Background Relapsed/refractory pediatric acute lymphoblastic leukemia (ALL) poses a substantial therapeutic challenge. This is especially true in children with multiple central nervous system (CNS)/combined relapses that have been through radiation and bone marrow transplant (BMT) with no curative options left. We previously reported complete remissions (CR) and prolonged persistence of engineered T cells in children with ALL treated with CTL019 (CD19 CAR T cells). We now report on outcomes of 12 children with prior CNS relapse, isolated or combined with bone marrow (BM) relapse, treated with CTL019. Objectives Establish the safety and efficacy of CTL019 for children with a history of CNS relapse of CD19+ ALL. In all patients, establish the frequency and magnitude of CTL019 trafficking to CNS. Design We identified ALL pts who had an isolated CNS or combined BM/CNS relapse as their indication for CTL019 therapy. CNS relapse was defined as CNS3 by lumbar puncture (≥ 5 WBC/uL with blasts present on cytospin), or brain/ocular involvement by imaging. Treatment for the CNS relapse prior to CTL019 was determined by the local treating physician. All pts had to be CNS1 (no blasts) or CNS2 (<5 WBC/uL with blasts on cytospin) at the time of infusion and all pts with ocular involvement had to undergo focal radiation with evidence of response. Post-infusion, pts had diagnostic lumbar punctures (LP) done at D28, and months 3, 6, 9, and 12. Pts received no CNS directed therapy post-infusion other than CTL019. Results Of 53 pts with CD19+ ALL infused with CTL019, 12 had a CNS3 status 1-12 months prior to infusion (median 4 months). Seven had an isolated CNS relapse and 5 were combined BM/CNS. Three pts with CNS involvement by LP also had ocular involvement and 2 had parenchymal changes on brain MRI. All 12 pts had prior CNS directed radiation and 11/12 had undergone a prior BMT. Patients ranged from a 2nd to a 6th relapse pre-CTL019: one 1st, six 2nd, three 3rd and 2 with 4+ CNS relapses. One day prior to infusion, 4 pts (2 with prior CNS, 2 with no prior CNS ALL) had blasts detected in the CSF (CNS2a). All pts were CNS1 on day 28 post infusion, and none have recurred in the CNS. 47 pts (89%) had at least 1 CSF sample evaluated by PCR. 46/47 (98%) of the initial (D28) CSF samples showed high levels of gene marking indicating CTL019 cells, ranging from 1530 to 252,356 copies/ug genomic DNA. Persistence in the CSF was similar to that seen in peripheral blood and bone marrow. Of the 46 pts with CTL019 cells in the CSF, 42 (91%) had cells detected by PCR at their most recent CSF sampling. This included all patients (9/9 pts; 2177 to 15,727 copies by PCR) whose final CSF sample was obtained per protocol at month 12. 8/9 of these pts remain in remission. Encephalopathy, a known side effect of CTL019 therapy, was not increased in pts with a prior CNS relapse. Grade 2-3 encephalopathy was observed in 3/12 (25%) of pts with prior CNS relapse and 12/41 (29%) of non-CNS pts. Grade 2-4 seizure occurred in 4 pts (1 with history of CNS relapse as well as prior seizure). Eight of the 12 CNS pts (67%) remain in a continual CR 3 - 22 months post infusion (median 8 months). Four pts had recurrent BM disease and were CNS negative at subsequent relapse. The patient with the 6th CNS relapse of Ph+ ALL remains in a CR 22 months post infusion. To date none of the 53 pts, regardless of site of prior relapse, has had a subsequent CNS relapse. Conclusion Single agent CTL019 immunotherapy can induce potent and durable responses in pts with CNS involvement of their relapsed/refractory ALL. Neurotoxicity does not appear to be enhanced in CNS pts, who tolerated therapy equally well. Due to this promising data, a cohort designed for patients who are CNS3 at time of infusion is now enrolling to further assess safety and efficacy in this setting. The unexpected trafficking and durable persistence of CAR T cells to CSF after intravenous infusion may enable treatment of other CNS malignancies. Disclosures Rheingold: Endo: Other: Husband's employer, has equity interest; Novartis: Consultancy. Off Label Use: CTL019 is not yet FDA approved for therapy for ALL. Maude:Novartis: Consultancy, Research Funding. Aplenc:Sigma Tau: Consultancy. Lacey:Novartis: Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. Melenhorst:Novartis: Research Funding. Shaw:Novartis: Research Funding. Teachey:Novartis: Research Funding. June:University of Pennsylvania: Patents & Royalties: financial interests due to intellectual property and patents in the field of cell and gene therapy. Conflicts of interest are managed in accordance with University of Pennsylvania policy and oversight; Novartis: Research Funding. Grupp:Novartis: Consultancy, Research Funding.
The advent of immune checkpoint inhibition has pushed the treatment paradigm for resectable non-small-cell lung cancer (NSCLC) toward neoadjuvant therapy. A growing number of promising trials have examined the utility of neoadjuvant immunotherapy, both alone and in combination with other modalities such as radiation therapy (RT) and chemotherapy. The phase II LCMC3 and NEOSTAR trials demonstrated a role for neoadjuvant immunotherapy in inducing meaningful pathologic responses, and another phase II trial established the feasibility of combining neoadjuvant durvalumab with RT. Significant interest in neoadjuvant chemoimmunotherapy resulted in the conduct of multiple successful phase II trials including the Columbia trial, NADIM, SAKK 16/14, and NADIM II. Across these trials, neoadjuvant chemoimmunotherapy led to high rates of pathologic response and improved surgical outcomes without compromising surgical timing or feasibility. CheckMate-816, which was a randomized phase III trial studying neoadjuvant nivolumab in addition to chemotherapy, definitively established a benefit for neoadjuvant chemoimmunotherapy compared to chemotherapy alone for resectable NSCLC. Despite the growing literature and success of these trials, several outstanding questions remain, including the relationship between pathologic response and patient survival, the role of biomarkers such as programmed death ligand 1 and circulating tumor DNA in determining patient selection and treatment course, and the utility of additional adjuvant therapies. Longer follow-up of CheckMate-816 and other ongoing phase III trials may help address these questions. Ultimately, the complexity of managing resectable NSCLC highlights the importance of a multidisciplinary approach to patient care.
e20593 Background: Epidermal growth factor receptor-mutated [ EGFR(+)] NSCLC has historically been associated with young, non-smoking patients, especially those of Asian descent. Our medical center serves a diverse population within New York City and includes patients from neighborhoods that are predominantly Hispanic/Latino. We therefore sought to describe the population of patients with EGFR(+) NSCLC treated at our cancer center. Methods: We used our single institution lung cancer database to identify 2092 patients diagnosed with NSCLC between 2013-2019; of these, 375 had EGFR(+) disease. We collected retrospective data on patient demographics and disease outcomes. The chi-square test and t-tests were performed to compare between subgroups of patients. Results: Between 2013-2019, 17.9% of patients diagnosed with NSCLC at our center had an identified EGFR mutation. Incidence of EGFR mutations was higher in Asian NSCLC patients (46.7%) compared to Black (13.1%), white (16.8%), and Hispanic (16.0%) NSCLC patients. Within the 375 patients diagnosed with EGFR(+) NSCLC, however, the distribution was 62.1% white (233 patients), 13.6% Asian (51 patients), 11.2% Hispanic (42 patients), 8.3% Black (31 patients), and 4.8% unknown/other race (18 patients). Over half (57.7%) of patients with EGFR(+) NSCLC had a history of smoking, and most (68.9%) were female. Median age at diagnosis was 71 years. Frequency of tyrosine kinase inhibitor (TKI)-sensitive mutations (L858R and exon 19 deletion) was 85.7% in Hispanic patients, 91.7% in Asian patients, 76.4% in white patients, and 71.0% in Black patients. Significantly more Hispanic EGFR(+) patients were diagnosed at Stage IV (65.4%) compared to 40.4% of Asian patients, 36.7% of Black patients, and 25.7% of white patients (p < 0.02 for all comparisons). Among patients diagnosed with Stage IV disease, Hispanic patients had worse average survival compared to non-Hispanic patients (19.4 months vs. 27.9 months, p = 0.01). Conclusions: EGFR-mutant NSCLC is thought to be especially common among patients who are younger, Asian, and/or never smokers. Our population of EGFR(+) NSCLC, however, encompasses a racially diverse group of patients, most of whom were older at the time of diagnosis and many of whom had a history of smoking. This population of patients, most of whom harbor a TKI-sensitive mutation, supports the use of routine mutational testing that is agnostic to patient demographics. Our data also suggest that Hispanic patients in particular are diagnosed with more advanced disease and have shorter survival; the reasons for such disparities within the EGFR(+) NSCLC population warrant further study.
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