Faculty Bibliography

Background: Osimertinib, a third-generation EGFR inhibitor, has become the first-line therapy for patients with metastatic EGFR-mutant NSCLCs since 2018. Osimertinib is well-tolerated, therefore, it opens opportunities to be combined with other therapeutic agents to enhance the treatment outcome. In preclinical models, it has been shown that upregulated VEGF signaling mediates acquired resistance to EGFR therapies. In xenograft models, combination of anti-VEGF medications with EGFR inhibitors were significantly more effective than erlotinib or gefitinib alone. Ramucirumab, a monoclonal antibody targeting VEGF receptor 2, is approved with docetaxel in as second line treatment for NSCLCs. In clinical trial evaluations, the phase 3 RELAY trial (NCT02411448) studying ramucirumab plus erlotinib in patients with metastatic untreated EGFR-mutant NSCLC patients showed a statistically significant improvement in progression-free survival in the combination group compared to erlotinib alone. A phase I study of osimertinib with ramucirumab (NCT02789345) demonstrated safety and feasibility of this combination. With strong preclinical and clinical evidence showing dual inhibition of VEGF/EGFR signaling prolongs progression-free survival for EGFR-mutant lung cancers, and demonstrated safety, we are conducting a phase 2 trial to evaluate the osimertinib ramucirumab combination's efficacy in treatment-naive EGFR-mutant NSCLC.
Method(s): The OSI+RAM trial is a randomized phase 2 study with the primary endpoint being progression-free survival in osi+ram group as compared to osimertinib monotherapy group. The major inclusion criteria include patients with metastatic NSCLC harboring EGFR mutations (L858R/Exon 19 del). The major exclusion criteria include prior anti-EGFR or anti-VEGF treatments. Patients with stable CNS metastasis are allowed. Based on the results from erlotinib bevacizumab (NEJ026) study, we expect an improvement of PFS from 18.9 months to 29.7 months, corresponding to a hazard ratio of 0.65. The trial plans to enroll total of 150 patients, with 100 allocating to osi+ram arm and 50 to osimertinib monotherapy. Total of 9 study sites in the USA are planned. Hoosier Cancer Research Network will facilitate the execution of the trial. The trial protocol has received IND exemption from US FDA and has been approved by IRB at MD Anderson Cancer Center. The first subject is expected to be enrolled in May 2019. A planned interim analysis will be performed after the first 75 subjects are enrolled. NCT03909334.
Result(s): Section not applicable
Conclusion(s): Section not applicable Keywords: Ramucirumab, CNS metastasis, EGFR
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Background: No targeted therapy is currently approved for patients with RET fusion-positive non-small cell lung cancer (NSCLC). LOXO-292 is a highly selective RET inhibitor with activity against diverse RET fusions, activating RET mutations and brain metastases. Based on initial data from LIBRETTO-001, LOXO-292 received FDA Breakthrough Designation for the treatment of RET fusion-positive NSCLC in August 2018.
Method(s): This global phase 1/2 study (87 sites, 15 countries) enrolled patients with advanced RET-altered solid tumors including RET fusion-positive NSCLC (NCT03157128). LOXO-292 was dosed orally in 28-day cycles. The phase 1 portion established the MTD/RP2D (160 mg BID). The phase 2 portion enrolled patients to one of six cohorts based on tumor type, RET alteration, and prior therapies. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints included DoR, CNS ORR, CNS DoR, PFS, OS, safety and PK.
Result(s): As of 17-June 2019, 247 RET fusion-positive NSCLC patients were treated. The primary analysis set (PAS) for LOXO-292 registration, as defined with the US FDA, consists of the first 105 consecutively enrolled RET fusion-positive NSCLC patients who received prior platinum-based chemotherapy; 54 patients (51%) also received prior immune checkpoint inhibitors (ICIs). The majority of PAS responders have been followed for >=6 months from first response. Of the remaining 142 patients, 74 previously treated with platinum-based chemotherapy have not had sufficient follow-up, 56 did not receive prior platinum-based chemotherapy and 12 did not have measurable disease at baseline. Among PAS patients, the investigator-assessed ORR was 70% (95% CI 60-78%, n=73/105, 3 PRs pending confirmation). Responses did not differ by fusion partner or the type or number of prior therapies, including chemotherapy, ICIs and multikinase inhibitors with anti-RET activity. The median DoR was 20.3 months (95% CI 16.6-NR) with a median follow-up of 7.5 months (range 1.9-21.1 months); as evidenced by the wide confidence interval, this DoR estimate is not statistically stable due to a low number of events (12 of 70 confirmed responders). The intracranial ORR was 90% (n=9/10: 2 confirmed CRs, 7 confirmed PRs) for patients with measurable brain metastases at baseline. The ORR in evaluable treatment naive RET fusion-positive NSCLC patients was 88% (95% CI 72-97%, n=29/33, 10 PRs pending confirmation). In the safety data set of all 247 patients, 5 treatment-related AEs occurred in >=15% of patients: dry mouth, AST increased, diarrhea, ALT increased, and hypertension. Most AEs were grade 1-2. Only 3 of 247 (1.2%) NSCLC patients discontinued LOXO-292 for treatment-related AEs. Updated data will be presented at the meeting.
Conclusion(s): LOXO-292 had marked antitumor activity in RET fusion-positive NSCLC patients and was well tolerated. These data will form the basis of an FDA NDA submission later this year. Keywords: RET fusion, selective RET inhibitor, NSCLC
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Background: bTMB assays determine TMB using a noninvasive blood test. B-F1RST (ITT, n=152) is the first prospective trial to evaluate bTMB as a biomarker to predict benefit of 1L atezo monotherapy in advanced NSCLC. bTMB high (score of >=16; >= 14.5 mut/Mb) predicted better ORR with atezo vs bTMB low (< 16; 28.6% vs 4.4%) in the biomarker evaluable population (BEP) with >= 6 mo follow up in the primary analysis. Numerical benefit for bTMB high was seen in median (m)PFS and mOS. Here we report the B-F1RST final analysis.
Method(s): Eligibility criteria included untreated stage IIIB-IVB NSCLC and ECOG PS 0/1. Pts received atezo 1200 mg IV q3w until PD, intolerance or loss of benefit. Co-primary endpoints were investigator assessed ORR for efficacy (ITT) and PFS for biomarker analysis (BEP) at a prespecified bTMB cutoff of 16 for high (>= 16) vs low (< 16). PFS and OS, a secondary endpoint, were further evaluated at various bTMB cutoffs. Serum C-reactive protein (CRP), an inflammation marker in cancer, was evaluated as a surrogate biomarker, ratio of CRP at C3D1 to CRP at screening, to predict PFS and OS.
Result(s): With >= 18 mo follow up (data cutoff, 14 May 2019) in ITT pts, ORR was 17% (95% CI: 12, 24), mPFS was 4.1 mo (95% CI: 2.8, 4.9) and mOS was 14.8mo (95% CI: 12.7, 21.3). In bTMB >= 16 vs<16, mPFS was 5.0 vs 3.5 mo and mOS was 23.9 vs 13.4 mo (Table). For CRP ratio <0.5 vs >=0.5, mPFS was 14.1 vs 4.6 mo (HR, 0.43 [90% CI: 0.24, 0.77]), and mOS was NE vs 15.9 mo (HR, 0.30 [90% CI: 0.13, 0.72]). 14% of pts had treatment-related (TR) serious AEs, and 20% had Gr 3-4 TRAEs. 18% of pts had AEs that led to discontinuation.
Conclusion(s): B-F1RST shows the clinical utility of bTMB as a predictive biomarker for pts receiving 1L atezo monotherapy. The final analysis confirmed that pts with bTMB >= 16 had numerical benefit for PFS and OS. Decrease in serum CRP over 6 wk predicted PFS and OS benefit. No new safety signals were seen. (Table Presented)

OBJECTIVES/OBJECTIVE:Despite improved outcomes associated with immunotherapies for non-small cell lung cancer (NSCLC), many patients do not respond to treatment. Therefore, there is still an unmet need for molecularly targeted therapies in this patient population. Fusions of the RET oncogene have been identified as driver alterations in patients with NSCLC. Lenvatinib is a multityrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, RET, and other targets. This study evaluated the safety and efficacy of lenvatinib in patients with RET fusion-positive lung adenocarcinoma. MATERIALS AND METHODS/METHODS:In this phase 2, multicenter, open-label study (NCT01877083), patients with RET-positive lung adenocarcinoma received oral lenvatinib 24 mg/day. The primary end point was objective response rate (ORR) by investigator review per Response Evaluation Criteria In Solid Tumors v1.1 criteria. The secondary end points included safety and tolerability, progression-free survival (PFS), and overall survival (OS). RESULTS:Of 536 patients who screened for study inclusion and exclusion, 25 patients with RET translocations (KIF5B-RET [n = 13] and CCDC6-RET [n = 12]) were identified and received lenvatinib. The overall ORR was 16% (95% CI: 4.5%-36.1%). At data cutoff (February 3, 2016), the median PFS was 7.3 months (95% CI: 3.6-10.2) and the median OS was not reached. Duration of response was not estimable at the time of data cutoff. All patients experienced a treatment-emergent adverse event (TEAE); 23 (92%) patients experienced a TEAE of ≥ grade 3, and 6 (24%) patients discontinued lenvatinib due to a TEAE. The most common TEAEs were hypertension (68%), nausea (60%), decreased appetite (52%), diarrhea (52%), and proteinuria (48%). CONCLUSIONS:Lenvatinib demonstrated activity in patients with RET fusion-positive lung adenocarcinomas; although the response rate was relatively low, the median PFS supports the activity of lenvatinib in these patients.

OBJECTIVE:The use of a neoadjuvant chemoradiation followed by surgery in patients with stage IIIA NSCLC is controversial and the benefit of surgery is limited. There are currently no clinically validated biomarkers to select patients for such an approach. In this study we evaluate computed tomography (CT) derived intratumoral and peritumoral texture and nodule shape features in their ability to predict major pathological response (MPR). MPR being defined as ≤10% of residual viable tumor, assessed at the time of surgery. MATERIAL AND METHODS/METHODS:Ninety patients with stage III NSCLC treated with chemoradiation prior to surgical resection were selected. The patients were divided randomly into two equal sets, one for training and one for independent testing. The radiomic texture and shape features were extracted from within the nodule (intra) and from the parenchymal regions immediately surrounding the nodule (peritumoral). A univariate regression analysis was performed on the image and clinicopathologic variables and then included into a multivariable logistic regression (MLR) for binary outcome prediction of MPR. The radiomic signature risk-score was generated by using a multivariate Cox regression model and association of the signature with OS and DFS was also evaluated. RESULTS:Thirteen stable and predictive intratumoral and peritumoral radiomic texture features were found to be predictive of MPR. The MLR classifier yielded an AUC of 0.90 ± 0.025 within the training set and a corresponding AUC = 0.86 in prediction of MPR within the test set. The radiomic signature was also significantly associated with OS (HR = 11.18, 95% CI = 3.17, 44.1; p-value = 0.008) and DFS (HR = 2.78, 95% CI = 1.11, 4.12; p-value = 0.0042) in the testing set. CONCLUSION/CONCLUSIONS:Texture features extracted within and around the lung tumor on CT images appears to be associated with the likelihood of MPR, OS and DFS to chemoradiation.

PURPOSE/OBJECTIVE:To determine the tumor tissue/cell distribution, functional associations and clinical significance of PD-1, LAG-3 and TIM-3 in human non-small-cell lung cancer (NSCLC). EXPERIMENTAL DESIGN/METHODS:Using multiplexed quantitative immunofluorescence (QIF) we measured CD3, PD-1, LAG-3 and TIM-3 in >800 NSCLCs from three tissuemicroarray-based cohorts. Associations between markers and tumor genomics were studied in TCGA-NSCLC dataset. Using mass-cytometry (CyTOF) analysis from 20 resected NSCLCs, we determined the levels, co-expression and functional profile of PD-1, LAG-3 and TIM-3 expressing immune cells. Finally, we measured the markers in 90 NSCLCs from patients treated with PD-1 axis blockers. RESULTS:PD-1, LAG-3 and TIM-3 were detected in TILs from 55%, 41.5% and 25.3% of cases, respectively. These markers showed association with each other, but not with clinicopathologic variables and survival in cases without immunotherapy. The markers were lower in EGFR-mutated adenocarcinomas and partially associated with tumor-mutational burden. In single-cell CyTOF analysis, PD-1 and LAG-3 were predominantly localized on T/NKT-cells; while TIM-3 was higher in NK-cells and macrophages. Co-expression of PD-1,LAG-3 and TIM-3 was associated with T-cell activation, effector function and proliferation, but also with pro-apoptotic markers. LAG-3 and TIM-3 were present in TILs lacking PD-1 and elevated baseline LAG-3 was associated with shorter progression-free survival after PD-1 axis blockade. CONCLUSIONS:PD-1, LAG-3 and TIM-3 have distinct tissue/cell distribution, functional implications and genomic correlates in NSCLC. Expression of these receptors is associated with activation, but also with pro-apoptotic T-cell phenotype. Elevated LAG-3 is associated with insensitivity to PD-1 blockade suggesting independence of these immune evasion pathways.

PURPOSE/OBJECTIVE:Despite high tumor mutation burden, immune checkpoint blockade has limited efficacy in small cell lung cancer (SCLC). We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibition could render SCLC more susceptible to immune checkpoint blockade. METHODS:Single-arm, phase II trial (NCT02484404) enrolled relapsed SCLC patients who received durvalumab 1500 mg q 4 weeks and olaparib 300 mg BID. The primary outcome was objective response rate (ORR). Correlative studies included mandatory pre and on-treatment biopsies which were assessed to define SCLC immune-phenotypes: desert (CD8+ T cell prevalence low), excluded (CD8+ T cells in stroma immediately adjacent/within tumor) or inflamed (CD8+ T cells in direct contact with tumor). RESULTS:Twenty patients enrolled. The median age was 64 years and most patients (60%) had platinum-resistant/refractory disease. Of 19 evaluable patients, confirmed partial or complete responses were observed in 2 patients (10.5%), including a patient with EGFR-transformed SCLC. Clinical benefit was observed in four (21.1%; 95% CI: 6.1-45.6%) patients with confirmed responses or prolonged stable disease (8 months+). Most common treatment-related adverse events were anemia (80%), lymphopenia (60%), and leucopenia (50%). Nine of 14 (64%) tumors exhibited an excluded phenotype; 21% and 14% of tumors exhibited inflamed and desert phenotypes, respectively. Tumor responses were observed in all instances when pretreatment tumors showed an inflamed phenotype. Of the five tumors without an inflamed phenotype at baseline, no on-treatment increase in T-cell infiltration or PD-L1 expression on tumor infiltrating immune cells was observed. CONCLUSIONS:The combination did not meet the preset bar for efficacy. Pre- and on-treatment biopsies suggest that tumor-immune phenotypes may be relevant for SCLC responses to immune checkpoint blockade combinations. The predictive value of pre-existing CD8+ T-cell infiltrates observed in this study needs to be confirmed in larger cohorts.

Aim: To determine real-world time on treatment (rwToT) with first-line pembrolizumab monotherapy for metastatic non-small-cell lung cancer (NSCLC) with programmed death ligand-1 (PD-L1) tumor proportion score (TPS) ≥50%. Methods: The Kaplan-Meier rwToT was estimated from electronic health record data for adults who initiated first-line pembrolizumab monotherapy for stage IV, PD-L1 TPS ≥50% NSCLC, with negative/unknown EGFR/ALK aberrations, and ≥6 months' follow-up until database cutoff. Results: A total of 386 patients with ECOG 0-1 had a median rwToT of 6.9 months (95% CI: 5.6-8.3) and 12-month on-treatment rate of 36.4% (31.2-41.6) versus 40.3% (32.5-47.9) and 37.6% (31.9-43.4) in KEYNOTE-024 (KN024) and KN042 (stage IV/TPS ≥50% subpopulation), respectively. The 24-month restricted-mean rwTOT (extrapolated) was 10.5 months (9.4-11.7), versus 11.0 (9.5-12.5) and 10.4 (9.3-11.5) in KN024 and KN042, respectively. Conclusion: First-line pembrolizumab monotherapy rwToT in metastatic PD-L1 TPS ≥50% NSCLC for trial-matched patients is similar to treatment duration in KN024 and KN042.

Modulating T cell homeostatic mechanisms with checkpoint blockade can efficiently promote endogenous anti-tumor T cell responses^1-11. However, many patients still do not benefit from checkpoint blockade¹², highlighting the need for targeting of alternative immune pathways¹³. Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) is an attractive target for immunotherapy, owing to its capacity to promote effector T cell (T_eff) functions^14,15 and hamper regulatory T cell (T_reg) suppression^16-20. On the basis of the potent preclinical anti-tumor activity of agonist anti-GITR antibodies, reported by us and others^16,21,22, we initiated the first in-human phase 1 trial of GITR agonism with the anti-GITR antibody TRX518 ( NCT01239134 ). Here, we report the safety profile and immune effects of TRX518 monotherapy in patients with advanced cancer and provide mechanistic preclinical evidence to rationally combine GITR agonism with checkpoint blockade in future clinical trials. We demonstrate that TRX518 reduces circulating and intratumoral T_reg cells to similar extents, providing an easily assessable biomarker of anti-GITR activity. Despite T_reg reductions and increased T_eff:T_reg ratios, substantial clinical responses were not seen. Similarly, in mice with advanced tumors, GITR agonism was not sufficient to activate cytolytic T cells due to persistent exhaustion. We demonstrate that T cell reinvigoration with PD-1 blockade can overcome resistance of advanced tumors to anti-GITR monotherapy. These findings led us to start investigating TRX518 with PD-1 pathway blockade in patients with advanced refractory tumors ( NCT02628574 ).

Even in diffuse large B-cell lymphoma (DLBCL), a cancer of professional antigen-presenting cells, response rates to immune checkpoint blockade therapy have been limited. One reason for DLBCL immune evasion is epigenetic repression instead of activation of the antigen-presenting MHC-a dissection of mechanisms underlying this repression suggests an opening for restoring B-cell maturation and, along the way, MHC expression as a novel modality of cytoreducing DLBCL and simultaneously augmenting possibilities for immunotherapy.See related article by Ennishi et al., p. 546.