BackgroundMRx0518 is a novel, human gut microbiome-derived, single-strain, live biotherapeutic in clinical development for treatment of solid tumours. Preclinically, MRx0518 induced broad ...immunostimulatory activity and demonstrated anti-tumorigenic effects in a range of murine tumor models. MRx0518 increased CD4+ and CD8+ T cell and NK cell tumor infiltration and decreased Tregs. Activation of tumour TLR5 was observed and linked to the bacterial flagellin moiety, which was shown to strongly induce NFκB, cytokine responses and IFNγ+ CD4+ and CD8+ T cells.MethodsHeavily pre-treated patients refractory to ICIs were enrolled from March 2019 to March 2020. Patients had experienced at least SD from previous ICI (monotherapy or combination) but eventually progressed as confirmed by two radiological scans ≥4 weeks apart in the absence of rapid clinical progression and within 12 weeks of last dose of ICI. Patients were treated with 1 capsule of MRx0518 (1 × 1010 to 1 × 1011 CFU) BID and pembrolizumab (200 mg every 3 weeks) for up to 35 cycles or disease progression. Tumour response was assessed every 9 weeks per RECIST 1.1. The primary objective was to evaluate safety of the combination by monitoring toxicities in the first cycle of treatment. Secondary objectives were to evaluate efficacy via ORR, DOR, DCR and PFS.ResultsIn Part A, patients with mRCC (n=9) and mNSCLC (n=3) were recruited. At data cut-off (21 Aug 20), 5 patients remain on study treatment. 83% of patients were male and 17% were female. Median number of prior lines of therapy was 3. 10 patients received nivolumab previously (83%), one received avelumab (8%) and one received pembrolizumab and nivolumab (8%). 83% of patients had experienced SD as best response to prior ICI and 17% had PR as best response. Of 6 patients with available PD-L1 results, 5 had a positive CPS/TPS (≥1) and 1 negative (<1). The combination shows a positive safety profile with no treatment-related SAEs or toxicity-related drug discontinuations. No increase in irAEs has been reported.On study treatment, 2 RCC patients and 1 NSCLC patient experienced a PR, with an additional 2 RCC patients experiencing durable SD (6 and 13 months), a protocol defined DCR of 42%. Median PFS is 2.14 months at data cut-off (table 1).Abstract 283 Table 1Summary of RECIST v1.1 response dataConclusionsThis data represents first-in-class proof of concept for a live biotherapeutic in an oncology setting. The combination was tolerable and there were preliminary signals of efficacy. Part B (phase II) in NSCLC, RCC and bladder cancer is ongoing.Trial Registration www.clinicaltrials.gov NCT03637803Ethics ApprovalThis study was approved by University of Texas MD Anderson’s Institutional Review Board; approval ref. 2018-0290
The VEGF pathway has been recognized as a key mediator of angiogenesis to support tumorigenesis. Multiple therapeutic agents targeting VEGF and VEGF receptors have been developed and approved for use ...in NSCLCs. Preclinical studies have found that the VEGF and EGFR pathways share common downstream signaling, and these pathways can function exclusively of one another during oncogenesis. In EGFR-mutant NSCLCs, up-regulated EGFR signaling increases VEGF through hypoxia-independent mechanisms, and elevated VEGF, in turn, contributes to the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs). In clinical trials, the addition of anti-VEGF therapy to EGFR TKIs considerably improved clinical outcomes. In recently reported large randomized studies, the addition of bevacizumab or ramucirumab to EGFR TKIs substantially improved progression-free survival in patients with TKI-naive EGFR-mutant NSCLC. This article reviews the preclinical and clinical data supporting dual inhibition of EGFR and VEGF in EGFR-mutant NSCLC as a way to improve patient outcomes.
Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and ...metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently "normalize" tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
MET exon 14 skipping alterations (METex14) represent one of the newest discovered driver oncogene alterations for non‐small cell lung cancer (NSCLC), which serve to define a distinct elderly patient ...population. New challenges in detection and treatment have emerged.
In the last 15 years, the successes of tumor molecular profiling and therapeutic stratification in patients with advanced‐stage disease have made NSCLC a poster child in the era of precision medicine. Each of the oncogenic drivers defines a distinct patient population. The selection of treatments based on oncogenic drivers such as EGFR, ALK, and ROS1, among others, has been transformative in terms of the duration and quality of life for patients with NSCLC receiving effective inhibitors. METex14 have emerged as one of the newest additions of driver oncogenes for NSCLC.
This commentary evaluates the evidence that established MET exon 14 skipping as an actionable driver oncogene in NSCLC, the unique patient population defined by MET exon 14 skipping alterations, and the clinical challenges to care for this elderly patient population.
BackgroundTumor and nodal downstaging following neoadjuvant therapy in resectable non-small cell lung cancer (NSCLC) are important markers of therapeutic response associated with favorable prognosis. ...We studied the impact of four different systemic neoadjuvant therapies on tumor, nodal and overall pathological downstaging of surgically resectable I-IIIA NSCLC (AJCC 7th edition).MethodsOur study cohorts consisted of NSCLC patients treated with three cycles of neoadjuvant platinum doublet chemotherapy from 2001–2012 (N=302, 84%), and patients treated on the NEOSTAR study (NCT03158129) who received neoadjuvant nivolumab (N=21,6%), nivolumab plus ipilimumab (N=16, 4%), or platinum doublet chemotherapy plus nivolumab (N=22, 6%). Clinical and pathological (yp) T and N staging were evaluated for downstaging and upstaging; differences were assessed using Fisher’s exact test.ResultsFollowing neoadjuvant platinum doublet chemotherapy, nivolumab, nivolumab plus ipilimumab and platinum doublet chemotherapy plus nivolumab, the rates of clinical-to-pathological ypT downstaging were 26% (N=79), 29% (N=6), 38% (N=6) and 59% (N=13), respectively, p =0.012 (table 1). The rates of clinical-to-pathological ypN downstaging in patients with clinical N1 or N2 disease with each therapy were 55% (N=96), 50% (N=3), 50% (N=2), and 42% (N=5) respectively, p =0.862. Overall clinical-to-pathological (ypT and/or ypN) downstaging rates were 38% (N=114), 38% (N=8), 38% (N=6), and 68% (N=15) respectively, p=0.048. The proportions of patients being overall upstaged following each therapy were 28% (N=85), 38% (N=8), 38% (N=6) and 14% (N=3), respectively, p=0.251. These results suggest superior downstaging effect and clinically meaningful lower upstaging probability of combined platinum doublet chemotherapy plus nivolumab as compared to other neoadjuvant regimens.Abstract 277 Table 1Response to Chemotherapy, Immunotherapy, and Combination TherapyConclusionsThe combination of neoadjuvant platinum doublet chemotherapy with nivolumab achieves the most robust tumor and overall pathological downstaging and decreases the probability of upstaging at surgery. Whether the overall downstaging effect results in improved survival will be determined with longer follow-up, in conjunction with results from ongoing phase III neoadjuvant chemo-immunotherapy trials.Trial RegistrationNCT03158129Ethics ApprovalThis study was approved by the University of Texas MD Anderson Institutional Review Board with a waiver of informed consent, protocol 2020-0337.
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Background: Chemotherapy is the current standard of care for pts with EGFR-mutant NSCLC whose tumor develops EGFR TKI resistance. We are conducting a real-world study to understand resistance ...mechanisms to EGFR TKI and outcomes with subsequent therapies (targeted and non-targeted). Here we report outcome results for standard of care given after resistance to a first-line (1L) EGFR TKI. Methods: This is a non-interventional descriptive cohort study using electronic medical record data and biomarker data from the United States TEMPUS database, which will continue until end of 2024 with new pts entering the study cohort over time. The study period for this reported analysis on real-world chemotherapy outcomes was any time until June 2022. Drug resistance was defined as disease progression on an EGFR TKI. Pts entering the study cohort were adult, with stage IIIB–IV NSCLC, had received an EGFR TKI either as a monotherapy or in combination with other systemic therapies, and had disease progression after EGFR TKI initiation. Pts were followed after tumor progression and from the initiation of a chemotherapy regimen, to describe treatment patterns and treatment outcomes (real-world progression-free survival rw-PFS and overall survival OS). Results: Of 21,425 pts with NSCLC, 1,087 patients were eligible for inclusion into the study cohort, with their stage IIIB–IV NSCLC diagnosis spanning from 1999 to 2021. A total of 588 pts (54.1%) received a 1L EGFR TKI and a subsequent second-line (2L) systemic therapy after disease progression. Of these, 100 pts received 2L chemotherapy regimens (platinum-based chemotherapy, n = 48; taxane monotherapy, n = 12; taxane + other chemotherapy, n = 3; pemetrexed, n = 28; other chemotherapy-only regimens, n = 9). Overall, these chemotherapy-treated pts had a median rw-PFS of 4.3 months (95% CI: 3.3, 5.1), and a median OS of 14.2 months (95% CI: 11.8, 22.2). Conclusions: Here, we show that after disease progression on a 1L EGFR TKI, patients had poor disease outcomes on 2L chemotherapy, indicating an unmet medical need as these pts likely developed EGFR TKI resistance. Treatment adaptation based on identified mechanism of resistance such as MET amplification, may improve outcomes for these patients.
First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) ...that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.
Uncommon EGFR mutations represent a rare subgroup of NSCLC. Data on the efficacy of different generations of tyrosine kinase inhibitors (TKIs) in these rare mutations are scattered and limited to ...mostly retrospective small cohorts because these patients were usually excluded from clinical trials. This was a systematic review on the efficacy of TKIs in patients harboring uncommon EGFR mutations, defined as mutations other than exon 20 insertions mutations or T790M. Response rates (RRs) for different generations of TKIs were determined for individual uncommon mutations, compound mutations, and according to classical-like and P-loop alpha helix compressing mutations classes. This study was conducted in accordance with the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 1836 patients from 38 studies were included in the final analysis. Most available data (92.6%) were from patients treated with first- or second-generation TKIs. G719X, S768I, E709X, L747X, and E709-T710delinsD showed RRs ranging from 47.8% to 72.3% to second-generation TKIs, generally higher than for first- or third-generation TKIs. L861Q mutation exhibited 75% (95% confidence interval CI: 56.6%–88.5%) RRs to third-generation TKIs. Compound mutations with G719X, E709X, or S768I consistently showed RRs above 50% to second- and third-generation TKIs, although fewer data were available for third generations. For classical-like mutations, RRs were 35.4% (95% CI: 27.2%–44.2%), 51.9% (95% CI: 44.4%–59.3%), and 67.9% (95% CI: 47.6%–84.1%) to first-, second-, and third-generation TKIs, whereas for P-loop alpha helix compressing mutations classes mutations, RRs were 37.2% (95% CI: 32.4%–42.1%), 59.6% (95% CI: 54.8%–64.3%), and 46.3% (95% CI: 32.6%–60.4%), respectively. This systematic review supports the use of second-generation TKI afatinib for G719X, S768I, E709X, and L747X mutations and for compound uncommon mutations. For other uncommon mutations such as L861Q, third-generation TKI, such as osimertinib, could also be considered, given its activity and toxicity profile.
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