The 30-month OS rates of 11.2% (< 65 years) and 13.0% (≥65 years) with nivolumab were more than tripled versus corresponding IC rates of 1.4% and 3.3%, respectively. The nivolumab arm had a lower rate of treatment-related adverse events versus IC regardless of age, consistent with the overall patient population. Conclusion: In CheckMate 141, nivolumab resulted in a higher survival versus IC in patients < 65 and ≥65 years, with a manageable safety profile in both age groups. ClinicalTrials.gov: NCT02105636.

Introduction Immune checkpoint blockade (ICB) has revolutionized the treatment of NSCLC, but only approximately 15% of patients achieve durable benefit. Understanding mechanisms of resistance to ICB is pivotal in developing more effective treatment strategies. Recent studies showed that human leukocyte antigen (HLA) class I heterozygosity might be important in mediating benefit from ICB. We aimed to investigate the impact of HLA class I genotype on outcomes of patients with NSCLC treated with ICB. Methods We collected HLA typing, genomic, and clinical data from patients with advanced NSCLC treated with ICB at M. D. Anderson Cancer Center. We compared HLA class I–heterozygous and HLA class I–homozygous patients for progression-free survival (PFS) and overall survival (OS). HLA I supertype/alleles were also analyzed. To validate our findings, we also analyzed two previously published independent cohorts of patients with NSCLC (the CheckMate-012 and Chowell cohorts). Results No significant correlations were observed for HLA class I zygosity and PFS or OS in the M. D. Anderson Cancer Center (n = 200), CheckMate-012 (n = 75), or Chowell (n = 371) cohorts. No HLA class I supertype/allele was consistently shown to be correlated with PFS or OS. Predictors of worse outcome across the three cohorts included presence of targetable driver mutation, serine/threonine kinase 11 gene (STK11) mutation, negative programmed death ligand 1 expression, and low tumor mutational burden. Conclusions HLA class I genotype is not correlated with survival in advanced NSCLC treated with ICB. This suggests that the impact of HLA class I diversity may be disease specific and that tumor genomic and immune markers are more impactful in predicting benefit from ICB in NSCLC.

1588 Background: Emerging clinical studies report correlation of time-of-day infusion (TOI) to immunotherapy outcomes and the intricate interplay of the human circadian rhythm and cancer and immunotherapy exposure. Preclinical and clinical studies have shown cancer chronotherapy to play important role in transcriptional rhythmicity of oncogenic process. We evaluated the association of TOI and immunotherapy outcomes in a large cohort to determine impact of TOI on overall survival (OS) and progression free survival (PFS). Methods: We reviewed charts of patients with solid tumors who received immunotherapy, specifically anti programmed cell death protein 1 (PD1) and anti-programmed death-ligand 1 (PD-L1) agents at MD Anderson Cancer Center. Infusion times were divided into two hours cohorts from 8am-8pm and one overnight cohort from 8pm-8am. Accelerated failure time models were used to model OS (log-normal distribution) and PFS (Weibull distribution) with relation to TOI after adjusting for factors such as age, gender, tumor type and prednisone > 10mg daily use within 1 month of immunotherapy initiation to minimize confounding factors. Results: Of 6151 patients with advanced tumors, 4441 patients received immunotherapy therapy after adjusting for minimum 140 patients in each tumor cohort from 10/15/2016 until 10/15/2021. Tumor types included advanced lung cancer (31.4%), melanoma (28.7%), renal (14.4%), breast (7.6%), colon (6.2%), liver cancer (3.9%) and head and neck (H&N) cancers (2.8%). Median age was 63 (15-99) with 58% males and 42% female. 1894 (43%) patients received investigational agents and 2547 (57%) received standard of care therapies. Mechanism of action of various agents: anti PD1, anti-PDL1, TGF-βRII and anti-PDL1, anti-PD-1 with OX40+ T Cell activation, PD-1 / PD-L1 bispecific antibody, PD-L1 dependent 4-1BB agonist and anti PD-1 and CTLA-4 activity. Among all patients, median OS was 26.4 months while median PFS was 4.8 months. Preponderance of immunotherapy TOI occurred between 12-2pm and 2-4pm in all patients. Patients receiving overnight TOI with lung, renal and breast cancer demonstrated significantly (p < 0.05) poorer OS compared to TOI (10am-4pm) whereas in melanoma, significantly lower OS was seen with overnight, 8-10am and 6-8pm compared to 10am-4pm TOIs. Among H&N cancer patients, early TOI (8-10am) was associated with significantly lower OS compared to afternoon TOI (12pm-4pm). PFS trends were less distinct than for OS but showed a slighted inverted tendency towards lower PFS following daytime TOI. Conclusions: In this large cohort of patients treated with immunotherapy, clinically significant association of TOI with overall survival is seen. These intriguing findings warrant prospective validation in a future randomized trial to harness the role of chronomodulation of cancer therapies for improving outcomes.

9049 Background: Primary resistance to immune checkpoint inhibitor (ICI) therapy remains a major challenge in clinical oncology. Here, we describe the clinical outcome of patients who experienced radiologic progression within 12 weeks of therapy with nivolumab and ipilimumab (I+N) for metastatic non-small cell lung cancer (mNSCLC). Methods: The LONESTAR study is an ongoing phase III study (NCT03391869). Study enrolls patients with immunotherapy naïve mNSCLC (prior chemotherapy is allowed). All patients receive I+N for 12 weeks and are randomized to experimental therapy vs. control arm if they did not have disease progression. Patients who experience radiologic progression per RECIST v1.1 are not randomized and removed from the study. Treatment beyond progression is allowed if they clinically benefit from the systemic therapy. We prospectively collected clinicopathologic and radiologic outcome data from patients who experienced radiologic progression within 12 weeks of I+N therapy and have not randomized to investigational therapy. We described the primary progression pattern. We collected subsequent treatment, radiologic, and toxicity data and calculated clinical outcomes, including progression-free survival (PFS) and overall survival (OS). Results: Of the 194 patients who received at least one dose of I+N therapy, 72 patients had clinical and/or radiologic progression at ≤ 12 weeks. Thirty-five (35; 48%) patients did not receive subsequent treatment, 21 (29%) patients received subsequent 2nd line systemic therapy, and 16 (22%) patients were continued on I+N beyond radiologic progression due to ongoing clinical benefit. Among patients treated with 2nd line therapy, 13 patients were treated with platinum doublet +/- anti-PD-(L)1, seven (7) patients were treated with single-agent chemotherapy +/- VEGF inhibitor, and one (1) patient was treated with targeted therapy. The PFS for the 2nd line therapy was 6.5 months (95%CI: 4.8, 8.9), and OS was 10.4 months (95%Cl: 6.6, 16.1). Among the 16 patients treated with I+N beyond progression, 13 had a mixed response to induction therapy, where primary progression was most frequently observed in mediastinal lymph nodes. LCT with radiotherapy was utilized with I+N in 10 patients. The median duration of post-progression treatment with I+N plus LCT was 8.7 months (95%Cl: 5.9, 22.3) and 5.6 months (95%Cl 4.4, 11.5) with I+N alone. The OS was 19.5 months (95% CI: 6.2,18.7). Conclusions: In this study cohort, primary resistance to I+N was observed in 37% of the patients, and in a subset of these patients treated with post-progression I+N, either alone or in combination with LCT, durable clinical benefit was observed. Further studies are warranted to identify which patients are most likely to benefit from post-progression I+N. Clinical trial information: NCT03391869.

12112 Background: Systemic corticosteroids are commonly prescribed for palliation of dyspnea in patients with cancer; however, evidence to support their use is limited. A small RCT suggested that dexamethasone may be efficacious. In this confirmatory RCT, we compared the effect of high dose dexamethasone and placebo on dyspnea in patients with cancer. Methods: This NCI-funded, multi-site, double-blind, parallel group RCT enrolled ambulatory patients with cancer, age ≥18, dyspnea ≥4/10 and randomly assigned them to receive dexamethasone 8 mg orally every 12 hours for 7 days followed by 4 mg orally every 12 hours for 7 days or matching placebo capsules. Permuted block randomization (block size = 6, 2:1) was conducted, stratified by baseline dyspnea and study site. Patients, research staff and clinicians were blinded. The primary outcome was change in average dyspnea intensity assessed with a 0-10 numeric rating scale (0 = none, 10 = worst) between baseline and day 7. Secondary outcomes included the Edmonton Symptom Assessment Scale (ESAS) and adverse effects (CTCAE v4.02). Intention-to-treat analysis was conducted with linear models to compare between groups. The planned sample size of 201 patients provided 80% power to detect a mean difference of 1.0 between treatment groups with a two-sided α of 5%, assuming a standard deviation of 2.0 and 15% attrition. (Clinicaltrials.gov NCT03367156). Results: Between 1/11/2017 and 4/23/2021, we enrolled 149 patients and 128 received the blinded study interventions (dexamethasone n = 85, placebo n = 43). Enrollment was terminated early by the Data Safety Monitoring Board when futility criterion was met in pre-planned interim analysis. The mean change in dyspnea NRS intensity between baseline and day 7 was -1.6 (95% CI -2, -1.2) in the dexamethasone group and -1.6 (95% CI -2.3, -0.9) in the placebo group, with no significant between-group difference (mean 0, 95% CI -0.8, 0.7; P = 0.91). Secondary analyses showed that the dexamethasone group had a significantly better ESAS appetite (mean difference -1.2, 95% CI -2.2, -0.1; P = 0.03) and well being (mean -1, 95% CI -1.8, -0.2; P = 0.02), and worse ESAS anxiety (mean 1.1, 95% CI 0.3, 1.9; P = 0.01) and depression (mean 0.9, 95% CI 0.1, 1.7; P = 0.02) compared to placebo. Similar magnitude of changes in dyspnea and ESAS symptoms were observed by day 14. Adverse effects were reported more frequently in the dexamethasone group (any grade): insomnia (38% v. 12%), neuropsychiatric symptoms (31% vs. 7%), infections (21% v. 12%), dyspepsia (26% v. 12%), edema (18% v. 9%), hiccups (12% v. 7%), flushing (9% v. 5%) and respiratory distress (6% v. 0%). More patients in the dexamethasone group required hospitalization within 30 d of last study medication (25% vs. 7%, P = 0.02). Conclusions: High dose dexamethasone did not improve dyspnea in patients with cancer more than placebo and was associated with more adverse events. Clinical trial information: NCT03367156.