Efficacy of anti-PD-1/PD-L1 antibody after discontinuation of antibody due to non-progressive disease in NSCLC Patients

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

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Monitoring immunotherapy response in non-small cell lung cancer patients using 5-hydroxymethylcytosine signatures in circulating cell free DNA.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e21505 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e21505-e21505

Author(s):

Gulfem Guler ◽

David Haan ◽

Yuhong Ning ◽

Jeremy Ku ◽

Erin McCarthy ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progressive Disease ◽

Small Cell ◽

Small Cell Lung ◽

Tumor Biopsy ◽

Lung Cancer Patients ◽

Free Dna ◽

Nsclc Patients

e21505 Background: Liquid biopsies are gaining prominence for not only cancer diagnosis but also patient monitoring. Mutational signals derived from cell-free DNA (cfDNA) show promise to assess response to cancer treatment, including immunotherapy. However, reliance of these methods on mutational data from tissue biopsies limit their applicability when a tumor biopsy is unavailable, or when mutational landscape of tumor changes under the selective pressures of cancer drug treatment. Epigenomic approaches have the potential to address these shortcomings. Methods: Blood draws were obtained from a cohort of non-small cell lung cancer (NSCLC) patients (n = 19) who went on to anti-PD1 treatment prior to therapy start and while on therapy. cfDNA was isolated from plasma and was subsequently processed to generate 5hmC genome-wide profiles. Results: We analyzed cfDNA from NSCLC patients undergoing anti-PD1 therapy to investigate whether immunotherapy response can be detected from plasma. Using a predictive model trained on lung cancer and non-cancer samples, we were able to detect changes in prediction scores in patient treated with immunotherapy that were consistent with RECIST. Patients with progressive disease (n = 3), determined by RECIST, had prediction scores that increased while they received treatment. On the other hand, majority of the patients that exhibited partial response to treatment (n = 12) had predictive scores that decreased with treatment, again consistent with RECIST. Furthermore, score changes consistent with RECIST was observed one cycle prior to the RECIST timepoint in all except one patient, where an extra blood draw after baseline was available (n = 7). Annotation of the regions that account for differential scoring identified enhancer, 5’UTR and promoter regions. Comparison of partial responders to patients with progressive disease revealed genes involved in metastasis, oncogenes and tumor suppressors that change in opposing directions between these patient groups, consistent with the underlying biology. Conclusions: Our results suggest that 5hmC profiles from cfDNA can be used to determine immunotherapy response in non-small cell lung cancer patients. Compared with mutation based liquid biopsy methods to assess response, epigenomics-based methods have the advantage of being agnostic to starting tumor mutations, and not relying on a mutational analysis from tumor biopsy. Future work will help determine applicability of this method to other kinds of therapies and cancer types.

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The value of local consolidative therapy in Osimertinib-treated non-small cell lung cancer with oligo-residual disease

10.21203/rs.3.rs-34341/v2 ◽

2020 ◽

Author(s):

Ya Zeng ◽

JianJiao Ni ◽

Fan Yu ◽

Yue Zhou ◽

Yang Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Treatment Failure ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progressive Disease ◽

Residual Disease ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients ◽

Residual Lesions

Abstract Background: There was no study investigating real-world utilization and outcome of LCT in Osimertinib-treated NSCLC with oligo-residual disease. This study was to analyze the clinical value of local consolidative therapy (LCT) in Osimertinib-treated non-small cell lung cancer (NSCLC) patients with oligo-residual disease. Methods: Patients receiving standard Osimertinib treatment and developing oligo-residual disease (ﬁve or fewer residual metastatic lesions) were retrospectively reviewed. Local therapies performed to the oligo-residual tumor lesions or primary lung site before Osimertinib treatment failure were considered as LCT. Results: Of 108 patients recruited, first-line and second-line Osimertinib were administered in 25 and 83 patients, respectively, while LCT was performed in 14 patients. With a median follow-up of 43.6 months, 69 patients developed progressive disease. LCT significantly improved progression-free survival (PFS) (NR vs 12.8 months, p=0.01) and was independently associated with prolonged PFS (HR=0.29, 95%CI 0.12 to 0.68, p=0.004). Patients receiving LCT had a numerically longer overall survival (OS) (85.8 vs 77.1 months, p=0.58) and after adjusting for potentially confounding factors, LCT was associated with a non-significantly prolonged OS (HR=0.37, 95%CI 0.12-1.16, p=0.089). Pattern of failure analyses indicated that progressive disease developed at the originally existed oligo-residual lesions in 76.2% of the 63 patients who didn’t receive LCT and had Osimertinib treatment failure. Of note, 7 (70%) of the 10 patients who had oligo-residual cranial disease but didn’t receive LCT, developed more than five progressive lesions in the brain, which were no longer suitable for stereotactic radiosurgery. Conclusion: Among Osimertinib-treated NSCLC patients having oligo-residual lesions, LCT could improve local control and significantly increase PFS, which need to be verified by further investigations.

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TRLS-03. Intracranial activity of tepotinib in patients with MET exon 14 (METex14) skipping NSCLC enrolled in VISION

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.021 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii5-iii6

Author(s):

Christine M Bestvina ◽

Xiuning Le ◽

Remi Veillon ◽

Ian Anderson ◽

Jyoti Patel ◽

...

Keyword(s):

Brain Metastases ◽

Disease Control ◽

Progressive Disease ◽

Ad Hoc ◽

Objective Response ◽

Response Assessment ◽

Complete Response ◽

Duration Of Response ◽

Nsclc Patients ◽

The Brain

Abstract Background Brain metastases (BMs) are reported in 20–40% patients with METex14 skipping NSCLC. Tepotinib, a highly selective MET inhibitor, has demonstrated an objective response rate (ORR) of 45% and median duration of response (mDOR) of 11.1 months, in METex14 skipping NSCLC patients in Cohort A of the Phase II VISION study. Here, we report the intracranial activity of tepotinib in Cohort A. Methods Patients received oral tepotinib 500 mg QD. Study eligibility allowed for patients with BM (asymptomatic and symptomatic/stable). Primary endpoint: systemic objective response (RECIST v1.1); subgroup analysis in patients with BM (RECIST v1.1) was predefined. An ad hoc retrospective analysis of brain lesions (by CT/MRI) was conducted by an IRC using Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. Responses were determined in patients with ≥1 evaluable post-baseline tumor assessment. For non-measurable lesions (enhancing and non-enhancing non-target lesions [NTL]), disease control in the brain was defined as non-complete response/non-progressive disease. Data cut-off: July 1, 2020. Results Twenty-three patients had baseline BM. Systemic efficacy in patients with BM (ORR 47.8% [95% CI: 26.8, 69.4]; mDOR 9.5 months [95% CI: 5.5, not estimable]) was consistent with the overall population. Fifteen patients were evaluable by RANO-BM; 12 received prior radiotherapy for BM (median 6.4 weeks before treatment). Systemic best objective responses (BORs) were partial response (PR, n=9), stable disease (SD, n=3), and progressive disease (PD; n=3). Of seven patients with measurable CNS disease (all of whom received prior radiotherapy), intracranial BORs were PR (n=5), SD (n=1), and PD (n=1). For patients with NTL only (n=8), one had PD, and seven achieved intracranial disease control with three patients achieving CR of the enhancing NTL. Conclusions Tepotinib demonstrated intracranial activity in patients with METex14 skipping NSCLC with BM. Prospective evaluation of intracranial activity in VISION Cohort C is ongoing.

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Survival versus intrinsic and acquired resistance in advanced non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e19066 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e19066-e19066 ◽

Cited By ~ 1

Author(s):

David J. Stewart ◽

Pierre Saintigny ◽

Glenwood D. Goss ◽

Charles Lu

Keyword(s):

Progressive Disease ◽

Advanced Nsclc ◽

Acquired Resistance ◽

Resistance Pattern ◽

Time To Progression ◽

Incremental Change ◽

Clinical Resistance ◽

Resistance Patterns ◽

Nsclc Patients ◽

Serial Measurements

e19066 Background: While advanced NSCLC responds to platinum-based therapy (PBT), intrinsic and acquired resistance limits efficacy. We assessed impact of resistance patterns on overall survival (OS). Methods: Using serial measurements of tumor diameters from 130 NSCLC patients on PBT, we calculated % incremental change in tumor size compared to the most recent prior scan and % overall change from pre PBT. Results: 98/130 (75%) had measurable tumor shrinkage (TS) at 1st repeat scan (RS) post 2 cycles, of whom 81 had a 2nd RS post 4 cycles. Of these, 20 (25%) had tumor growth (TG) at the 2nd RS. Only 1 had initial TG then followed by TS. Of 41 with a 3rd RS <4 weeks post cycle 6, 13/41 (32%) had TG. The greatest % incremental TS (compared to most recent prior scan) was seen early (at 1st RS) for 76% of patients. Rate of TS decreased with later cycles in these patients. 11 patients had rapid TS on 1st RS, then gradual further shrinkage over >3 subsequent scans, while 15 had progressive gradual TS over >4 scans without initial rapid TS. By Spearman coefficients, maximum % TS from pre PBT over all scans correlated with OS (r=0.46, p<0.0001), time to progression (TTP) (r=0.69, p<0.0001) and post-progression survival (PPS) (r=0.30, p=0.001). TTP also correlated with OS (r=0.63, p<0.0001), TTP correlated with PPS (r=0.44, p<0.0001), and OS correlated with PPS (r=0.95, p<0.0001). Median OS (11.0 months for all patients) varied with TS pattern (p<0.0001): OS for patients with first TG at 1st, 2nd, 3rd and 4th RS was 5.9, 10.8, 10.5 and 15.1 months. OS was 18.2 months in patients with most TS at 1st RS followed by gradual further TS over later scans, and was 30.5 months with progressive gradual TS without rapid TS at 1st RS. OS with RECIST partial response (23% of patients), minor TS (52%), minor TG (13%) and RECIST progressive disease (13%) was 16.9, 12.4, 9.8 and 4.0 months (p<0.0001). Conclusions: OS, TTP and PPS correlate strongly with response (degree of TS/TG) and with resistance pattern. OS is longest with progressive further TS over multiple scans. Within this group, partial acquired resistance (decreased TS rate after initial rapid TS) has shorter OS than with sustained incremental TS. The underlying biological factors driving clinical resistance remain undefined.

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Predictive factors for combined anti-PD-1 and anti-angiogenic therapy in multiline treatment of advanced non-small cell lung cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15059 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15059-e15059

Author(s):

Yina Wang ◽

Xiaobin Li ◽

Yao Chen ◽

Mingyan Xu ◽

Lele Song

Keyword(s):

Lung Cancer ◽

Clinical Efficacy ◽

Clinical Benefit ◽

Progressive Disease ◽

Combined Therapy ◽

Second Line ◽

Angiogenic Therapy ◽

Or Gene ◽

Nsclc Patients ◽

Combined Immunotherapy

e15059 Background: Immune checkpoint inhibitors (ICIs), such as PD-1/ PD-L1 inhibitors, have made a significant breakthrough in lung cancer first-line treatment. However, there are few reports on stratification, therapeutic response and prognosis prediction of NSCLC patients treated with immunotherapy combined with anti-angiogenic therapy in multiline therapy. The aim of this study was to investigate the clinical efficacy of anti-PD-1 plus anti-angiogenic therapy in the second-line or multiline treatment of NSCLC, and to explore potential predictive biomarkers for response and prognosis in this combined therapy. Methods: A total of 22 advanced NSCLC patients were recruited in this study, in which 14 patients received this combined immunotherapy as second-line therapy, and 8 patients as multiline therapy. Genomic profiles were determined with blood by a 451-gene next-generation sequencing panel. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: All patients were followed up until progression or the end of this study. The objective response rate (ORR) assessed by an independent radiology review was 22.7%, and the median progression-free survival (PFS) time for all patients was 5.25 months. Surprisingly, the pre-therapeutic blood tumor mutation burden (bTMB) could not discriminate clinical benefit from non-benefit group in this combined therapy (P = 0.167). However, we found that the concentration of pre-therapeutic blood circulating free DNA (cfDNA) was an independent predictor of PFS (HR = 27.75, P = 0.003), in which higher cfDNA concentration correlated with poorer outcomes. Meanwhile, patients harboring MIKI67 gene mutations or gene variations related to hyper-progressive disease showed significantly shorter PFS time (p < 0.05). In addition, patients with negative ctDNA before therapy might benefit more from this combined immunotherapy (P = 0.068). Conclusions: Our study suggested that the combined strategies may improve clinical efficacy of ICIs in second and multiline therapy. The pre-therapeutic bTMB was not predictive for clinical benefit in multiline combined therapy. Patients with pre-therapeutic high concentration of cfDNA, MIKI67 mutations or gene variations related to hyper-progressive disease may be less likely to benefit from the combined therapy. Our findings may improve the prediction of therapeutic effect and prognosis in future combined treatment involving immunotherapy.

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Monitoring of peripheral lymphocyte and neutrophil counts to predict efficacy of nivolumab (nivo).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20583 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20583-e20583 ◽

Cited By ~ 1

Author(s):

Yosuke Kawashima ◽

Shingo Nishikawa ◽

Ryo Ariyasu ◽

Junji Koyama ◽

Masafumi Saiki ◽

...

Keyword(s):

Peripheral Blood ◽

Progressive Disease ◽

Overall Response Rate ◽

Response Rate ◽

Test Results ◽

Reactive Protein ◽

Blood Tests ◽

Programmed Death ◽

Programmed Death 1 ◽

Nsclc Patients

e20583 Background: Programmed death-1 (PD-1) antibody is a key drug for treating non-small cell lung cancer (NSCLC), but the response rate is about 20% in non-selected populations and efficacy is difficult to predict. We examined correlations between peripheral blood tests, including counts of lymphocytes (Lym), neutrophils (Neu), and C-reactive protein (CRP), and the efficacy of nivolumab (nivo) monotherapy. Methods: Eighty NSCLC patients treated with nivo (3mg/kg every 2 weeks) in our hospital between December 2015 and September 2016 were evaluated. Peripheral blood tests on day (d) 0 (the day before 1st nivo), d15 (the day of 2nd nivo), d29 (the day of 3rdnivo) were evaluated. Absolute counts and the change ratio (%) of Lym, Neu and CRP from baseline (d0) were calculated. Response to nivo was evaluated according to RECIST v1.1. Results: Response to nivo was partial response in 23 cases, stable disease in 13 and progressive disease (PD) in 44 patients (overall response rate, 28%; disease control rate, 45%). Absolute counts of Lym, Neu and CRP at baseline did not differ significantly between non-PD and PD (Lym, 1323/µl vs. 1376/µl; Neu, 4830/µl vs. 5189/µl; CRP, 3.48 mg/dl vs. 3.38 mg/dl). Neu was significantly increased from baseline to d15 and d29 in the PD population compared with the non-PD population (δNeu (d15): 25.2% vs. -6.3%, P= 0.008; δNeu (d29): 16.7% vs. -8.6%, P= 0.006). CRP was also significantly increased from baseline to d29 in the PD population compared with the non-PD population (δCRP: 60.1% vs. -21.2%, P= 0.010). In contrast, Lym was significantly increased from baseline to d29 in the non-PD population compared with the PD population (δLym: 9.6% vs. –6.7%, P= 0.010). Conclusions: Changes in peripheral blood test results after nivo differed between non-PD and PD populations. Monitoring of Neu and Lym and CRP may allow prediction of the efficacy of nivo.

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The value of local consolidative therapy in Osimertinib-treated non-small cell lung cancer with oligo-residual disease

Radiation Oncology ◽

10.1186/s13014-020-01651-y ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Ya Zeng ◽

Jianjiao Ni ◽

Fan Yu ◽

Yue Zhou ◽

Yang Zhao ◽

...

Keyword(s):

Lung Cancer ◽

Treatment Failure ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progressive Disease ◽

Residual Disease ◽

Small Cell ◽

Small Cell Lung ◽

Nsclc Patients ◽

Residual Lesions

Abstract Background There was no study investigating real-world utilization and outcome of LCT in Osimertinib-treated NSCLC with oligo-residual disease. This study was to analyze the clinical value of local consolidative therapy (LCT) in Osimertinib-treated non-small cell lung cancer (NSCLC) patients with oligo-residual disease. Methods Patients receiving standard Osimertinib treatment and developing oligo-residual disease (five or fewer residual metastatic lesions) were retrospectively reviewed. Local therapies performed to the oligo-residual tumor lesions or primary lung site before Osimertinib treatment failure were considered as LCT. Results Of 108 patients recruited, first-line and second-line Osimertinib were administered in 25 and 83 patients, respectively, while LCT was performed in 14 patients. With a median follow-up of 43.6 months, 69 patients developed progressive disease. LCT significantly improved progression-free survival (PFS) (NR vs 12.8 months, p = 0.01) and was independently associated with prolonged PFS (HR = 0.29, 95%CI 0.12 to 0.68, p = 0.004). Patients receiving LCT had a numerically longer overall survival (OS) (85.8 vs 77.1 months, p = 0.58) and after adjusting for potentially confounding factors, LCT was associated with a non-significantly prolonged OS (HR = 0.37, 95%CI 0.12–1.16, p = 0.089). Pattern of failure analyses indicated that progressive disease developed at the originally existed oligo-residual lesions in 76.2% of the 63 patients who didn’t receive LCT and had Osimertinib treatment failure. Of note, 7 (70%) of the 10 patients who had oligo-residual cranial disease but didn’t receive LCT, developed more than five progressive lesions in the brain, which were no longer suitable for stereotactic radiosurgery. Conclusion Among Osimertinib-treated NSCLC patients having oligo-residual lesions, LCT could improve local control and significantly increase PFS, which need to be verified by further investigations.

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