bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world (RW) treatment (tx) patterns and outcomes of 3,455 previously untreated mantle cell lymphoma (MCL) patients (pts) in U.S. routine clinical practice.
Authors: Martin Peter , Wang Michael , Kumar Anita , Qi Keqin , Daly Katherine , Parisi Lori , Zhu Angeline , Salles Gilles A.
Published: June 2021

7504

Background: MCL is a non-Hodgkin lymphoma with heterogeneous biology and outcomes. We characterized RW tx patterns and outcomes of MCL pts to identify factors associated with outcomes in the US. Methods: This retrospective study included adult MCL pts diagnosed Jan 2011-Nov 2020 in the nationwide Flatiron Health EHR-derived deidentified database. Pt characteristics, tx patterns, time to next tx (rwTTNT, defined as start of first-line [1L] tx to subsequent tx or death) and rwOS were evaluated. Results: 3455 pts were included, 85.3% from a community oncology setting. In 2946 (85.2%) pts with documented 1L MCL tx, median age was 69.5 y (range 27.7-85.3); 9.5% had blastoid/pleomorphic MCL. 262 (39.6%) and 235 (35.6%) of 661 pts with available MCL international prognostic index (MIPI) had intermediate and high risk, respectively. 150/1253 pts (12.0%) with available ECOG PS had PS ≥ 2. Chemoimmunotherapy was the most common 1L tx, including BR in 1223 (41.5%), R-CHOP in 512 (17.4%) and cytarabine (ara-C)-containing tx in 414 (14.1%). 667 pts received R maintenance (MR). In 1036 pts < 65 y, 243 pts received 1L stem cell transplant (SCT), mainly autologous. In 1L-treated pts, with median follow-up of survivors of 45.3 mos (range 0.03-117.2), median rwTTNT was 24 mos; 36-mo rwOS was 67%. The Table shows tx received and outcomes by age and SCT status. MVA analyses showed age ≥ 65 y, ECOG PS ≥ 2, LDH/ULN ≥ 1, WBC ≥ 10 × 109/L, bulky disease (≥ 5 cm) and blastoid/pleomorphic morphology were associated with shorter rwTTNT and rwOS; MR was independently associated with longer rwTTNT and rwOS. In pts < 65 y who were alive and did not initiate subsequent tx within 6 mos of 1L tx (“SCT-eligible”), 36-mo rwTTNT and rwOS were similar between pts treated with vs without SCT: 65% vs 59% and 86% vs 85%, respectively. Conclusions: In this large RW cohort of primarily community-based US practices, median 1L rwTTNT for MCL pts was ̃ 2 y. BR was the most commonly used 1L tx. SCT was uncommon even in pts < 65 y, suggesting RW considerations may influence SCT eligibility and availability. Also, SCT was not clearly associated with rwOS. As with other reports, older age and high-risk disease features were predictive of worse outcome in RW, while MR appeared to be associated with better outcomes. Outcomes across the board appear worse than prospective trials, suggesting a need to focus on developing tx that can be delivered effectively in the community setting.[Table: see text]
Acalabrutinib ± obinutuzumab versus obinutuzumab + chlorambucil in treatment-naïve chronic lymphocytic leukemia: Elevate-TN four-year follow up.
Authors: Sharman Jeff Porter , Egyed Miklos , Jurczak Wojciech , Skarbnik Alan , Pagel John M. , Kamdar Manali K. , Munir Talha , Corbett Gillian , Fogliatto Laura Maria , Herishanu Yair , Banerji Versha , Coutre Steve E. , Walker Patricia , Karlsson Karin , Ghia Paolo , Janssens Ann , Wierda William G. , Patel Priti , Wang Min Hui , Byrd John C.
Published: June 2021

7509

Background: Early results from ELEVATE-TN (NCT02475681) at a median follow-up of 28.3 mo demonstrated superior efficacy of acalabrutinib (A) ± obinutuzumab (O) compared with O + chlorambucil (Clb) in patients (pts) with treatment-naïve (TN) chronic lymphocytic leukemia (CLL) (Sharman et al. Lancet 2020;395:1278-91). Results from a 4-year update are reported here. Methods: Pts received A±O or O+Clb. Crossover to A monotherapy was permitted in pts who progressed on O+Clb. Investigator-assessed (INV) progression-free survival (PFS), INV overall response rate (ORR), overall survival (OS), and safety were evaluated. Results: 535 pts (A+O, n=179; A, n=179; O+Clb, n=177) were randomized with a median age of 70 y; 63% had unmutated IGHV and 9% del(17p). At a median follow-up of 46.9 mo (range, 0.0–59.4; data cutoff: Sept 11, 2020), the median PFS was not reached (NR) for A+O and A pts vs 27.8 mo for O+Clb pts (both P<0.0001). In pts with unmutated IGHV, the median PFS was NR (A+O and A) vs 22.2 mo among O+Clb pts (both P<0.0001). In pts with del(17p), the median PFS was NR (A+O and A) vs 17.7 mo for O+Clb ( P<0.005). Estimated 48-mo PFS rates were 87% for A+O, 78% for A, and 25% for O+Clb. Median OS was NR in any treatment arm with a trend towards significance in the A+O group (A+O vs O+Clb, P=0.0604); estimated 48-mo OS rates were 93% (A+O), 88% (A), and 88% (O+Clb). ORR was significantly higher with A+O (96.1%; 95% CI 92.1–98.1) vs O+Clb (82.5%; 95% CI 76.2–87.4; P<0.0001); ORR with A was 89.9% (95% CI 84.7–93.5; P=0.035 vs O+Clb). Complete response/complete response with incomplete hematologic recovery (CR/CRi) rates were higher with A+O (26.8%/3.9%) vs O+Clb (12.4%/0.6%); 10.6%/0.6% had CR/CRi with A. Common adverse events (AEs) and AEs of interest are shown in the Table. Overall treatment discontinuation rates were 25.1% (A+O), 30.7% (A), and 22.6% (O+Clb); the most common reasons were AEs (12.8%, 12.3%, 14.7%, respectively) and progressive disease (4.5%, 7.8%, 1.7%). Most pts (77.4%) completed O+Clb treatment. Conclusions: With a median follow-up of 46.9 mo (̃4y), the efficacy and safety of A+O and A monotherapy was maintained, with an increase in CR since the interim analysis (from 21% to 27% [A+O] and from 7% to 11% [A]) and low rates of discontinuation.[Table: see text]
Polatuzumab vedotin (Pola) + rituximab (R) + lenalidomide (Len) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): Primary analysis of a phase 1b/2 trial.
Authors: Magid Diefenbach Catherine S. , Abrisqueta Pau , Gonzalez-Barca Eva , Panizo Carlos , Arguinano Perez Jose Maria , Miall Fiona , Bastos-Oreiro Mariana , Lopez-Guillermo Armando , Banerjee Lalita , McMillan Andrew , Hirata Jamie , Musick Lisa , Saha Sourish , Croft Brandon , Seymour Erlene Kuizon
Published: June 2021

7512

Background: The combination of Pola-R-Len may enhance anti-tumor response in R/R DLBCL. We report the primary analysis of the R/R DLBCL cohort in a Phase 1b/2 study (GO29834; NCT02600897). Methods: Pts received induction with 6 x 28-Day (D) cycles (C) of: Pola 1.8mg/kg intravenous (IV; C1−6: D1); R 375mg/m2 IV (C1−6: D1) and oral Len 10–20mg (dose escalation) or recommended Phase 2 dose (RP2D) daily on D1–21. Pts with a response at end of induction (EOI) received 6 months (mo) consolidation with R 375mg/m2 (D1 every 2 mo) and Len 10mg (D1–21 monthly). Primary endpoints were safety/tolerability and positron emission tomography (PET)-complete response (CR) rate at EOI by independent review committee (IRC) by modified Lugano criteria. Results: At primary analysis (Sep 08, 2020), 57 pts were enrolled. Median age was 71 years (range 28–92); male (67%); Ann Arbor Stage III–IV (86%); International Prognostic Index 3–5 (60%); median 2 prior therapies; prior bone marrow transplant (11%); prior CAR-T therapy (5%); primary refractory (49%) and refractory to last therapy (65%). Grade 3–4 adverse events (AEs) were experienced by 75% of pts, most commonly, neutropenia (58%), thrombocytopenia (14%), infections (14%) and anemia (11%). AEs led to Len dose reduction in 25% and interruption in 63% of pts. One Grade 5 treatment-related AE (neutropenic sepsis) was reported. In total, 49 pts were treated at RP2D (Pola 1.8mg/kg + Len 20mg). IRC PET-CR rate at EOI was 29% (Table). A best overall response (BOR) assessed by investigator (INV) was seen in 36/49 (74%) pts with 17/49 (35%) pts achieving a CR; of these, 14/17 (82%) remain in remission at the cutoff date. Median duration of response (DOR) was 8.1 mo (95% confidence interval [CI]: 4.7–not evaluable [NE]). After a median follow-up of 9.7 mo, median progression-free survival (PFS) and overall survival (OS) were 6.3 mo (95% CI: 4.5–9.7) and 10.9 mo (95% CI: 7.4–NE), respectively. Conclusions: Our study of the novel triplet combination, Pola-R-Len, demonstrates a tolerable safety profile. This first efficacy report of Pola-R-Len shows promising activity in a difficult-to-treat R/R DLBCL population, particularly in pts achieving CR, a large proportion of whom remain in remission at the cutoff date. Further evaluation of Pola-R-Len and the impact of consolidation therapy is warranted to address the significant unmet need in this patient population. Clinical trial information: NCT02600897. [Table: see text]
Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).
Authors: Düll Johannes , Maddocks Kami J. , Gonzalez-Barca Eva , Jurczak Wojciech , Liberati Anna Marina , Obr Aleš , Gaidano Gianluca , Abrisqueta Pau , André Marc , Dreyling Martin H. , Menne Tobias , Dirnberger-Hertweck Maren , Weirather Johannes , Ambarkhane Sumeet Vijay , Salles Gilles A.
Published: June 2021

7513

Background: L-MIND (NCT02399085) is an ongoing, open-label, Phase II study of tafasitamab (MOR208), an Fc-modified, humanized, anti-CD19 monoclonal antibody, plus LEN in ASCT-ineligible patients (pts) with R/R DLBCL. Primary analyses and 2-year efficacy results were previously presented; we report an updated efficacy analysis with ≥35 months follow up (cut-off: October 30, 2020). Methods: Pts were aged ≥18 years with ASCT-ineligible R/R DLBCL, had 1–3 prior systemic therapies (Tx), including ≥1 CD20-targeting regimen, with an ECOG status of 0–2. Pts received 28-day cycles (C) of tafasitamab (12 mg/kg IV), once weekly during C1–3, with a loading dose on Day 4 of C1, then every 2 weeks (Q2W) during C4–12. LEN (25 mg PO) was administered on Days 1–21 of C1–12. After C12, progression-free pts received tafasitamab Q2W until disease progression. The primary endpoint was objective response rate (ORR), assessed by IRC. Secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Results: Eighty of 81 enrolled pts received tafasitamab + LEN and were included in the full analysis set (1 prior Tx, n=40; 2+ prior Tx, n=40). At data cut-off, the overall ORR was 57.5% (n=46/80), including complete response (CR) in 40% of pts (n=32/80) and partial response (PR) in 17.5% of pts (n=14/80) (Table). Kaplan-Meier estimates: median DoR=43.9 months (95% CI: 26.1–not reached [NR]), and NR in pts who achieved a CR (95% CI: 43.9–NR); median PFS=11.6 months (95% CI: 6.3–45.7), with median follow-up 33.9 months; median OS=33.5 months (95% CI: 18.3–NR), with median follow-up 42.7 months. There were no unexpected toxicities or new safety signals. Conclusions: Combination Tx with tafasitamab + LEN followed by tafasitamab monotherapy provided durable responses in pts with R/R DLBCL not eligible for ASCT, with a manageable safety profile. These long-term data indicate the potential of tafasitamab + LEN followed by extended tafasitamab monotherapy in achieving prolonged remission and survival benefit in this patient population, especially at first relapse. Clinical trial information: NCT02399085. [Table: see text]
Comparative efficacy of tisagenlecleucel (tisa-cel) and lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL).
Authors: Schuster Stephen J. , Zhang Jie , Yang Hongbo , Agarwal Abhijit , Tang Wenxi , Martinez-Prieto Marcela , Bollu Vamsi , Ma Qiufei , Kuzan David , Maziarz Richard T. , Kersten Marie José
Published: June 2021

7535

Background: Chimeric antigen receptor T-cell therapies tisa-cel and liso-cel are effective treatments for r/r DLBCL (Schuster 2019, Abramson 2020). This study compared efficacy outcomes of tisa-cel and liso-cel in r/r DLBCL using matching-adjusted indirect comparison (MAIC). Methods: Individual patient-level data (IPD) from JULIET (tisa-cel; NCT02445248; 02/2020 datacut) were weighted to match the patient population in TRANSCEND (liso-cel; NCT02631044; 08/2019 datacut). Baseline prognostic factors available in both trials were adjusted for age, sex, histology, ECOG performance status [ECOG PS], left ventricular ejection fraction, radiologic sum of product diameters, lactate dehydrogenase, prior stem cell transplantation [SCT], use of bridging therapy, and number of and refractoriness to prior therapies, in the MAIC. Overall survival (OS), progression-free survival (PFS), complete response (CR) rate, and overall response (OR) rate were compared. Primary analyses compared infused patients in JULIET (N=106, excluding 8 without lymphodepleting chemotherapy [LDC] and 1 large cell neuroendocrine carcinoma) with efficacy-evaluable set in TRANSCEND (N=256, infused patients). A scenario analysis compared JULIET infused to TRANSCEND primary analysis set (PAS) (N=133, dose level 2, excluding those with ECOG PS 2, prior allogeneic SCT, primary mediastinal B-cell lymphoma, follicular lymphoma [FL] 3B, or transformation from indolent lymphoma besides FL). Sensitivity analyses included JULIET patients with only fludarabine-based LDC or only adjusted significantly different baseline prognostic factors. Safety outcomes were not compared because adverse event management has evolved and differed between the two trials; MAIC is unable to adjust for such differences. Results: After adjusting for differences in baseline characteristics, OS, PFS, and CR were comparable between tisa-cel infused patients and the liso-cel efficacy-evaluable set (Table). The results were consistent across all scenario and sensitivity analyses. OR rate trended higher in the TRANSCEND efficacy-evaluable set (72.7% vs. 62.9%, p=0.07) and was higher in TRANSCEND PAS than in the respectively matched JULIET infused set (74.4% vs. 60.9%, p < 0.05). Conclusions: The MAIC results indicate there is no evidence suggesting differences in OS, PFS and CR between tisa-cel and liso-cel in r/r DLBCL. Analyses using IPD from both trials and/or real-world evidence are warranted to confirm these findings.[Table: see text]
First-MIND: A phase Ib, open-label, randomized study to assess safety of tafasitamab (tafa) or tafa + lenalidomide (LEN) in addition to R-CHOP in patients with newly diagnosed DLBCL.
Authors: Belada David , Kopeckova Katerina , Bergua Juan Miguel , André Marc , Perez Persona Ernesto , Pichler Petra , Klöpfer Pia , Brackertz Bettina , Lohrmann Emanuel , Lahiry Anirban , Shah Neha , Brugger Wolfram , Burke John M. , Nowakowski Grzegorz S.
Published: June 2021

7540

Background: Tafasitamab is a humanized, Fc-modified anti-CD19 monoclonal antibody that enhances antibody-dependent cellular cytotoxicity and phagocytosis. It is FDA-approved with LEN for adult patients (pts) with relapsed/refractory (R/R) DLBCL ineligible for autologous stem cell transplantation. First-MIND (NCT04134936) is a Phase Ib, open-label, randomized study of tafa + R-CHOP or tafa + LEN + R-CHOP in newly diagnosed DLBCL. Methods: Eligible pts were ≥18 years, treatment-naïve, with histologically confirmed DLBCL not otherwise specified, international prognostic index (IPI) 2–5 and ECOG performance status (PS) 0–2. Pts with known double- or triple-hit and transformed lymphoma were excluded. Treatment (Tx) comprised six 21-day cycles of tafa (12 mg/kg IV, Day [D] 1, 8, 15) + R-CHOP (arm A) or tafa (12 mg/kg IV, D1, 8, 15) + LEN (25 mg orally, D1–10) + R-CHOP (arm B). G-CSF and VTE prophylaxis was mandatory. Primary objective is safety; secondary objectives are ORR, PET-CR rate at end of Tx, PFS, long-term safety, pharmacokinetics, immunogenicity. Results: From Dec 2019 to Aug 2020, 83 pts were screened in Europe and the US; 66 were randomized (33 per arm). Data cut-off for this analysis: 9 Dec 2020; study is ongoing. Median age was 64.5 years (range 20–86). Overall, 30% (20/66) of pts were ≥70 years and many had high-risk disease: IPI 2 29%, IPI 3 46%, IPI 4 26%. ECOG PS: 47% of pts were ECOG PS 0, 44% PS 1, 9% PS 2. Most pts had stage III/IV disease (92%); 46% had bulky disease. All pts experienced a treatment-emergent adverse event (TEAE). Grade ≥3 neutropenia and thrombocytopenia occurred in 54.5% and 12.1% (arm A) and 66.7% and 30.3% (arm B) of pts, respectively (Table). Serious TEAEs occurred in 42.4% (arm A) and 51.5% (arm B) of pts. There were three deaths, unrelated to tafa and/or LEN (sepsis, urosepsis, and COVID-19 pneumonia). R-CHOP dose intensity was maintained in both arms. Among 60 pts who completed tumor assessments after cycle 3, ORR was 89.7% (arm A) and 93.5% (arm B). Conclusions: These data suggest R-CHOP + tafa or tafa + LEN is tolerable in pts with Tx-naïve DLBCL and that R-CHOP dosing is not affected. Toxicities are similar to those expected with R-CHOP or R-CHOP + LEN. Updated safety and early efficacy data will be presented at the conference. Clinical trial information: NCT04134936. [Table: see text]
Efficacy and safety of zanubrutinib versus rituximab-based chemoimmunotherapy in Waldenström macroglobulinemia (WM): Matching-adjusted indirect comparisons.
Authors: Castillo Jorge J. , Yang Keri , Liu Rongzhe , Wang Yu , Cohen Aileen , Zimmerman Todd M. , Zhao Qian , Gao Xin , Tang Boxiong
Published: June 2021

7559

Background: Given a lack of WM randomized trials directly comparing zanubrutinib with chemoimmunotherapy, this study aimed to indirectly compare zanubrutinib with bendamustine-rituximab (BR) and with dexamethasone-rituximab-cyclophosphamide (DRC) separately through matching-adjusted indirect comparisons (MAIC). Methods: MAIC were conducted to re-weight the individual data of 102 WM patients (83 relapsed/refractory [R/R] and 19 treatment-naïve [TN]) treated with zanubrutinib in the ASPEN trial (NCT03053440) so that the weighted average baseline characteristics of patients treated with zanubrutinib matched those of 71 R/R patients treated with BR, and 72 TN patients treated with DRC separately. Matching variables for MAIC with BR included age, prior lines of therapy, IgM concentration, International Prognostic Scoring System for WM score, and extramedullary disease (EMD); and for MAIC with DRC included age, platelet count, hemoglobin concentration, and EMD. Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) of comparators were digitized to re-create patient-level data. Comparisons of survival and adverse event incidence between treatments were conducted using Cox proportional hazards models and modified Poisson models. Results: Compared to DRC, zanubrutinib was associated with longer PFS (hazard ratio [HR]: 0.39 [95% confidence interval 0.18-0.82] and 0.35 [0.14-0.86] pre- and post-matching, respectively) and longer OS (HR: 0.56 [0.20-1.53] and 0.47 [0.14-1.62] pre- and post-matching, respectively), and insignificantly higher incidences of neutropenia (risk ratio [RR]: 1.63 [0.71-3.77] and 1.47 [0.58-3.74] pre- and post-matching, respectively). Compared to BR, zanubrutinib was associated with longer PFS (HR: 0.32 [0.15-0.69] and 0.37 [0.15-0.91] pre- and post-matching, respectively), longer OS (HR: 0.31 [0.12, 0.80] and 0.29 [0.10-0.85] pre- and post-matching, respectively), lower incidences of neutropenia (RR: 0.45 [0.26-0.78] and 0.50 [0.27-0.91] pre- and post-matching, respectively) and lower incidences of pneumonia (RR: 0.18 [0.02-1.55] and 0.26 [0.03-2.28] pre- and post-matching, respectively). Conclusions: Zanubrutinib demonstrated longer PFS than DRC, and longer PFS and OS than BR in WM, before and after matching adjustment based on patient characteristics. [Table: see text]
Analysis of minimal residual disease in bone marrow by NGF and in peripheral blood by mass spectrometry in newly diagnosed multiple myeloma patients enrolled in the GEM2012MENOS65 clinical trial.
Authors: Puig Noemi , Paiva Bruno , Contreras Teresa , Cedena M. Teresa , Rosiñol Laura , Martínez Joaquín , Oriol Albert , Blanchard Maria Jesus , Rios Rafael , Iñigo María Belén , Sureda Balari Anna , Miguel Teodoro Hernández-Garcia , de La Rubia Javier , Krsnik Isabel , José María Moraleda , Orfao Alberto , Blade Joan , F. San-Miguel Jesús , Lahuerta Juan José , Mateos Maria-Victoria
Published: June 2021

8010

Background: Analysis of minimal residual disease (MRD) in the bone marrow (BM) of patients with multiple myeloma (MM) is accepted by the IMWG to evaluate treatment efficacy and is a well-established prognostic factor. However, there is an unmet need to explore the clinical value of MRD in peripheral blood (PB). Methods: Newly diagnosed MM patients enrolled in the GEM2012MENOS65 trial received six induction (Ind) cycles of bortezomib, lenalidomide, and dexamethasone (VRD) followed by autologous stem cell transplantation (ASCT) and 2 further cycles of consolidation (Cons) with VRD. MRD was analyzed in BM using Next Generation Flow (NGF) and in serum by Mass Spectrometry (MS) using IgG/A/M, κ, λ, free κ and free λ specific beads, both after Ind, at day 100 after ASCT, and after Cons. Sequential samples from the first 184 patients were analyzed. Results: Results of both methods were in agreement (NGF+/MS+ and NGF-/MS-) in 83% of cases post-Ind (152/184), 80% post-ASCT (139/174) and 76% post-Cons (128/169). Stratifying by the log range of MRD by NGF, discordances (NGF+/MS- and NGF-/MS+) seemed to increase at the lower MRD ranges, being 22%, 21% and 19% from ≥10−5 to <10−4 and 21%, 21%, 23% at ≥x10−6(post-Ind, ASCT and Cons, respectively). Analysis of discordances showed that they could be partly explained by the higher percentages of cases found to be positive by MS as compared by NGF at part of the time-points analyzed and at each log range of MRD. From ≥10−5 to <10−4, MRD was detected by NGF in 36%, 28%, 20% of cases post-Ind, ASCT and Cons, respectively vs MS in 37%, 29%, 21% of them; at ≥x10−6, NGF was positive in 11%, 14%, 19% of cases vs MS in 23%, 19% and 16% of them. Considering NGF as a reference, the negative predictive value (NPV) of MS per MRD range (≥10−5 to <10−4 and ≥x10−6, respectively) was: post-Ind: 83% (p<0,0001), 94% (p=0,034); post-ASCT 86% (p<0,0001), 90% (p=0,022); post-Cons 89% (p<0,0001), 85% (p=0,0469). Despite these discordances, the prognostic value of each technique in terms of undetectable MRD and progression-free survival (PFS) was consistent at all time-points (Table) and further, discordant cases (NGF+/MS- and NGF-/MS+) did not display a significantly different PFS as compared to NGF-/MS- cases. Conclusions: The results of MRD assessed by NGF in BM and by MS in PB show a significant concordance and are associated with a similar prognostic value analyzed in terms of PFS. Given its high NPV, MRD in peripheral blood by MS provides a gateway for BM aspiration/biopsy and MRD assessment by NGF.[Table: see text]
Isatuximab plus carfilzomib and dexamethasone versus carfilzomib and dexamethasone in elderly patients with relapsed multiple myeloma: IKEMA subgroup analysis.
Authors: Facon Thierry , Moreau Philippe , Martin Thomas G. , Spicka Ivan , Oriol Albert , Koh Youngil , Lim Andrew , Mikala Gabor , Rosiñol Laura , Yağci Münci , Cavo Michele , Yong Kwee , Risse Marie-Laure , Asset Gaëlle , Schwab Sandrine , Martinez Gracia
Published: June 2021

8026

Background: A prespecified interim efficacy analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib (K) and dexamethasone (d) (Isa-Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (HR 0.531; 99% CI, 0.318–0.889; P=0.0007), with a clinically meaningful increase in minimal residual disease negativity (MRD-) (29.6% vs 13.0%) and complete response (CR) (39.7% vs 27.6%) rates, and a manageable safety profile. This subgroup analysis of IKEMA examined efficacy and safety in pts aged <70 and ≥70 years. Methods: Pts with 1–3 prior lines of therapy were randomized 3:2 to receive Isa-Kd (n=179) or Kd (n=123). The primary end point was PFS, as assessed by an independent response committee. We compared outcomes in pts <70 vs ≥70 years; division into different or additional age groups resulted in smaller sample sizes. Results: Of the 302 randomized pts, 71.5% were aged <70 years (Isa-Kd: 70.9%; Kd: 72.4%) and 28.5% were aged ≥70 years (Isa-Kd: 29.1%; Kd: 27.6%). Consistent with the significant improvement of PFS in the overall population, the addition of Isa to Kd resulted in improved PFS independently of age (Table). The CR, ≥very good partial response (VGPR), and MRD- rates were higher with Isa-Kd vs Kd. Within the Isa-Kd arm, CR rate and ≥VGPR rate were similar in elderly and younger pts. MRD- was observed in 32.3% of younger pts and 23.1% of elderly pts with Isa-Kd. In both arms, Grade ≥3 and serious treatment-emergent adverse events (TEAEs) were more frequently reported in elderly pts vs pts <70 years old (Table). For both age groups, the incidence of Grade ≥3 TEAEs was higher whereas the incidence of serious TEAEs was similar between Isa-Kd and Kd. In the elderly subgroup, 3 (5.9%) pts receiving Isa-Kd and 1 (2.9%) receiving Kd had fatal TEAEs (Isa-Kd, infection; Kd, general health deterioration due to progressive disease). The most common Grade ≥3 TEAEs in pts aged <70 and ≥70 years treated with Isa-Kd vs Kd were hypertension (18.3% vs 17.0% [<70 years] and 25.5% vs 26.5% [≥70 years]) and pneumonia (14.3% vs 9.1% [<70 years] and 21.6% vs 20.6% [≥70 years]). Conclusions: The addition of Isa to Kd improved PFS and quality of response in elderly pts, with a manageable safety profile, consistent with the benefit observed in the overall IKEMA study population. Isa-Kd provides a potential new treatment option for elderly pts with RMM. Funding: Sanofi. Clinical trial information: NCT03275285. [Table: see text]
KEYNOTE-799: Phase 2 trial of pembrolizumab plus platinum chemotherapy and radiotherapy for unresectable, locally advanced, stage 3 NSCLC.
Authors: Jabbour Salma K. , Lee Ki Hyeong , Frost Nicolaj , Breder Valeriy Vladimirovich , Kowalski Dariusz M. , Alawin Issam Abdelkarim , Levchenko Evgeny , Reguart Noemi , Martinez-Marti Alex , Houghton Baerin , Paoli Jean-Baptiste , Safina Sufia , Park Keunchil , Komiya Takefumi , Sanford Amy , Boolell Vishal , Liu Hong , Samkari Ayman , Keller Steven M. , Reck Martin
Published: June 2021

8512

Background: KEYNOTE-799 (NCT03631784) is an ongoing study of the anti‒PD-1 antibody pembrolizumab (pembro) plus concurrent chemoradiation therapy (cCRT) in patients (pts) with unresectable, locally advanced stage III NSCLC. Prior results from this study in a subset of pts (primary efficacy population) showed an ORR of 69.6% in cohort A (squamous and nonsquamous, n = 112) and 70.5% in cohort B (nonsquamous, n = 61), and grade ≥3 pneumonitis in 8.0% and 7.9% of pts, respectively. Here, we present results for all pts enrolled in KEYNOTE-799. Methods: This nonrandomized, multisite, open-label phase 2 trial enrolled pts aged ≥18 y with previously untreated, unresectable, pathologically confirmed, stage IIIA‒C NSCLC with measurable disease per RECIST v1.1. Pts in cohort A (squamous and nonsquamous) received 1 cycle of carboplatin AUC 6 and paclitaxel 200 mg/m2 and pembro 200 mg. After 3 wks, pts received carboplatin AUC 2 and paclitaxel 45 mg/m2 QW for 6 wks and 2 cycles of pembro 200 mg Q3W plus standard thoracic radiotherapy (TRT). Pts in cohort B (nonsquamous only) received 3 cycles of cisplatin 75 mg/m2, pemetrexed 500 mg/m2,and pembro 200 mg Q3W, and TRT in cycles 2 and 3. All pts received an additional 14 cycles of pembro 200 mg Q3W. Primary endpoints were ORR per RECIST v1.1 by blinded independent central review (BICR) and the incidence of grade ≥3 pneumonitis (per NCI CTCAE v4.0). Efficacy and safety were assessed in all pts as-treated. Results: Of 216 pts enrolled in KEYNOTE-799 (cohort A, n = 112; cohort B, n = 104), 112 in cohort A and 102 in cohort B received treatment. As of October 28, 2020, the median (range) time from first dose to database cutoff was 18.5 (13.6–23.8) mo in cohort A and 13.7 (2.9–23.5) mo in cohort B. ORR (95% CI) was 70.5% (61.2%‒78.8%) in cohort A and 70.6% (60.7%‒79.2%) in cohort B. Median DOR was not reached in either cohort (Table). ORR was similar regardless of PD-L1 status ([TPS <1% and TPS ≥1%]; Cohort A, 66.7% and 75.8%; Cohort B, 71.4% and 72.5%) and tumor histology (Cohort A, squamous, 71.2% and nonsquamous, 69.2%). Grade ≥3 pneumonitis occurred in 9 pts (8.0%) in cohort A and 7 (6.9%) in cohort B. Grade 3‒5 treatment-related AEs occurred in 72 pts (64.3%) in cohort A and 51 (50.0%) in cohort B. Conclusions: Pembro plus cCRT continues to demonstrate promising antitumor activity, regardless of PD-L1 TPS and tumor histology, and manageable safety in pts with previously untreated, locally advanced, stage III NSCLC with longer follow-up. Clinical trial information: NCT03631784. [Table: see text]
Residual ctDNA after treatment predicts early relapse in patients with early-stage NSCLC.
Authors: Gale Davina , Heider Katrin , Perry Malcolm , Marsico Giovanni , Ruiz-Valdepeñas Andrea , Rundell Viona , Wulff Jerome , Sharma Garima , Howarth Karen , Gilligan David , Harden Susan , Rassl Doris M. , Rintoul Robert , Rosenfeld Nitzan
Published: June 2021

8517

Background: Liquid biopsies based on circulating tumor DNA (ctDNA) analysis are being investigated for detection of residual disease and recurrence. Conclusive evidence for utility of ctDNA in early-stage non-small cell lung cancer (NSCLC) is awaited. Due to low ctDNA levels in early-stage disease or post-treatment, effective methods require high analytical sensitivity to detect mutant allele fractions (MAF) below 0.01%. Methods: We analysed 363 plasma samples from 88 patients with NSCLC recruited to the LUng cancer CIrculating tumour DNA (LUCID) study, with disease stage I (49%), II (28%) and III (23%). 62% were adenocarcinomas. Plasma was collected before and after treatment, and at 3, 6 and 9 months after surgery (N = 69) or chemoradiotherapy (N = 19). Additional plasma was collected at disease relapse for 17 patients. Median follow-up was 3 years, and 40 patients progressed or died of any cause. We employed the RaDaR™ assay, a highly sensitive personalized assay using deep sequencing of up to 48 tumor-specific variants. Variants identified by tumor exome analysis were tested by deep sequencing of tumor tissue and buffy coat DNA to verify somatic mutations and exclude clonal hematopoiesis. The RaDaR assay demonstrated 90% sensitivity at 0.001% MAF in analytical validation studies. Results: ctDNA was detected in 26% of samples, at median MAF of 0.047% (range: 0.0007% to > 2%), and prior to treatment in 87%, 77% and 24% for disease stage III, II and I respectively. For 62 patients, plasma was collected at a landmark timepoint, between 2 weeks and 4 months after initial treatment. ctDNA detection at the landmark timepoint was strongly predictive of clinical disease relapse, with Hazard Ratio of 20.7 (CI: 7.7-55.5, p-value < 0.0001). All 11 cases with ctDNA detected at landmark had disease progression, a median of 121 days after detection, and these included all 8 patients that relapsed within 300 days of treatment. Across 27 patients whose disease progressed during the study, ctDNA was detected at any timepoint post-treatment in 17 cases, with a median lead time of 203 days, and up to 741 days prior to clinical progression. ctDNA was detected post-treatment, in 13 of the 15 patients that progressed and had ctDNA detected prior to treatment. Conclusions: Our results support an emerging paradigm shift, by demonstrating that liquid biopsies can reliably detect recurrence of NSCLC at a preclinical stage, many months before clinical progression, thereby offering the opportunity for earlier therapeutic intervention. Clinical trial information: NCT04153526.
Osimertinib as neoadjuvant treatment for resectable stage II-IIIB EGFR mutant lung adenocarcinoma (NEOS).
Authors: Lyu Chao , Fang Wentao , Ma Haitao , Wang Jia , Jiao Wenjie , Wang Rui , Wu Nan , Xu Shi-Dong , Yang Yue
Published: June 2021

8524

Background: Neoadjuvant treatment has demonstrated efficacy in several types of cancer and is increasingly used for the treatment of early-stage cancers with the potential of cancer downstaging to enhance complete surgical resection and to improve clinical outcomes. Recent evidences have demonstrated that the neoadjuvant use of first/second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) may provide clinically meaningful improvement in EGFRm non-small cell lung cancer (NSCLC) patients, however, limited data were reported on osimertinib, the third-generation EGFR-TKI, in the neoadjuvant setting. Here we present an interim analysis of osimertinib as neoadjuvant treatment for resectable EGFRm NSCLC. Methods: NEOS is a prospective, multi-center, single-arm study to evaluate the efficacy and safety of osimertinib as neoadjuvant treatment in resectable EGFRm (19del/L858R) lung adenocarcinoma. Eligible patients were treated with osimertinib 80 mg orally per day for six weeks followed by surgery. Assessment of response to neoadjuvant therapy was performed according to RECIST 1.1. The primary endpoint was response rate. Secondary endpoints included safety, R0 surgical resection rate, quality of life, major pathologic response (MPR) rate, pathological complete response (pCR) rate, and N2 downstaging rate. Results: As of Dec. 17, 2020, 18 eligible patients (median age 61 [range 46-73], 27.8% male, 22.2% ECOG PS 1) have been enrolled. Patients with clinical stages IIa, IIb, and IIIa (8th AJCC) accounted for 16.7%, 22.2% and 61.1%, respectively. Half (9/18) of the patients had EGFR exon 21 L858R mutations and the other half (9/18) had EGFR exon 19del mutations. Amongst all 15 patients who completed efficacy assessment after neoadjuvant osimertinib, the response rate (RR) was 73.3% (11/15) and the disease control rate (DCR) was 100% (15/15). R0 surgical resection was performed in 93.3% (14/15) patients. Pathological downstaging occurred in 53.3% (8/15) patients. 42.9% (3/7) of the patients with confirmed N2 lymph nodes experienced downstaging to N0 disease after receiving neoadjuvant osimertinib. One patient was identified with a pCR. Adverse events (AEs) were reported in 66.7% (12/18) of patients, with the most common AE being rash (8/18, 44.4%), oral ulceration (8/18, 44.4%), and diarrhea (5/18, 27.8%). No grade 3-5 AEs or serious AEs were reported. Conclusions: Interim analysis from this study indicated neoadjuvant osimertinib as an effective and feasible treatment in patients with resectable stage II-IIIB EGFRm NSCLC. The trial is ongoing and the final results will be provided in the future. Clinical trial information: ChiCTR1800016948.
Cost evaluation of adjunctive osimertinib use in resected epidermal growth factor receptor-positive non-small cell lung cancer.
Authors: Choi Briana , Alrawashdh Neda , McBride Ali , Abraham Ivo
Published: June 2021

8525

Background: About 30% of patients with epidermal growth factor receptor positive (EGFR+) non small cell lung cancer (NSCLC) are eligible for surgical resection. Osimertinib, a first line therapy for advanced EGFR+ NSCLC (stages 1B, 2, 3A), has shown clinical efficacy compared to placebo as an adjunctive therapy post resection. We evaluated the cost effectiveness/utility of this regimen. Methods: A two health state Markov model was built (disease free vs. disease recurrence or death). Disease free survival (DFS) curves were digitized and fitted to exponential function. 3 year timeline as patients received osimertinib for 3 years in published data. US payer perspective and 3% discount rate were applied. Drug costs were per Redbook whole acquisition cost and monitoring costs were from published data (US$ 2020). No adverse events > 5% were reported hence none were included. Life years (LY) and quality adjusted life years (QALY) were estimated for each stage. Incremental cost-effectiveness and utility ratios (ICER/ICUR) for LY and QALY gained were estimated in base case (BCA) and probabilistic sensitivity analyses (PSA). Results: Shown in the table are BCA and (PSA) results. Using LY as outcome, for stage 1B, incremental DFSLY of 0.40 (0.39) and incremental cost of $500,782 ($501,034) yielded an ICER/DFSLYG of ̃$1.3 million (M) (̃$1.2 M). For stage 2, incremental DFSLY of 0.79 (0.79) and incremental cost of $503,144 ($503,092) resulted in an ICER/DFSLYG of $636,913 ($638,278). For stage 3A, incremental of DFSLY of 0.18 (0.07) and incremental cost of $322,356 ($293,377) yielded an ICER/DFSLYG of ̃$1.2 M (̃1.2 M). The incremental costs are the same for QALY outcomes. Using QALY as outcome, for stage 1B, incremental of DFSQALY of 0.26 (0.27) yielded an ICUR/DFSQALY of ̃$1.9 M. In stage 2, incremental DFSQALY of 0.53 (0.53) resulted in an ICUR/DFSQALY of $950,616 ($952,654). For stage 1C, incremental DFSQALY of 0.18 (0.07) yielded an ICUR/DFSQALY of ̃$1.8 M (̃$3.7 M). Conclusions: The ICERs and ICURs indicate that cost effectiveness varies markedly across stages of disease. Stage 2 showed the lowest cost to outcome association. In general, the cost burden of adjunctive maintenance therapy with osimertinib in resected EGFR+ NSCLC is substantial relative to the observed clinical benefit. The incremental benefit of osimertinib in stage 2b is more evident than the ones in 1B and 3A.[Table: see text]
Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.
Authors: Sankar Kamya , Bryant Alex K. , Green Michael , Ramnath Nithya
Published: June 2021

8546

Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p < 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.
Randomized phase III trial of aumolertinib (HS-10296, Au) versus gefitinib (G) as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) and EGFR exon 19 del or L858R mutations (EGFRm).
Authors: Lu Shun , Dong Xiaorong , Jian Hong , Chen Jianhua , Chen Gongyan , Sun Yuping , Ji Yinghua , Wang Ziping , Shi Jianhua , Lu Junguo , Chen Shaoshui , Zhang Guojun , Lv Dongqing , Liu Chunling , Li Juan , Yu Xinmin , Lin Zhong , Yu Zhuang , Wang Zhehai , Cui Jiuwei ,   Hansoh Pharma Clinical Development Group
Published: June 2021

9013

Background: Au is a novel, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) with favorable pharmacologic properties that selectively inhibits both EGFR sensitizing and resistance mutations. Au has been approved in China for treatment of patients (pts) with EGFR mutant NSCLC with EGFR T790M upon progression of disease on previous EGFR TKIs (Proc. AACR 2020, Abstract CT190). This Phase III trial assessed the efficacy and safety of Au versus G as initial treatment of patients with advanced NSCLC with EGFRm. Methods: Pts with previously untreated metastatic or locally advanced NSCLC and EGFR exon 19 deletion or L858R were randomly assigned in a 1:1 ratio to receive either Au (110 mg once daily) or G (250 mg once daily). The primary endpoint was progression-free survival (PFS) by RECIST v1.1 per investigator assessment. At 262 PFS events, the study had 90% power to detect a PFS HR = 0.67. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR) and safety. Results: Between Nov 30, 2018 and Sept 6, 2019, 429 patients across 53 sites in China were enrolled and randomized. Pt. characteristics were well-balanced. At the planned final event-driven PFS analysis, Au significantly prolonged PFS (median 19.3 vs 9.9 months, HR 0.46, p-value <0.0001). DoR was also significantly prolonged with Au. Median OS has not been reached. Efficacy and relevant safety results are summarized in Table. Despite a significantly longer duration of treatment (median 463 vs 254 days), Au was associated with a lower incidence of rash, diarrhea, AST/ALT increase, and treatment related serious adverse events (SAEs) (4.2% vs 11.2%). Au was associated with more frequent events of CPK increased, platelet count decreased, and neutrophil count decreased, which were predominantly low grade. Conclusions: Au significantly prolonged PFS and DoR compared to G as first-line therapy in pts with advanced NSCLC with EGFRm. Au demonstrated a favorable safety profile, especially regarding toxicities mediated by wild-type EGFR. These results establish Au as a promising option for advanced NSCLC with EGFRm. Clinical trial information: NCT03849768. [Table: see text]
Mobocertinib (TAK-788) in EGFR exon 20 insertion (ex20ins)+ metastatic NSCLC (mNSCLC): Additional results from platinum-pretreated patients (pts) and EXCLAIM cohort of phase 1/2 study.
Authors: Ramalingam Suresh S. , Zhou Caicun , Kim Tae Min , Kim Sang-We , Yang James Chih-Hsin , Riely Gregory J. , Mekhail Tarek , Nguyen Danny , García Campelo Maria Rosario , Felip Enriqueta , Vincent Sylvie , Jin Shu , Bunn Veronica , Lin Jianchang , Lin Huamao Mark , Mehta Minal , Janne Pasi A.
Published: June 2021

9014

Background: No approved targeted therapies are available for EGFR ex20ins+ mNSCLC. Mobocertinib, a first-in-class, potent, oral TKI targeting EGFR ex20ins mutations, has Breakthrough Therapy Designation in the US and China for post-platinum-based chemotherapy pts with EGFR ex20ins+ mNSCLC. Methods: This 3-part, open-label, multicenter study (NCT02716116) has dose-escalation/expansion and extension (EXCLAIM) cohorts. Pts with EGFR ex20ins+ mNSCLC, ECOG status 0–1, and ≥1 prior line of therapy for locally advanced/metastatic disease received mobocertinib 160 mg QD. Primary endpoint was confirmed objective response rate (ORR; RECIST v1.1) assessed by independent review committee (IRC). We present additional efficacy and safety data for 114 platinum-pretreated pts (PPP) and 96 pts from EXCLAIM safety cohort. Results: Results are from Nov 1, 2020, data cutoff. Among PPP pts (n=114; median age 60 y [27–84 y]), 66% were female, 60% were Asian, and 59% had ≥2 prior systemic anticancer lines. Confirmed ORR per IRC was 28%, including 1 complete response (CR); disease control rate (DCR) was 78% [95% CI: 69–85]; median duration of response (DOR) was 17.5 mo (Table). In EXCLAIM (n=96; median age 59 y [27–80 y]), 65% were female, 69% were Asian, and 49% had ≥2 prior lines. Confirmed ORR per IRC was 25%, with 1 CR; DCR was 76% [95% CI: 66–84]; median DOR was not reached (Table). In EXCLAIM, baseline brain metastases were present in 33/96 pts (34%); the first site of disease progression by IRC was the brain in 40% of all pts and 73% of pts with baseline brain metastases. Confirmed responses were seen in all prespecified subgroups in PPP and EXCLAIM. Efficacy by EGFR ex20ins mutation variant will be presented. Treatment-related adverse events (TRAEs; >20%) in PPP were diarrhea (91%), rash (45%), paronychia (38%), decreased appetite (35%), nausea (34%), dry skin (31%), vomiting (30%), increased blood creatinine (25%), stomatitis (24%), and pruritus (21%); the only grade ≥3 TRAE in ≥5% was diarrhea (22%). AEs leading to discontinuation in >2% were diarrhea (4%) and nausea (4%). A similar safety profile was observed in EXCLAIM. Conclusions: Mobocertinib demonstrated clinically meaningful benefit for pts with EGFR ex20ins+ mNSCLC in PPP and EXCLAIM cohorts, with a manageable safety profile. Clinical trial information: NCT02716116. [Table: see text]