bluuebunny/crossref_metadata_2025 huggingface dataset:
Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma.
Authors: Kumar Shaji , Harrison Simon J. , Cavo Michele , de La Rubia Javier , Popat Rakesh , Gasparetto Cristina , Hungria Vania , Salwender Hans , Suzuki Kenshi , Kim Inho , Gay Francesca , Mikala Gabor , Punnoose Elizabeth , Hong Wan-Jen , Sood Anjla , Jalaluddin Muhammad , Ross Jeremy A. , Pauff James M , Maciag Paulo Cesar , Moreau Philippe
Published: May 2020

8509

Background: Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor. In the Phase 3 BELLINI trial, addition of Ven to bortezomib (B) + dexamethasone (d) significantly improved response rates and progression-free survival (PFS) vs placebo (Pbo) and showed significant efficacy in patients (pts) with either t(11;14) or BCL2high gene expression. Here we present updated safety and efficacy data from the prespecified second interim overall survival (OS) analysis. Methods: In this multicenter, randomized, double-blind study (NCT02755597), pts with relapsed/refractory multiple myeloma (RRMM) with 1-3 prior lines of therapy were randomized 2:1 to Ven (800 mg) or Pbo in combination with B (1.3 mg/m2) and d (20 mg). The primary endpoint was PFS; key secondary endpoints included overall response and overall survival (OS). Results: 291 pts were randomized; 194 to Ven, 97 to Pbo. Pt characteristics were well balanced among arms. In the Ven arm, median age was 66, 17% had high-risk cytogenetics, 11% had t(11;14), and 34% had BCL2high gene expression. As of 13 Sept 2019, 59 pts were still on study, 45 (23%) Ven vs 14 (14%) Pbo. At a median follow-up of 28.6 months, there were 64 (33%) deaths in the Ven arm vs 24 (25%) in Pbo. At the initial data cutoff (26 Nov 2018), PFS HR was 0.63 (0.44,0.90) and OS HR was 2.03 (1.04,3.95). Table shows updated PFS and OS. Most common treatment-emergent adverse events (TEAEs) with Ven were diarrhea (59%), nausea (37%), and constipation (35%). Most common grade 3/4 AEs (Ven/Pbo) were neutropenia (21%/8%), thrombocytopenia (15%/30%), anemia (16%/15%), diarrhea (15%/12%), and pneumonia (18%/13%). Serious AEs occurred in 54% Ven and 52% Pbo pts. 24% discontinued Ven due to AEs vs 12% Pbo. There were 14 treatment-emergent deaths in the Ven arm and 1 in Pbo. Conclusions: The addition of Ven to Bd significantly improves PFS but resulted in increased mortality vs Pbo in the total population. Greatest PFS improvement with Ven was observed in pts with t(11;14) or BCL2high gene expression, where Ven shows a favorable benefit-risk profile. The study continues for final OS analysis. Clinical trial information: NCT02755597 . [Table: see text]
Once weekly selinexor, carfilzomib, and dexamethasone (SKd) in patients with relapsed/refractory multiple myeloma (MM).
Authors: Gasparetto Cristina , Lipe Brea , Tuchman Sascha , Callander Natalie Scott , Lentzsch Suzanne , Baljevic Muhamed , Rossi Adriana C. , Bahlis Nizar J. , White Darell , Chen Christine , Sutherland Heather J , Kotb Rami , LeBlanc Richard , Sebag Michael , Venner Christopher P , Bensinger William , Sheehan Heidi , Ju Yawen , Kai Kazuharu , Schiller Gary J.
Published: May 2020

8530

Background: Selinexor is a novel, first-in-class selective inhibitor of nuclear export (SINE), which blocks exportin 1 (XPO1), forcing the nuclear retention and activation of tumor suppressor proteins. Selinexor in combination with low dose dexamethasone (Sel-dex) was approved by the FDA, based on data from the STORM study wherein Sel-dex induced an overall response rate (ORR) of 26.2% in patients (pts) with refractory MM. We hypothesize that once weekly (QW) SKd may be an active well tolerated regimen and evaluated this combination in a dose escalation/expansion study. Methods: STOMP is a phase 1b/2 study evaluating various doses and enrolled pts with carfilzomib naive relapsed MM. Oral selinexor was dosed QW at 80 or 100 mg. Carfilzomib was dosed QW (on days 1, 8 and 15 of 28-day cycle) at 56 mg/m2 or 70 mg/m2. Dexamethasone was dosed at 40 mg QW. The primary objectives of the study are to assess the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), as well as explore the efficacy and safety of SKd. Results: As of January 2020, 18 pts were enrolled. Median age was 71 years (range: 50-76). Median number of prior regimens was 4 (range: 1-8). All pts (n = 18) were previously treated with bortezomib and lenalidomide, and 50% and 56% pts were refractory to bortezomib and lenalidomide respectively. Nine (50%) pts received prior pomalidomide treatment and 8 (44%) pts were refractory. Eleven (61%) pts received prior daratumumab treatment and 9 (50%) were refractory. The MTD was selinexor 80 mg QW, carfilzomib 56 mg/m2 QW and dexamethasone 40 mg QW. The ORR and CBR were 72% and 79% respectively with 4 complete responses, 7 very good partial responses, 2 partial responses, and 1 minimal response. Stable disease was observed in 3 pts. With a median follow-up period of 4.7 (1.8-16.3) months, median progression-free survival has not been reached. Common treatment-related adverse events (total, Grade ≥3) were thrombocytopenia (83.3%, 66.7%), nausea (66.7%, 0%), anemia (55.6%, 11.1%), fatigue (50%, 11.1%), anorexia (44%, 5.6%), weight loss (44%, 0%), and neutropenia (33.3%, 11.1%). Conclusions: Once weekly SKd demonstrated an encouraging ORR of 72% in pts with a median of 4 lines of prior therapy. The majority of responses are deep and predominantly CR and VGPR. The combination is well tolerated with no new safety signal, no Grade ≥3 nausea, vomiting, diarrhea, weight loss or anorexia. The side effects are a function of the dose and schedule and can be managed with dose modification and supportive care. Enrolment is ongoing and supports a phase 3 study of SKd. Clinical trial information: NCT02343042 .
Oncolytic virus pelareorep plus carfilzomib phase I trial in carfilzomib-refractory patients (NCI 9603): Responses with cytokine storm.
Authors: Sborov Douglas Weston , Viola Domenico , Dona Ada A , Nooka Ajay K. , Kaufman Jonathan L. , Lonial Sagar , Boise Lawrence , Dhodapkar Madhav V. , Joseph Nisha , Pichiorri Flavia , Hofmeister Craig C.
Published: May 2020

8535

Background: Viral oncolytic therapy with intravenous Pelareorep, the infusible form of reovirus, is supported by preclinical data indicating that its antitumor activity results from direct cytolysis and an immune response against infected MM cells. Our preclinical data has shown that monocytes serve as carriers of reovirus from the peripheral blood to the bone marrow (Dona et al, ASH, 2019). In this abstract we present patients treated to date that were Carfilzomib refractory at enrollment. Methods: Pelareorep (P), Carfilzomib (K), and dexamethasone (d) were all infused on days 1, 2, 8, 9, 15 and 16 of a 28-day cycle. Patients were pretreated with dexamethasone 20 mg intravenously, then Carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1, and 56 mg/m2 thereafter. Pelareorep dose levels were at 3x1010, 4.5*1010, and planned 9*1010 median tissue culture infectious dose (TCID50). Results: All 6 evaluable patients showed reovirus infection in the post-treatment marrow aspirates cycle 1 day 9. Despite all patients having Carfilzomib-refractory disease, 2 patients achieved partial responses, two patients with short duration stable disease but few side effects, and 2 patients with PD. Of the two responders, one patient developed fever and grade 4 thrombocytopenia during cycle 1 and withdrew mid cycle. The other patient with a PR developed a cytokine storm - this patient presented cycle 1 day 3 hypoxemic with pneumonia, systolic failure (LVEF 69%-- > 26%), with biochemical evidence of hemophagocytic syndrome with elevated IL-2R, IL-6, and ferritin > 25K. This patient responded to tocilizumab, but ultimately died two weeks later with sepsis. Autopsy revealed pneumonia, no areas of reovirus infection other than in myeloma cells, and reovirus productive infection in 5-35% of myeloma cells (i.e. capsid protein). Conclusions: While infection of myeloma cells was seen in all evaluable patients on cycle 1 day 9, those with a clinical response demonstrated concomitant CD8 & NK cell recruitment, PD L1 upregulation, activated caspase-3 expression, increased viral protein production within the myeloma cells, and these patients demonstrated mild to severe signs and symptoms consistent with secondary HLH. This is the first report of cytokine storm after oncolytic virus in a patient with a blood cancer, a syndrome thought to be related to T-cell activation from the combination treatment. This trial was supported by the NCI Division of Cancer Treatment & Diagnosis Cancer Therapy Evaluation Program (CTEP). Clinical trial information: NCT02101944 .
FDA analysis: Impact of BMI on efficacy outcomes in multiple myeloma trials.
Authors: Ershler Rachel , Fernandes Laura L , Kanapuru Bindu , Gwise Thomas , Kluetz Paul Gustav , Theoret Marc Robert , Gormley Nicole , Pazdur Richard
Published: May 2020

8543

Background: Obesity has been implicated as a risk factor for the development of certain types of cancers, including multiple myeloma. Previous studies in other tumor types suggest that overweight subjects may have better outcomes, however, in relapsed/refractory multiple myeloma (RRMM), it is unknown whether body weight affects outcomes to therapy. Methods: We conducted a retrospective analysis of 13 RRMM clinical trials submitted to the FDA between 2012-2018. Patients were divided into four groups, underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5- < 25 kg/m2), overweight (BMI 25.0- < 30 kg/m2) and obese (BMI > 30.0 kg/m2). A multivariate analysis for progression free survival (PFS) and overall survival (OS), stratified by study and adjusted for age, cytogenetic risk group (Standard, High, Unknown), immunoglobin subtype (IgG Y/N), ECOG status (0-1, > 1, UNK), sex (M/F) was used to estimate the HR. Results: A total of 5898 patients were included in this analysis. The median age was 65 years (range 30-91 years). A total of 87(1.5%) patients were underweight, 1853 (31%) were normal weight, 2212 (38%) were overweight, 1332 (23%) were obese, and 414 (7%) had missing BMI. The results of the multivariate analysis of PFS and OS are shown in the Table. Conclusions: Exploratory analysis of patients with RRMM found that patients who were overweight and obese had a trend towards slightly improved PFS and OS when compared to normal weight patients. Similar trends were observed in the analyses of overall response rate and BMI (not presented in the abstract). These results are consistent with previous studies in other malignancies. Limitations include the lack of adjustment for multiple testing, the small sample of patients in the underweight category, and heterogeneity in the treatment regimens and PFS assessments in the clinical trials included in the analysis. Future studies are needed to evaluate safety and impact of treatment regimens on efficacy outcome measures based on body weight. [Table: see text]
Sporadic late-onset nemaline myopathy with monoclonal paraprotein as a malignancy rather than disimmunity and treatment with chemotherapy-based approach.
Authors: Kotchetkov Rouslan , Susman David , Buadi Francis , Dispenzieri Angela
Published: May 2020

8545

Background: A subset of sporadic late-onset nemaline myopathy (SLONM) associated with monoclonal gammopathy of undetermined significance (MGUS) has more aggressive course, often fatal. Whether SLONM+MGUS is a malignancy or dysimmunity is unclear. Two approaches are used to treat SLONM+MGUS: 1) immunosuppression (IS) ± plasmapheresis/exchange; 2) chemotherapy (ChT) ± autologous stem cell transplantation (ASCT). Due to the rare occurrence of the disease the best treatment modality is not known. Methods: We conducted a literature search to identify previous treatment for patients with SLONM+MGUS using PubMed, Elsevier, Medline, and CINAHL databases from 1975 to 2019. All publications were carefully reviewed to remove “duplicate” patients. Overall, 28 reports were included for the final analysis. Results: 38 unique patients with SLONM+MGUS received either IS (n = 19) or ChT ± ASCT (n = 19). The median age was 48 years [24-75]. In the IT group 74% (n = 14) were males vs 53% (n = 10) in the ChT group. All patients had IgG monoclonal protein (MP): kappa in 57% (n = 11) in the IT, 42% (n = 8) in the ChT group. In the IT group MP values were 0.42 & 0.2 g/L (n = 2); in the ChT group median MP was 2.7 g/L [0.1-14, n = 14]. In the IT group 84% (n = 16) received steroids, 26% (n = 5) plasmapheresis, 53% (n = 10) non-steroid immunosuppressants, 11% (n = 2) rituximab, and 53% (n = 10) IVIG. Six patients (32%) had one IT modality; 13 (68%) had 2 or 3. In the ChT group 10 patients (53%) had ASCT; 6 patients (31%) had CyBorD or Lenalidomide+Dexamethasone + ASCT; 3 patients (16%) had chemotherapy without ASCT. 10 patients in IT group had neurological improvement (NI): 53% overall response (OR) with 16% (n = 3) complete remission (CR), and 37% (n = 7) partial response (PR). No improvement/progression had 9 patients (47%). In 2 patients (10%), neurological CR was associated with resolution of MP. Mean time to best response was 19 months. In ChT group 18 patients achieved NI: 94.7% OR with CR in 73.7% (n = 14) and PR in 21.0% (n = 4). Only one patient had no response to therapy. The best NI correlated with resolution of MP. Mean time to best response was 10 months. Conclusions: Our study with the most extensive cohort of patients with SLOMN+MGUS supports ChT ± consolidative ASCT aimed at complete elimination of the malignant plasma cell clone as the preferred treatment. Superior clinical benefits of ChT suggest that the presence of MP has clinical rather than undetermined significance, and SLOAN + MP should be considered as a malignancy rather than dysimmunity.
Phase II study of pembrolizumab (pembro) plus platinum doublet chemotherapy and radiotherapy as first-line therapy for unresectable, locally advanced stage III NSCLC: KEYNOTE-799.
Authors: Jabbour Salma K. , Lee Ki Hyeong , Frost Nicolaj , Kowalski Dariusz , Breder Valeriy Vladimirovich , Pollock Theodore , Reguart Noemi , Houghton Baerin , Quantin Xavier , Keller Steven M. , Liu Hong , Piperdi Bilal , Reck Martin
Published: May 2020

9008

Background: KEYNOTE-799 (NCT03631784) evaluates pembro plus concurrent chemoradiation therapy (CCRT) in pts with unresectable, locally advanced stage III NSCLC. Methods: In this phase 2, nonrandomized, open-label trial, pts with previously untreated, unresectable, pathologically confirmed stage IIIA–C NSCLC with measurable disease (RECIST 1.1) received up to 17 cycles of pembro 200 mg Q3W starting with cycle 1 plus standard thoracic radiotherapy (60 Gy in 30 daily 2-Gy fractions) in cycles 2–3 and investigator’s choice of paclitaxel 200 mg/m2 + carboplatin AUC 6 Q3W for cycle 1, then paclitaxel 45 mg/m2 + carboplatin AUC 2 QW for cycles 2–3 (cohort A), or cisplatin 75 mg/m2 + pemetrexed 500 mg/m2 Q3W (nonsquamous only) in cycles 1–3 (cohort B). Primary endpoints were ORR (CR/PR per RECIST 1.1 by blinded independent central review) and rate of grade ≥3 pneumonitis (per NCI CTCAE v4.0). CIs were estimated using the Clopper-Pearson method. Safety was assessed in all treated patients; efficacy was assessed in pts with ≥15 wks follow-up. Results: As of Jan 3, 2020, 112 and 73 pts have been enrolled in cohorts A and B, respectively; 63 in cohort A and 52 in cohort B continue on treatment. Median (range) follow up was 8.3 (0.7–14.0) mo in cohort A and 5.8 (0.2–13.7) mo in cohort B. ORR (90% CI) was 67.0% (58.9%–74.3%) in cohort A and 56.6% (44.4%–68.2%) in cohort B (Table). Grade ≥3 pneumonitis occurred in 9 pts (8.0%; 90% CI, 4.3%–13.6%) in cohort A and 4 pts (5.5%; 90% CI, 1.9%–12.1%) in cohort B. Treatment-related grade ≥3 AEs occurred in 72 pts (64.3%) in cohort A and 30 pts (41.1%) in cohort B. 4 pts had treatment-related grade 5 pneumonitis (all in cohort A). Enrollment is complete for cohort A and ongoing in cohort B. Conclusions: Pembro plus CCRT shows promising antitumor activity in pts with unresectable, locally advanced stage III NSCLC. Toxicity was as anticipated with pembro plus CCRT. Clinical trial information: NCT03631784. [Table: see text]
Molecular subtypes and clinical outcomes to initial systemic treatment in patients with small cell lung cancer.
Authors: Lai Wei-Chu Victoria , Egger Jacklynn V. , Rizvi Hira , Richards Allison L. , Beras Amanda , Baine Marina K. , Hsieh Min-Shu , Chang Jason C. , Rekhtman Natasha , Plodkowski Andrew J. , Ginsberg Michelle S. , Kris Mark G. , Hellmann Matthew David , Sen Triparna , Poirier John T. , Rudin Charles M.
Published: May 2020

9018

Background: Investigators have proposed that differential expression of the transcription regulators ASCL1 and NeuroD1 can be used to define molecular subtypes of small cell lung cancers (SCLCs). Here we evaluate SCLC subtypes based on ASCL1 and NeuroD1 expression in patients (pts) treated with first-line (1L) chemotherapy profiled with targeted next-generation sequencing (NGS). Methods: We used NGS (MSK-IMPACT) to profile tumors from pts with SCLCs. We performed IHC to assess ASCL1 (A) or NeuroD1 (N). Objective response rate (ORR) to therapy was determined using RECIST. PFS and OS were analyzed using Kaplan-Meier. Results: 281 pts with SCLCs were profiled with NGS (102 LS-SCLC; 179 ES-SCLC). Most frequently mutated genes were TP53 (90%), RB1 (68%), KMT2D (22%), NOTCH1 (15%), FAT1 (14%), PTPRD (12%). Mutations in BIRC3, FOXL2, TENT5C, TET1, NRAS, KIT, TSHR, ESR1 were enriched in ASCL1-/NeuroD1+ (A-/N+), and mutations in KMT2D and EP300 were enriched in A-/N- (p<0.05). Copy number alterations in WWTR1, ATR, IKZF1, PALB2, PIK3CB were enriched in A-/N+ (p<0.05). IHC for ASCL1 and NeuroD1 was performed on 78 samples: 11 A-/N-, 32 A+/N-, 4 A-/N+, 31 A+/N+. Overall survival at 1 year based on subtype was 25% in A-/N- (2/9), 60% in A-/N+ or A+/N- (13/32), and 55% in A+/N+ (10/25). For the 10 pts who survived 2 years, 5 were A+/N- and 5 were A+/N+. 146 pts treated with 1L platinum had RECIST-evaluable disease. ORR was 75% (110/146; 95% CI 68-82%). Median PFS was 7 months with CR/PR and 3.5 months with SD/PD (HR 0.32; 95% CI 0.18-0.56). Median OS was 17 months with CR/PR and 11 months with SD/PD (HR 0.55; 95% CI 0.34-0.9). Mutations in RUNX1, EPHA7, CDKN2A, FLT1 and copy number alterations in FGFR1, CCND1 were enriched in patients with SD/PD (p<0.05). PFS rate at 6 months was 25% in A-N- (1/4), 60% in A-/N+ or A+/N- (9/15), and 55% in A+/N+ (6/11). For the 7 pts who survived 2 years, 3 were A+/N- and 4 were A+/N+. Conclusions: Molecular subtypes defined by ASCL1 and NeuroD1 encompass molecular characteristics that may predict patient outcomes. Further investigation is needed to delineate the underlying biological differences among the various subtypes to help define therapeutic vulnerabilities of each subtype of SCLC. Completion of IHC for ASCL1, NeuroD1 and additional key transcription factors POU2F3 and YAP1 are in progress for the entire cohort. WES and RNA sequencing are occurring in parallel and will be correlated with IHC results and clinical outcomes.
Base excision repair (BER) inhibitor TRC 102 (Methoxyamine) combined with pemetrexed (PEM)-based chemo-radiation (CRT) for locally advanced non-squamous non-small cell lung cancer (NS-NSCLC): Results of a phase I trial.
Authors: Biswas Tithi , Dowlati Afshin , Kunos Charles , Pink John , Oleinick Nancy , Malik Shakun M. , Fu Pingfu , Bruno Debora S. , Bajor David Lawrence , Patel Monaliben , Machtay Mitchell
Published: May 2020

9027

Background: About 35% of all NSCLC presents with locally advanced disease and chemo-radiation results in 5-year OS of only ~31%. PEM-platinum combination is approved in stage IV NSCLC and has similar efficacy to platinum-etoposide in stage 3 NSCLC and a favorable toxicity profile (Proclaim trial). TRC102 is an oral small molecule inhibitor of BER. TRC102 potentiates the cytotoxicity of antimetabolites and alkylators and reverses chemotherapy resistance by rapidly and covalently binding to chemotherapy-induced abasic sites in DNA. TRC102 increased radio-sensitization by PEM of NSCLC cell lines and H1299 and A549 xenografts. Methods: Between 11/2015 and 5/2019, 15 patients were enrolled in a 3+ 3 design: 12 with stage III and 3 with oligometastatic stage IV NS-NSCLC. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D) of TRC102 in combination with PEM, cisplatin and radiotherapy. Secondary objectives were to assess toxicity, tumor response and PFS at 6 months. Based on pre-clinical data, PEM-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated on day 21 and day 23 of the second cycle. After completion of radiotherapy, two additional cycles of PEM-cisplatin were given. Toxicities were assessed by NCI CTACAE version 4 and 5. Results: Median patient age was 69 years (45-79) and median follow up was 16.6 months (3.1-38.6). There were no DLTs or grade 5 toxicity. Hematologic and GI toxicities were the most common adverse events (Table) and radiation pneumonitis was not seen. The RP2D of TRC102 was 200 mg when given with cisplatin/radiotherapy and PEM. Of 15 evaluable patients, 3 had CR (20%) and 12 had PR (80%). The 2-year PFS rate was 49%. Conclusions: PEM-TRC102 combined with cisplatin/radiotherapy in non-squamous NSCLC was safe and well tolerated, and did not cause safety signals beyond those expected from CRT. Preliminary response data and PFS in this cohort was encouraging. A phase 2 trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen is warranted. Clinical trial information: NCT02535325. [Table: see text]
Outcomes of patients with stage III non-small cell lung cancer (NSCLC) that harbor a STK11 mutation.
Authors: An Josiah , Yan Melissa , Yu Nanmeng , Chennamadhavuni Adithya , Furqan Muhammad , Kruser Timothy , Sita Timothy L , Nguyen Ryan , Feldman Lawrence Eric , Pasquinelli Mary , Hanna Nasser H. , Abu Hejleh Taher
Published: May 2020

9033

Background: STK11 mutation ( STK11m) in patients with stage IV NSCLC is associated with inferior survival and poor response to immune check point inhibitors (ICI). The significance of STK11m in patients (pts) with stage III NSCLC treated with concurrent chemoradiation (CCRT) with and without consolidation ICI is unknown. Methods: Patient demographics, disease characteristics, treatment received and outcomes in pts with stage III NSCLC that harbor STK11m were retrospectively reviewed from 4 cancer centers. A cohort of pts with stage III NSCLC and wild type STK11 (STK11w) from the University of Iowa served as a comparison group. SPSS version 25 was used for data analysis. Results: 75 pts with stage III NSCLC who had gene sequencing were included. 16/75 (21%) had STK11m. The clinical characteristics for the 16 STK11m and 59 STK11w pts showed ( STK11m vs. STK11w): mean age: 58 vs. 64 yrs, non-squamous histology: 11/16 (69%) vs. 37/59 (63%), KRAS co-mutation: 6/16 (38%) vs. 11/59 (19%), TP53 co-mutation: 9/16 (56%) vs. 15/59 (25%), PD-L1 ≥ 50%: 2/16 (13%) vs. 10/59 (17%), received CCRT 11/16 (69%) vs. 59/59 (100%) and consolidation ICI 6/16 (38%) vs. 17/59 (29%). Regarding the 6 STK11m pts who received ICI (4 pembrolizumab, 2 durvalumab), the median number of ICI infusions was 8 (range, 3-17) vs. 7 (range, 1-25) in the 17 pts with STK11w who received ICI (durvalumab). Progression free survival (PFS) for the STK11m vs. STK11w pts who received CCRT but not ICI was (4.2 vs. 34.3 months, respectively. P = 0.168), for the STK11m vs. STK11w pts who received CCRT and ICI was (11.3 vs. 17.5 months, respectively. P = 0.174), and for the STK11m vs. STK11w pts who received CCRT regardless of receiving ICI (11.3 vs. 32.9 months, respectively. P = 0.021). The median overall survival for STK11m pts (16 pts) was 25.5 months (95% CI, 13.7 to 37.2) while not yet reached for the STK11w group. Conclusions: In stage III NSCLC, STK11m was associated with inferior clinical outcomes. Larger studies are needed to identify the prognostic implications of STK11m in stage III NSCLC and whether ICI impacts survival for this subgroup.
Real-world treatment patterns and clinical outcomes in EGFR-mutant unresectable locally advanced NSCLC (LA-NSCLC): A retrospective multicenter study of 367 patients.
Authors: Bi Nan , Wang Luhua , Xu Kunpeng , Ge Hong , E Mingyan , Zhang Li , Cao Jianzhong , Zhang Xu , Xia Bing , Zhao Lujun , Li Jiancheng , Hu Chen
Published: May 2020

9047

Background: The chemoradiation therapy (CRT) is the standard care for unresectable LA-NSCLC. The addition of EGFR-TKIs in first-line treatment of EGFR-mutant subpopulation is debatable. Methods: We retrospectively collected data for patients with unresectable stage III NSCLC harboring EGFR mutations from nine major academic cancer institutions in China from Jan 2012 to December 2018. Patients with ALK rearrangements were excluded. Patients were categorized into three subgroups according to the primary treatment: 1) RT+TKI: Combined RT and EGFR-TKI with/out chemotherapy; 2) no TKI: CRT alone; 3) upfront TKI: EGFR-TKI followed by RT at local-regional progression. PFS and OS were calculated from the date of diagnosis. Log-rank test was used to assess for differences and Cox proportional hazards model was used to adjust for covariates. Results: A total of 367 patients met selection criteria were included in the study. Patients receiving TKI were older (≥60 years: 54.7% TKI v 36.4% and RT+TKI 33.3% CRT; P = 0.001), and more patients receiving CRT had uncommon EGFR mutations ( 10.3% CRT v 2.3% RT+TKI and 4.0% TKI; P = 0.020). Other baseline characteristics were well balanced among groups. With a median follow-up of 40.8 months, the median PFS and OS were 16.6 and 55.4 months for the entire cohort. The median PFS and OS for the three subgroups were shown in the table. On multivariable analysis, after adjusting for age, KPS status, smoking status, stage, and type of EGFR mutations, TKI+RT was independently associated with improved PFS (HR, 0.57; 95% CI, 0.41 to 0.78 ) and OS (HR, 0.61; 95% CI, 0.39 to 0.97) relative to upfront TKI; TKI+RT was also associated with improved PFS (HR, 0.38; 95% CI, 0.27 to 0.54 ) relative to CRT, but not OS (HR, 0.66; 95% CI, 0.40 to 1.11). Conclusions: The use of upfront EGFR-TKI with deferred RT at progression was associated with inferior OS in patients with EGFR-mutant unresectable LA-NSCLC. First-line use of radiotherapy and EGFR-TKI was associated with the longest PFS and OS, which requires further prospective, randomized evaluation. [Table: see text]
The impact of residual metabolic primary tumor volume after completion of thoracic irradiation in patients with inoperable stage III NSCLC.
Authors: Roengvoraphoj Olarn , Gjika Arteda , Mille Erik , Taugner Julian , Käsmann Lukas , Eze Chukwuka , Belka Claus , Manapov Farkhad
Published: May 2020

9049

Background: The metabolic tumor volume (MTV) is a functional and volumetric PET/CT parameter that has been investigated in recent years with respect to its predictive and prognostic value in different tumor entities. In this study, we investigated the role of residual MTV after completion of thoracic irradiation in inoperable stage III non-small cell lung cancer (NSCLC). Methods: We analyzed retrospective and prospective data of 56 patients with inoperable stage III NSCLC treated with chemoradiotherapy (CRT) and chemoradioimmunotherapy (CRT-IO). All patients received an 18F-FDG-PET/CT 3 to max. 6 months after completion of thoracic irradiation. The measurement of the residual MTV of the primary tumor was performed by calculating the SUVmean of the liver + 2SD as threshold. The patients were divided into the following groups: residual-MTV < 1ml; residual-MTV 1-25ml and residual-MTV > 26ml. Survival, local recurrence, and distant metastasis rates were calculated using the Kaplan-Meier method from the last day of thoracic irradiation. Results: The median follow-up was 45 months (range 16-74) in the CRT group and 16 months in the CRT-IO group (range13-19). Twenty-two (39%) patients had a residual MTV < 1ml (1st group), 19 (34%) a residual MTV between 1-25ml (2nd group) and 15 (27%) a residual MTV > 25ml (3rd group) after completion of thoracic irradiation. Median overall survival was 61, 20 and 12 months (p = 0.006) in the 1st, 2nd and 3rd groups, respectively. 12-month survival was 86%, 50% and 33% after CRT vs. 88%, 71% and 50% after CRT-IO in the 1st, 2nd and 3rd groups, respectively. The median time to in-field recurrence in the 1st, 2nd and 3rd groups was 51, 20 and 15 months (p = 0.011). The prognostic value of the residual MTV on OS was confirmed exclusively in the CRT patient cohort (p = 0.04), but not in the CRT-IO patient cohort (p = 0.174). Residual MTV demonstrated no influence on the local recurrence rate in the CRT-IO patient cohort, but only in patients treated with CRT (p = 0.007). Conclusions: Patients with inoperable stage III NSCLC in whom the residual MTV was < 1ml after completion of thoracic irradiation showed significantly better survival than patients with a residual MTV of 1-25ml and MTV > 25ml. The subgroup analysis confirmed the prognostic value of residual MTV only in patients who received chemoradiotherapy without consolidation immunotherapy.
Neoadjuvant endobronchial delivery of gene mediated cytotoxic immunotherapy (GMCI) for non-small cell lung cancer (NSCLC): Safety and immunologic activity.
Authors: Aguilar Laura K. , Predina Jarrod D. , Haas Andrew , O'Brien Shaun , Moon Edmund K. , Martinez Marina , Corbett Christopher , Sulyok Lydia Frenzel , Bryski Mitchell G. , Eruslanov Evgeniy , Deshpande Charuhas , Guzik Brian W. , Manzanera Andrea G. , Aguilar-Cordova Estuardo , Singhal Sunil , Albelda Steven M.
Published: May 2020

9050

Background: GMCI is a tumor-specific immuno-oncology approach implemented through local delivery of aglatimagene besadenovec(AdV-tk) followed by anti-herpetic prodrug. This leads to immunogenic tumor cell death, antigen presenting cell activation, and T cell stimulation resulting in CD8+ T cell dependent protection, as demonstrated in preclinical models and clinical trials in other tumor types. This is the first study to assess endobronchial delivery of AdV-tk for NSCLC. Methods: This Phase I dose escalation trial enrolled patients with suspected NSCLC who were candidates for surgery. A single AdV-tk injection was performed by endobronchial ultrasound (n = 11) or mediastinoscopy (n = 1) during the diagnostic staging procedure 3 weeks prior to surgery. Three dose levels were evaluated: 2.5x 1011, 5x1011, and 1x1012 vector particles (vp) in a 3+3 design. Valacyclovir was administered for 14 days, starting the day after AdV-tk injection. To assess the local and systemic effects of GMCI, immune biomarkers were evaluated in blood and tumor samples before and after GMCI. Results: From 2017-2019, 12 patients (9 men, 3 women, median age 65 [range 55-80]) received GMCI followed by surgery. Average tumor size was 5.1 cm (largest diameter) and final pathologic stage was I (n = 4), II (n = 3), and III (n = 5). Treatment-related adverse events were CTC grade 1 fever (n = 1), flu-like symptoms (n = 1) and nausea/vomiting/diarrhea (n = 1). The only > grade 2 lab abnormality was transient grade 3 lymphopenia (n = 2). A measurable reduction in tumor size was observed in one patient. The average amount of tumor necrosis was 29.4%. Significant infiltration of CD8+T cells (5.2-fold compared to baseline, p = 0.001) was found in tumor 19-22 days after AdV-tk injection. Within the CD8+tumor infiltrating lymphocytes, there was increased expression of CD38 (2.5-fold, p = 0.002), Ki67 (4.8-fold, p = 0.02), PD1 (1.9-fold, p = 0.002), CD39 (2.9-fold, p = 0.04) and CTLA-4 (4.8-fold, p < 0.001), without significant detected differences in Tim3 or TIGIT. Simultaneously, peripheral blood CD8+ cells displayed significant increases in CD38 (3.4-fold, p = 0.006), HLA-DR (4.2-fold, p = 0.002), and Ki67 (5.8-fold, p = 0.017). Conclusions: Intratumoral injection of AdV-tk into lung tumors was safe and feasible. Further, AdV-tk effectively induced peripheral blood and intra-tumoral CD8 T cell activation. Consequent upregulation of inhibitory receptors suggests a potential benefit for combination therapies. Clinical trial information: NCT03131037.
Phase I study of TRC102 in combination with cisplatin and pemetrexed in patients with advanced solid tumors/Phase II study of TRC102 with pemetrexed in patients with mesothelioma refractory to pemetrexed and cisplatin or carboplatin.
Authors: Koczywas Marianna , Frankel Paul Henry , Riess Jonathan W. , El-Khoueiry Anthony B. , Villaruz Liza C , Leong Stephen , Ruel Christopher , Synold Timothy W. , O'Connor Timothy , Newman Edward M.
Published: May 2020

9055

Background: Treatment options remain limited in malignant pleural mesothelioma refractory to pemetrexed +/- platinum. TRC102 (methoxyamine hydrochloride) is a novel biochemical inhibitor of the BER pathway. Available data support the hypothesis that TRC102 bound DNA is a substrate for topoisomerase II, which cleaves TRC102-bound DNA sites to produce strand breaks in cancer cells that cause cellular apoptosis and enhance the cytotoxic effects of chemotherapy. Methods: This was a parallel cohort trial of a Phase I of TRC102 in combination with cisplatin (CDDP) and pemetrexed in patients with advanced solid tumors (Arm A) and a Phase II of TRC102 with pemetrexed in patients with mesothelioma refractory to platinum and pemetrexed (Arm B). Results: In Arm A dose escalation, 16 pts (11M/5F) were treated; 9 evaluable through 3 TRC102 dose levels (50, 75, and 100 mg/day, PO), with CDDP 60 mg/m2 and pemetrexed 500 mg/m2 (levels 1- 3); and 5 evaluable at TRC102 100 mg/day PO, CDDP 75 mg/m2, pemetrexed 500 mg/m2 (level 4). Cycles were every 21 days. There were no DLT’s, establishing level 4 as the RP2D. The only grade 4 treatment-related AE was thrombocytopenia on cycle 22 (level 2). Cycle 1 grade 3 AEs were 1 hypophosphatemia (level 1) and 1 leukopenia (level 2). There were 3 PRs (all parotid salivary gland tumors). Median PFS (95%CI) = 7.1% (1.4 – 15.5) mos. Arm B was designed as the first stage of a two stage Gehan design trial of patients with mesothelioma who had progressed on or recurred within 6 months of pemetrexed + platinum frontline treatment. 14 pts were treated with TRC102 50 mg/day D1-4 and pemetrexed 500 mg/m2 every 21 days. There were 2 PRs (both in epithelioid cancer of which 1 was confirmed), meeting the pre-specified criteria for continued interest ( > 0/14). mPFS (95% CI) was 4.3 (1.4 - 6.8) mos. 8 pts had stable disease for at least 1 cycle (4 stable at cycles 6, 9, 10 and 12). There were 1 grade 4 neutropenia and 5 grade 3 AE’s (1 each – anemia, neutropenia, leukopenia, fatigue, hyponatremia). Conclusions: TRC102 in combination with CDDP and pemetrexed exhibited antitumor activity, particularly in salivary gland tumors, and a tolerable safety profile at the doses tested. The combination of TRC102 and pemetrexed demonstrated activity in malignant mesothelioma that progressed on prior pemetrexed. Additional studies are warranted to confirm preliminary signals of activity. Clinical trial information: NCT02535312.
Effect of anlotinib in advanced small cell lung cancer (SCLC) patients relapsed within three months after second-line treatment: A subgroup analysis from a randomized, double-blind phase II trial (ALTER 1202).
Authors: Shi Jianhua , Cheng Ying , Wang Qiming , Li Kai , Wu Lin , Han Baohui , Chen Gongyan , He Jianxing , Wang Jie , Qin Haifeng , Li Xiao-Ling
Published: May 2020

9063

Background: Anlotinib had significantly improved progress-free survival (PFS) and overall survival (OS) of advanced small cell lung cancer (SCLC) patients received at least two lines chemotherapy in the ALTER 1202 trial. Here, we reported the effect of anlotinib in advance SCLC patients relapsed within 3 months after second-line treatment. Methods: The ALTER 1202 was a randomized, double-blind phase 2 trial including patients with advanced SCLC that received at least two previous lines of chemotherapy. Eligible patients were randomized in a 2:1 ratio to receive either anlotinib or placebo until tumor progression or unacceptable toxicity. The subgroup analysis assessed the effect of anlotinib in patients relapsed within 3 months after second-line treatment. The primary outcome was PFS. The secondary outcomes were OS, objective response rate (ORR), disease control rate (DCR) and safety. This trial was registered with ClinicalTrials.gov, number NCT03059797. Results: In the ALTER1202 trial, 67 patients in anlotinib group and 34 patients in placebo group relapsed within 3 months after second-line treatment. Among them, the median PFS was 3.98 months (95% confidence interval [CI], 2.79 to 4.24) with anlotinib versus 0.72 months (95% CI, 0.69 to 0.82) with placebo (hazard ratio [HR], 0.14; 95% CI, 0.08 to 0.26; P < 0.0001). Meanwhile, anlotinib significantly prolonged OS compared with placebo (7.29 months [95% CI, 6.51 to 10.51] versus 4.37 months [95% CI, 2.33 to 6.47]; HR, 0.42 [95% CI, 0.23 to 0.74]; P = 0.0059) in patients relapsed within 3 months after second-line treatment. ORR was 4.48% (3 PR) for anlotinib and 2.94% (1 PR) for placebo (P = 0.708). DCR was 73.13% for anlotinib and 11.76% for placebo (P < 0.0001). The most common adverse events were hypertension (38.81%), anorexia (28.36%), fatigue (22.39%) and Elevation of alanine aminotransferase (17.91%). Conclusions: Anlotinib improved PFS and OS in advanced SCLC patients relapsed within 3 months after second-line treatment and was well tolerated.
Prevalence of autoimmune diseases in thymic epithelial tumors (TET) insights from RYTHMIC.
Authors: Benitez Jose Carlos , Boucher Marie Eve , Dansin Eric , Kerjouan Mallorie , Mazieres Julien , Pichon Eric , Thillays Francois , Falcoz Pierre-Emmanuel , Roch Benoit , Oulkhouir Youssef , Fabien Calcagno , Thiberville Luc , Clément Duchene Christelle , Morin Franck , Missy Pascale , Thomas Pascal Alexandre , Maury Jean-Michel , Molina Thierry , Girard Nicolas , Besse Benjamin
Published: May 2020

9073

Background: TET are associated with autoimmune disorders (AID) in up to 30% of patients (pts). However, there have been wide variations in the reported prevalence of AID in TET pts in small single-center series. RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a French network mandated to systematically discuss every case of TET. We aimed to describe the prevalence of AID in a large French population. Methods: RYTHMIC database, hosted by IFCT (Intergroupe Francophone de Cancérologie Thoracique), prospectively includes all consecutive pts with a diagnosis of TET discussed in French national or regional tumor boards. We analyzed epidemiologic, clinical and pathological characteristics of pts with TET’s related AID. Results: From January 2012 to December 2019, 2909 pts were included in the database. The mean age at diagnosis of TET was 54 and 52% were male. In the overall population, Masaoka Koga stages were well balanced with 12.6% (n = 187) stage I, 8.8% (n = 131) stage IIa, 8.4% (n = 124) stage IIb, 11.1% (n = 164) stage III and 8.5% (n = 125) stage IV. There were 364 (12.5%) events of AID in 302 pts. 62 pts (17%) had more than 1 AID. Among the events, 236 were myasthenia gravis (MG) (64.8%), 19 Hypo-gammaglobulinemia syndrome (5.2%), 15 pure red cell aplasia (4.1%), 18 thyroiditis (4.9%) and 16 systemic erythematous lupus (4.4%). Diagnosis of AID was mostly done at tumor diagnosis (n = 239, 65.7%) but some patient had AID diagnosed before diagnosis (n = 67, 18.4%) or during follow up (n = 32, 8.8%). Among pts presenting AID, B2 was the most common subtype (n = 133, 36.5%). The incidence of AID per subtype was as follow: A (n = 10/81, 12.3%), AB (n = 48/225, 21.3%), B1 (n = 35/130, 26.9%), B2 (n = 133/295, 45.0%), B3 (n = 46/113, 40.7%), thymic carcinoma (n = 16/275, 5.8%). Conclusions: The prevalence of AID in pts with TET was 12.5%, > 40% in B2 and B3 subtypes. Diagnosis of AID can be delayed compared to the diagnosis of TET. Immunotherapy indication should be carefully assessed in pts with TET other than thymic carcinoma.
Low-dose oral etoposide is an active option for patients with heavily pre-treated thymic epithelial tumors.
Authors: Ottaviano Margaret , Tortora Marianna , Giuliano Mario , Terracciano Daniela , Di Lauro Vincenzo , Picozzi Fernanda , Parola Sara , Riccio Vittorio , De Placido Pietro , Pietroluongo Erica , Liotti Antonietta , La Civita Evelina , Guggino Gianluca , Cicalese Marcellino , Curcio Carlo , Longo Michele , Botti Gerardo , Daniele Bruno , De Placido Sabino , Palmieri Giovannella
Published: May 2020

9074

Background: Platinum based regimens are used in the first line setting for advanced Thymic Epithelial Tumors (TETs). Angiogenesis plays an important role in TETs: VEGF is overexpressed in TETs, and associated with aggressiveness and advanced stage. Etoposide inhibits angiogenesis in vitro and in vivo by decreasing VEGF production and microvessel density. The aim of this study is to assess the activity of metronomic oral etoposide, with identification of circulating predictive and pharmacodynamics biomarkers. Methods: Patients with advanced platinum pretreated TET referred from 2014 to 2019 at Rare Tumors Reference Center of Naples, were prospectively enrolled in this study. Oral etoposide 50 mg daily for 3 weeks on and 1 week off every 28 days, has been delivered until progression of disease, complete response or unacceptable toxicity. Response rate (RR), progression free survival (PFS), toxicity and ratio between time to etoposide progression (TTPe) and time to previous best treatment progression (TTPp) were evaluated. Serum samples were prospectively obtained from ten patients with simultaneously radiological assessment. cfDNA quantification was assessed using Qubit Fluorometric Quantitation. Results: 21 patients were enrolled: median age 59 years range (41 - 88); 70% male, 60% T (4 B1, 3 B2, 4 B3, 1 B1-B2); 40% had TC. A median of 5 (range 1-9) prior therapy regimens had been administered. Median follow-up since etoposide was 5 years (range 0.5-5). Obtaining an overall response rate of 85%, 3 patients achieved complete response and 15 partial response. Median PFS was 16 months [95%CI 3-60] with respectively a median PFS of 12 for T (95%CI 3-38) and 19 for TC (95%CI 6-60). No grade 3-4 related events occurred, G1-2 myelotoxicity has been registered in 20% of patients. Therapy is still ongoing for 15 patients and all are still alive. Median TTPe was 16 months, TTPp was 9 months and TTPe / TTPp ratio equal to 1.7. The median cfDNA of 8 responder patients, before starting therapy, was 2.2 ng/μl (0.178-5.24), dropping dramatically at radiological response to 0.5 ng/μl (0.323-2.56). 2 out of 3 non-responder patients had a median baseline value of 2.49 ng/μl, increasing to 4.6 ng/μl at progression. Variation of circulating VEGF correlates with radiological response. Conclusions: Taking into account that other antiangiogenic drugs, showing some activity in second and further lines treatment, are very expensive and associated with several side effects, we suggest that low dose oral etoposide might become the preferred treatment option in heavily pretreated TETs.
Nivolumab + ipilimumab versus platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer: Three-year update from CheckMate 227 Part 1.
Authors: Ramalingam Suresh S. , Ciuleanu Tudor Eliade , Pluzanski Adam , Lee Jong-Seok , Schenker Michael , Bernabe Caro Reyes , Lee Ki Hyeong , Zurawski Bogdan , Audigier-Valette Clarisse , Provencio Mariano , Linardou Helena , Kim Sang-We , Borghaei Hossein , Hellmann Matthew David , O'Byrne Kenneth John , Paz-Ares Luis G. , Reck Martin , Nathan Faith Ellen , Brahmer Julie R.
Published: May 2020

9500

Background: In the phase 3 CheckMate 227 Part 1 (NCT02477826; minimum follow-up, 29.3 mo), 1L NIVO + IPI significantly improved overall survival (OS) vs chemo in treatment-naive patients (pts) with aNSCLC and tumor PD-L1 expression ≥ 1% (primary analysis) or < 1% (pre-specified descriptive analysis). Here we report data with 3-y minimum follow-up. Methods: Pts with stage IV / recurrent NSCLC and PD-L1 ≥ 1% (n = 1189) were randomized 1:1:1 to NIVO (3 mg/kg Q2W) + IPI (1 mg/kg Q6W), NIVO (240 mg Q2W) alone, or chemo. Pts with PD-L1 < 1% (n = 550) were randomized to NIVO + IPI, NIVO (360 mg Q3W) + chemo, or chemo. Primary endpoint was OS with NIVO + IPI vs chemo in pts with PD-L1 ≥ 1%. An exploratory analysis of OS in pts by response status (CR/PR, SD, progressive disease [PD]) at 6 mo was conducted. Results: After a median follow-up of 43.1 mo (database lock, 28 Feb 2020), pts with PD-L1 ≥ 1% continued to derive OS benefit from NIVO + IPI vs chemo (HR: 0.79; 95% CI, 0.67–0.93); 3-y OS rates were 33% (NIVO + IPI), 29% (NIVO), and 22% (chemo). At 3 y, 18% of pts with PD-L1 ≥ 1% treated with NIVO + IPI remained progression-free vs 12% with NIVO and 4% with chemo; 38% of confirmed responders remained in response in the NIVO + IPI arm at 3 y vs 32% in the NIVO arm and 4% in the chemo arm. In pts with PD-L1 < 1%, OS HR for NIVO + IPI vs chemo was 0.64 (95% CI, 0.51–0.81); 3-y OS rates were 34% (NIVO + IPI), 20% (NIVO + chemo), and 15% (chemo); 13%, 8%, and 2% of pts remained progression-free; and 34%, 15%, and 0% of confirmed responders remained in response, respectively. Pts with PD-L1 ≥ 1% with either CR/PR at 6 mo had longer subsequent OS with NIVO + IPI vs chemo; pts with SD or PD at 6 mo had generally similar subsequent OS between treatments (Table); results in PD-L1 < 1% pts will be presented. Any-grade / grade 3–4 treatment-related AEs were observed in 77% / 33% of all pts treated with NIVO + IPI, and 82% / 36% with chemo. Conclusions: With 3 y minimum follow-up, NIVO + IPI continued to provide durable and long-term OS benefits vs chemo for pts in 1L aNSCLC. Pts with PD-L1 ≥ 1% who achieved CR/PR at 6 mo had marked OS benefit with NIVO + IPI vs chemo. No new safety signals were identified for NIVO + IPI. Clinical trial information: NCT02477826. [Table: see text]