bluuebunny/crossref_metadata_2025 huggingface dataset:
Continued monoclonal protein response beyond day 100 after auto-transplantation for multiple myeloma.
Authors: Gonsalves Wilson I. , Gertz Morie , Lin Yi , Lacy Martha , Dispenzieri Angela , Hayman Suzanne R. , Buadi Francis , Dingli David , Kapoor Prashant , McCurdy Arleigh Robertson , Singh Preet Paul , Gupta Vinay , Kumar Shaji
Published: March 2020

8587

Background: Patients (pts) undergoing an auto-transplant (ASCT) for multiple myeloma (MM) have disease assessment approximately 100 days later. This result may direct decisions of further therapy versus observation. However, some pts continue to experience a decline in their serum or urine monoclonal (M) - protein after day 100 without more therapy. Little is known about the prevalence and significance of this phenomenon. Methods: We identified 903 MM pts who underwent ASCT within 12 months (mos) of diagnosis (Dx) at our institution. Their day 100 post-ASCT M-protein from serum and urine electrophoresis with immunofixation as well as serum free light chains were compared to subsequent values during follow-up. The IMWG criteria were used to evaluate response. Results: Of the pts included, 510 (56%) were male and median age at ASCT was 59 (range 28-76). Median follow up from Dx and ASCT was 82 mos (95% CI; 75 - 86) and 74 mos (95% CI; 70 - 79) respectively. There were 453 (50%) pts seen in follow-up who had not achieved a CR at Day 100 nor initiated on maintenance therapy. Of these pts, 167 (37%) had a further decrease in their M-protein after day 100 at a median of 9.4 mos (95% CI; 8 – 10) post-ASCT. Given the time taken for maximal response, we assessed patients’ clinical response at one year post-ASCT. Compared to patients who did not have further clinical response between day 100 and 1 year, pts experiencing further response had a longer time to next therapy (TTNT) (43 mos vs. 17 mos, P < 0.001) as well as overall survival (OS) (96 mos vs. 62 mos, P < 0.001). Positive predictors for continued response included having an IgG isotype, evolution from a pre-existing MGUS, smoldering myeloma or solitary plasmacytoma and a Day 100 bone marrow plasma cell < 3%. In a multivariate analysis, elevated creatinine at Dx and lack of continued response predicted for shorter TTNT and OS post-ASCT. Older age and high-risk MM by FISH also predicted a shorter OS. Conclusions: In MM pts undergoing ASCT, continued M - protein response was seen in a third of the pts lacking a CR at day 100. This phenomenon appears prognostic and must be considered when interpreting studies evaluating post-ASCT response and the need for further therapy.
Strategies to overcome barriers to accrual (BtA) to NCI-sponsored clinical trials: A project of the NCI-Myeloma Steering Committee Accrual Working Group (NCI-MYSC AWG).
Authors: Weiss Matthias , Gertz Morie A. , Little Richard F. , Rajkumar Vincent , Jacobus Susanna J. , Abonour Rafat , Anderson Kenneth Carl , Barlogie Bart , Callander Natalie Scott , Gorak Edward J. , Matous Jeffrey , Mills Glenn Morris , Kane Robert C. , Katz Michael S. , Jensen LeeAnn , Omel James , Orlowski Robert Z. , Richardson Paul Gerard Guy , Munshi Nikhil C.
Published: March 2020

8592

Background: Accrual to NCI clinical trials(CT)is often slower than planned at times mandating premature closure resulting in loss of valuable resources and delay of scientific progress. Methods: The NCI-MYSC AWG identified 10 potential BtA. SWOG, ECOG and Alliance investigators were queried and agreed that these barriers impede accrual (results stratified for academic and community sites). The MYSC AWG developed in collaboration with NCI and FDA strategies to overcome these barriers. Results: Strategies listed for the 3 most often cited BtA: 1. Reimbursement for CT related expenses:increase awareness of improved reimbursement for phase II CT; tailor reimbursement according to CT complexity; request funds from industry and other sources ( http://biqsfp.cancer.gov ) for qualifying ancillary CT components. 2. Spectrum of available treatment options influences CT participation: educate patients and providers about the significance of a new CT using social media, presentations at national meetings and by adding educational material to CT protocol; encourage opinion leaders and advocacy groups not to promote a new therapy as “standard” in the absence of phase III data. 3. Requirement of CT specific therapy at NCI designated sites only: “MYSC AWG Drug Administration Table” describes NCI/FDA approved rules for CT specific drug administration; CT protocol will outline which standard treatment components of a CT can be administered at any site as long as protocol specific guidelines are followed and conduct is supervised by enrolling investigator. Examples of additional strategies to overcome identified BtA: determine feasibility, indication and insurance coverage of CT specific tests during protocol development; discourage narrow eligibility criteria; avoid competing CT; allow up to 1 cycle of commercially available therapy prior to enrollment; CIRB support for phase II CT. Conclusions: The MYSC Accrual Working Group developed in collaboration with NCI and FDA strategies to overcome barriers to myeloma clinical trial accrual. These strategies may be applicable to NCI-sponsored clinical trials evaluating interventions in other diseases.
Early mortality (EM) for newly diagnosed multiple myeloma (NDMM) in the Connect MM U.S. registry.
Authors: Terebelo Howard R. , Shah Jatin J. , Durie Brian G. , Abonour Rafat , Gasparetto Cristina , Mehta Jayesh , Narang Mohit , Thomas Sachdev P. , Toomey Kathleen , Pashos Chris L. , Swern Arlene S. , Sullivan Kristen A. , Street Thomas K. , Srinivasan Shankar , Nourbakhsh Ali , Hardin James W. , Rifkin Robert M.
Published: March 2020

8596

Background: EM occurring ≤ 6 mos from diagnosis of MM has been reported in several NDMM studies. Incidence of EM in the pre-novel-therapy era was 10–14% of patients (pts); causes included infection/pneumonia, renal failure, refractory disease, and cardiac events. Identifying risk factors and improving response rates (RR) could lower EM. Established risk factors only have a sensitivity of 61% and specificity of 74%. Introduction of novel therapies is improving RRs and changing the profile of morbidity risk factors. Fewer indwelling catheters, better antibiotics, and bisphosphonates have reduced morbidity and mortality in MM. This analysis aims to better understand the causes of EM in this new era. Methods: Connect MM is a prospective observational registry of NDMM pts. Since 2009, 1494 pts in 228 US centers have been enrolled. Baseline characteristics were compared for pts who died ≤ 6 mos after enrollment vs pts who survived > 6 mos. Multivariate logistic analyses identified significant associations between baseline characteristics and EM. Results: Most pts received novel therapies (91%). In the entire cohort, EM occurred in 103 pts (7%), of which 93 were treated (6.5%). EM associated characteristics by multivariate analyses (P< 0.05) were: age, ISS disease stage, PS, history of hypertension, hypercalcemia, lower clonal bone marrow cells (subject to further study), and platelet count. Venous thromboembolism and cytogenetics were not risk factors. Causes of the 103 early deaths were: MM progression (38%), cardiac failure (13%), infection (7%), pneumonia (6%), renal failure (4%), sudden death (3%), vascular event, bleeding, pulmonary embolism (1% each), other (15%) and unknown (13%). Conclusions: It is important to recognize EM as a distinct entity in MM. Better understanding of the biology and pt characteristics is required to further reduce its incidence. This is the first assessment of EM in a registry where almost all pts received novel agents. Of the 103 early deaths, 38% were due to MM, representing a 2.6% incidence in the total cohort (under further review). Although the 7% EM in Connect MM is encouraging, there is still room for improvement. Additional analyses on improvements and causes of death should be performed.
Results of a phase I/II study (NCT01365559) of carfilzomib (CFZ) replacing bortezomib (BTZ) in BTZ-containing regimens for BTZ-treated patients (pts) with relapsed and refractory multiple myeloma (MM).
Authors: Berenson James R. , Hilger James D. , Dichmann Robert , Patel-Donnelly Dipti , Boccia Ralph V. , Bessudo Alberto , Stampleman Laura , Gravenor Donald , Eshaghian Shahrooz , Chamras Hilda , Nassir Youram , Swift Regina A. , Vescio Robert A.
Published: March 2020

8599

Background: Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient phase I/II trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZEcontaining regimens to which pts have progressed. Methods: Eligible pts progressed while receiving their most recent BTZEcontaining regimen after at least 4 doses of BTZ at ≥1.0 mg/m² in ≤4 weeks per cycle. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZEcontaining regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen. Results: Of 37 enrolled pts, 33 were evaluable for efficacy and 37 for safety. Pts received a median of 4 prior treatments (range, 1-23) and 2 different BTZ-containing regimens (range, 1-13). Pts were treated with CFZ and a variety of different combinations of agents, including: bendamustine, clarithromycin, cyclophosphamide, dexamethasone, melphalan, methylprednisolone, pegylated liposomal doxorubicin, thalidomide, lenalidomide, and ascorbic acid. Pts have completed a median of 3 cycles with 12 pts going on to maintenance. One of 14 combinations, CFZ + ascorbic acid + cyclophosphamide, has reached a MTD at 45 mg/m2. Clinical benefit was seen in 23 (70%) evaluable pts (complete response = 6%; very good partial response = 18%; partial response = 21%; minor response = 24%) with another 18% showing stable disease. The median time to progression is 8.8 mo. (95% CI: 6.4-11.1 mo.) with 21 pts progressing overall and 9 progressing on study treatment. The most common ≥ G3 adverse events were lymphopenia (35% of pts), thrombocytopenia (19%), neutropenia (11%), and anemia (8%). Conclusions: These results suggest that replacement of BTZ with CFZ in a BTZ-containing combination regimen to which a MM patient is failing often leads to responses and is well-tolerated. Clinical trial information: NCT01365559.
Cure candidates: Characteristics of >10yr progression-free survivors (PFS-10) and continuous CR (CCR-10) after total therapy 1 and 2 (TT1, TT2) for multiple myeloma (MM).
Authors: Waheed Sarah , Van Rhee Frits , Rosenthal Adam , Usmani Saad Zafar , Waheed Mian Adnan , Hoering Antje , Barlogie Bart
Published: March 2020

8603

Background: Our TT studies demonstrate that long term progression free survival is achievable in MM pointing to the possible curability of MM. We report here on the base line characteristics of 33/231 TT1 patients and 109/475 TT2 patients qualifying for PFS-10, including 45/245 randomized to the control arm and 64/230 randomized to thalidomide. Methods: Baseline and response levels were compared between <10yr and >=10yr survivors and logistic regression applied to identify the critical features linked to PFS-10 status. Results: Compared to the remainder, PFS>=10yr and CCR>=10yr were characterized by lower frequencies of cytogenetic abnormalities (CA), B2M>=3.5mg/L and age >=65yr. More females and more patients with platelets >150.000/uL qualified for the >=10yr category. Finally, timely administration of 2 transplants was also over-represented in these patients. Conclusions: Long-term survival PFS-10 and CCR-10 were adversely affected by by CA and elevated B2M levels. Females more frequently attained PFS-10. Assessment of MRD by 8-color flow cytometry in these patients is in progress and will be presented at the meeting. Clinical trial information: NCT00580372, NCT 00083551. [Table: see text] [Table: see text]
HM1.24/CD317-directed immunotoxin to eliminate malignant plasma cells in vitro and in vivo.
Authors: Gramatzki Martin , Staudinger Matthias , Glorius Pia , Klausz Katja , Kellner Christian , Günther Andreas , Repp Roland , Burger Renate , Peipp Matthias
Published: March 2020

8604

Background: Targeted immunotherapy, based on antibodies against tumor-associated antigens, is a promising approach for the treatment of multiple myeloma (MM). Recently, antibody-based strategies delivering a toxic payload have documented impressive clinical activity in hematological malignancies. In particular, surface molecules overexpressed on malignant plasma cells and efficiently internalized represent promising targets for developing myeloma-directed immunoconstructs. Here, the identification of CD317 (HM1.24) as a potent target structure and the characterization of a novel CD317-directed single-chain immunotoxin, HM1.24-ETA', is described. Methods: Using a novel screening tool, a panel of antibodies against MM-associated antigens was evaluated for their ability to mediate antigen-dependent delivery of a truncated version of Pseudomonas exotoxin A (ETA’) to MM cells. HM1.24-ETA' was generated by genetic fusion of a CD317-specific single-chain Fv antibody and ETA'. The anti-myeloma activity of the E. coli-expressed immunotoxin was evaluated in vitro and in a xenograft mouse model. Results: By screening a panel of antibodies including CD38, CS1, IL-6R, CD138 and CD317, CD317 was identified as a suitable receptor to deliver ETA’ to MM cells. The subsequently designed recombinant HM1.24-ETA' immunotoxin efficiently inhibited growth of MM cell lines with halfmaximal growth inhibition at concentrations of less than 1 nM. Antigen-specific MM cell killing occurred via induction of apoptosis. The proliferation of IL-6 dependent INA-6 cells was completely inhibited by HM1.24-ETA' even in the presence of bone marrow stromal cells that otherwise strongly support tumor cell growth. Importantly, HM1.24-ETA' strongly triggered apoptosis (up to 80%) in freshly isolated tumor cells from 7 out of 7 MM patients. In a xenograft SCID mouse model, establishment of INA-6 plasma cell tumors was efficiently abrogated by treatment with HM1.24-ETA' immunotoxin (p < 0.04). Conclusions: The HM1.24-ETA' immunotoxin in vitro and in the preclinical xenograft model in vivo demonstrates that the CD317 antigen may represent a promising target structure for immunotherapy of MM using immunoconjugates with toxic payloads.
Risk-adapted maintenance therapy (MaintRx) after ASCT in first-line therapy for multiple myeloma (MM).
Authors: Kaufman Jonathan L. , Willey Joanne , Williams Michael E. , Tiscione Brynn , Buettner Arden , Neely Douglas , Green Mark R.
Published: March 2020

8607

Background: Maintenance lenalidomide improves survival in patients who have undergone induction therapy and then autologous stem cell transplant (ASCT) as first line management for MM. We studied how the extent of cytoreduction after induction therapy à ASCT (as measured by CR, VGPR, or PR as best response) influences MAINTRX prescribing preferences among American Hematology-Oncology physicians (AHOP). Methods: We studied 284 individual AHOPs using a proprietary, live, case-based market research tool to assess prescribing preferences. A core case scenario and variations based on extent of response to induction à ASCT was constructed. Preference data were acquired using blinded audience response technology. All responses for each scenario were obtained contemporaneously prior to any display of respondent selections. All sources of research support were double blinded. The core scenario involved a 59-year-old patient (42% plasma cells in BM, no cytogenetic abnormalities, CrCl 65ml/min, B2M 5.8, PS 1) treated with induction therapy of choice à ASCT. The same query was then posed in each of 3 settings: Following CR (or following VGPR or following PR) as best response, what, if any, further therapy would you recommend now? Results: See Table. Conclusions: Among patients with myeloma getting first-line therapy, MaintRx is almost uniformly preferred by AHOPs. Specific single or doublet therapy preferences are dependent upon best response to induction à ASCT treatment. Compared to the CR setting, preferences for 2 drug MaintRx are significantly increased in patients with VGPR (p <.0.001) or with PR (p < 0.001)] as best overall response. The potential for benefit from intensified MaintRx in these response subsets needs prospective phase III testing. [Table: see text]
Outcomes of patients with solitary plasmacytomas (SP) in the era of PET imaging and serum-free light chain (sFLC) testing: A single institution experience.
Authors: Koch Abby L. , Shain Kenneth H. , Alsina Melissa , Sullivan Daniel , Nishihori Taiga , Ochoa-Bayona Jose L. , Baz Rachid C.
Published: March 2020

8608

Background: SP can occur in bone (SPB) or in extramedullary sites (EMP) and generally accounts for ~ 3-5% of plasma cell dyscrasias. Up to 50% of SPB and 15% of EMP will progress to multiple myeloma (MM). We evaluated the utility and prognostic significance of positron emission tomography (PET) imaging and SFLC ratio (sFLCr). Methods: We retrospectively reviewed electronic medical records of patients with SP evaluated at Moffitt Cancer Center between 1990-2012. The diagnosis of SP was per IMWG criteria (BJH 2003, 121:749) (biopsy proven single site, negative skeletal survey, bone marrow biopsy with no more than 10% plasma cells). Initial and post therapy sFLCr as well as PET findings were correlated with progression to symptomatic MM (PFS). Radiation therapy (XRT) was at the discretion of the treating physician. Results: 135 patients were identified and 91 (67%) were males. The median age was 58 years (range 20-82). Consistent with prior reports, the PFS of the entire cohort was 43 months (95% CI 17.8-70). 23 patients had PET prior to progression. All patients had uptake in the primary lesion (except 4 who had resection of the primary). 8 patients had additional PET findings in other bony structure (PET+), and 15 did not (PET-). 2 and 6 of the PET- and PET+ patients progressed (median PFS Not reached (NR) vs. 8.1 months, p=0.021) respectively. Of the 49 patients with available sFLC data, 32 had an abnormal ratio (17 progressed) and 17 patients had a normal ratio (2 progressed). Abnormal baseline sFLCr was associated with progression (median PFS 19 months vs NR, p=0.012). Post XRT, 44 patients had an available sFLCr, of which 23 had an abnormal ratio and 21 a normal ratio. A persistent serum/urine m spike after XRT was associated with progression to MM (median PFS 20.8 months vs NR, p<0.0001). However, the association between Post XRT sFLCr and progression to MM was not statistically significant (median PFS 19 vs 43 months (abnormal vs normal ratio) p=0.2). Conclusions: PET imaging and sFLC are predictors of outcomes in SP and their routine inclusion in the diagnostic work up of patients with SP will result in a stage migration where patients outcomes are improved compared to historical controls.
Adjuvant radiotherapy after lymphadenectomy in melanoma patients: Final results of an intergroup randomized trial (ANZMTG 0.1.02/TROG 02.01).
Authors: Henderson Michael A. , Burmeister Bryan , Ainslie Jill , Fisher Richard , Di Iulio Julianna , Smithers Bernard Mark , Hong Angela , Shannon Kerwin F. , Scolyer Richard A , Carruthers Scott , Coventry Brendon J , Babington Scott , Duprat Joao , Hoekstra Harald J. , Thompson John F
Published: March 2020

9001

Background: The role of adjuvant radiotherapy following lymphadenectomy in melanoma patients identified as at high risk for further recurrence has been controversial. This final report of a multicenter randomized trial updates survival and lymph node field (LNF) control, and reports long term treatment toxicity, lymphedema and quality of life (QOL) (Lancet Oncol 2012;13:589-97). Methods: Patients at high risk of LNF relapse (≥1 parotid, ≥2 cervical or axillary or ≥3 groin positive nodes; or extra-nodal spread of tumour; or minimum metastatic node diameter of 3cm (neck or axilla) or 4cm (groin)) received adjuvant radiotherapy (ART) (48Gy in 20 fractions) or observation (OBS). LNF relapse, as a 1st relapse, was the primary endpoint; morbidity, QOL, patterns of relapse, disease free and overall survival were secondary endpoints. A target sample size of 250 enabled detection of a difference in 3 year relapse rates of 30% and 15% to be detected (2-sided logrank test, power of 80%). Results: 250 patients from 16 centres were randomized from Mar 02 to Sept 07 (123 ART; 127 OBS) with 217 fully eligible (109 ART, 108 OBS). Mean follow-up 73 months (range 21–116). LNF recurrence was reduced in the ART arm (HR=0.52 (0.31- 0.88) p=0.023) but there was no difference in survival (HR=1.13 (0.82 – 1.55) p =0.21). QOL was assessed by comparison of area under the curve from baseline to 5 years (or recurrence) with the FACT-G tool using both total score and the 4 major domains (physical, social, emotional and functional wellbeing), no difference. Regional symptoms (standardised questionnaire) were higher in the ART arm (p=0.035). Limb volumes were higher in the ART arm (leg 7.3% difference p=0.014, arm 3.4% p=0.25). Grade 2-4 RT toxicity was common for head + neck: skin (33%); axilla: skin (44%), subcutaneous tissue (41%); Groin: skin (46%), subcutaneous tissue (67%), other (38%). Conclusions: RT reduced the risk of LNF relapse by 52% but there was no impact on survival. In the ART arm loco-regional symptoms were worse, limb volumes were somewhat increased and Grade 2 - 4 long term RT toxicity was relatively common. However QOL as assessed by a validated tool (FACT-G) was similar in both groups. Clinical trial information: NCT00287196.
Clinical efficacy and safety of lambrolizumab (MK-3475, Anti-PD-1 monoclonal antibody) in patients with advanced melanoma.
Authors: Ribas Antoni , Robert Caroline , Daud Adil , Hodi F. Stephen , Wolchok Jedd D. , Kefford Richard , Patnaik Amita , Hwu Wen-Jen , Weber Jeffrey S. , Joshua Anthony , Hersey Peter , Gangadhar Tara C. , Joseph Richard Wayne , Dronca Roxana Stefania , Zarour Hassane M. , Ebbinghaus Scot , Gergich Kevin , Li Xiaoyun (Nicole) , Kang Soonmo Peter , Hamid Omid
Published: March 2020

9009

Background: Programmed death-1 (PD-1) is an inhibitory T-cell co-receptor that may lead to suppression of antitumor immunity. Lambrolizumab is a humanized monoclonal IgG4 antibody against PD-1. This study explored the safety and clinical activity of lambrolizumab in patients (pts) with advanced melanoma (MEL). Methods: In this ongoing phase 1b expansion study of MEL pts with or without previous ipilimumab (IPI) treatment, lambrolizumab was administered IV every 2 or 3 weeks until disease progression or unacceptable toxicity. Tumor response was assessed every 12 weeks by independent, central, blinded radiographic review per immune-related response criteria and RECIST 1.1. Results: As of December 1, 2012, 294 pts with MEL were enrolled, including 179 IPI-naive and 115 IPI-pretreated. Pts received lambrolizumab 10 mg/kg (n = 183) or 2 mg/kg (n = 111). Preliminary data from the first 85 consecutive pts dosed before April 25, 2012, who had independent radiologic review available as of December 3, 2012, indicate a confirmed overall response rate per RECIST 1.1 of greater than 35%, pooled across all doses and schedules and including both IPI-naive and IPI-pretreated patients. The median duration of response has not been reached as only 2 pts who had initial response discontinued due to disease progression, but the duration of confirmed responses range from 28+ to 240+ days (up to 8+ months). Among 133 pts who were dosed with lambrolizumab before July 31, 2012, and evaluable for adverse events (AEs) as of September 28, 2012, fatigue (22%), rash (18%), and pruritus (14%) were the most common drug-related AEs (mostly grade 1/2). The incidence of drug-related grade 3/4 AEs was 10% (24% regardless of attribution). Four drug-related cases of pneumonitis were reported, all of grade 1/2. Grade 3/4 drug-related hypothyroidism (n = 1) and hyperthyroidism (n = 1) were noted. Conclusions: Preliminary data suggest that lambrolizumab has significant antitumor activity and is well tolerated with manageable side effects in both IPI-naive and IPI-pretreated MEL pts. These data have led to an ongoing, international, randomized study of lambrolizumab versus chemotherapy in IPI-pretreated MEL. Clinical trial information: NCT01295827.
Whole exome and whole transcriptome sequencing in melanoma patients to identify mechanisms of resistance to combined RAF/MEK inhibition.
Authors: Wagle Nikhil , Van Allen Eliezer Mendel , Frederick Dennie T. , Cooper Zachary A. , Farlow Deborah Norman , Treacy Daniel , Goetz Eva M. , Johannessen Cory M. , Carter Scott L. , Taylor-Weiner Amaro , Hodis Eran , Lawrence Donald P. , Sullivan Ryan J. , Getz Gad , Gabriel Stacey B. , Flaherty Keith , Wargo Jennifer Ann , Garraway Levi A.
Published: March 2020

9015

Background: The RAF inhibitors vemurafenib and dabrafenib (D) and the MEK inhibitor trametinib (T) improve survival as monotherapies in BRAF-mutant melanoma. Since clinical mechanisms of resistance (MoR) result in MAPK pathway reactivation, recent efforts have focused on combined targeting of RAF and MEK. The combination of D and T (D/T) increased progression-free survival and response rate compared with D alone (Flaherty et al, NEJM, 2012). The MoR to this combination remain unknown. Methods: To look for clinical MoR to combined RAF/MEK inhibition, we performed whole exome (WES) and whole transcriptome sequencing (RNASeq) on tumors from 4 patients (pts) with acquired resistance and 1 pt with intrinsic resistance to D/T. Pre-treatment and post-resistance tumors from all pts were analyzed for point mutations, insertions/deletions, copy number alterations, alternatively spliced transcripts, rearrangements, and expression changes. Results: In 2 of 4 pts with acquired resistance, WES identified mutations in MEK1 and MEK2 that were undetectable in the pre-treatment tumors. In the 3rd pt, RNASeq identified an alternatively spliced isoform of BRAF lacking exons 2-10, also undetectable in the pre-treatment tumor. In the 4th pt, no obvious MoR were seen, though multiple alterations were enriched in the post-resistance tumor. The pt with intrinsic resistance had several alterations in genes that conferred resistance to RAF/MEK inhibition when overexpressed in BRAF-mutant cell lines. Integration of WES and RNASeq data also identified several co-existing alterations that may synergize to increase resistance. Conclusions: Analysis of combined WES and RNASeq data from pt samples provides a more complete picture of clinical MoR to MAPK-targeted therapy. Post-resistance tumors from 3 of 4 pts with acquired resistance to D/T had alterations in MAPK genes not detectable in the pre-treatment tumors, suggesting that resistance involves reactivation of the MAPK pathway despite combined RAF/MEK inhibition. Alternative dosing of current agents, more potent RAF/MEK inhibitors, and/or inhibition of the downstream kinase ERK may be needed for durable control of BRAF-mutant melanoma.
Comparison of BRAF inhibitor (BRAFi)-induced cutaneous squamous cell carcinoma (cuSCC) and secondary malignancies in BRAF mutation-positive metastatic melanoma (MM) patients (pts) treated with dabrafenib (D) as monotherapy or in combination with MEK1/2 inhibitor (MEKi) trametinib (T).
Authors: Cebon Jonathan S. , Flaherty Keith , Weber Jeffrey S. , Kim Kevin , Infante Jeffrey R. , Daud Adil , Hamid Omid , Kefford Richard , Schuchter Lynn Mara , Sosman Jeffrey Alan , Sznol Mario , Sharfman William Howard , Gonzalez Rene , Andrews Miles Cameron , Dronca Roxana Stefania , Long Georgina , Little Shonda M , Sun Peng , Patel Kiran , McWilliams Robert R.
Published: March 2020

9016

Background: The MAP kinase (MAPK) pathway is of critical importance for keratinocyte proliferation and maturation and is essential for epidermal homeostasis. Occurrence of hyperproliferative skin lesions including keratoacanthomas (KA) and cuSCC are considered a class effect of BRAFi [Anforth 2012, Chu 2012, Mattei 2012]. These effects, as well as promotion of pre-existing RAS-driven malignancies, may be caused by paradoxical activation of the MAPK pathway downstream of BRAF in wild-type BRAF cells. As MEK inhibition blocks downstream MAPK signaling, it was hypothesized that addition of a MEKi to a BRAFi would abrogate these effects [Su, 2012]. Methods: This 4-part phase I/II study enrolled 365 BRAFV600E/Kmutated MM pts in Parts B-D. In part C, 162 pts (BRAFi and MEKi treatment-naïve, ≥ 18 yrs; ECOG PS <2; RECIST measurable disease) were randomized to D monotherapy 150mg BID (D mono) vs. the combination of D (150 mg BID) and T (1 mg or 2 mg QD). Primary endpoints included safety and efficacy. Occurrence of cuSCC (including KA) across three arms in Part C and secondary malignancies with D+T across all Parts are provided below. Results: The difference in incidence of cuSCC between D mono and the D+T (150/1) was statistically significant, whereas the difference in incidence between D mono and D+T (150/2) was not. The median time to onset of cuSCC was 30 days in D mono compared to 282 and 152 days with D+T (150/1 and 150/2, respectively). Of 365 pts who received D+T, 2 (<1%) cases of new cancers (colorectal and gliobastoma) and 2 (<1%) cases of new primary malignant melanoma were reported. Conclusions: These data support the experimental hypothesis that the occurrence of cuSCC (including KA) can be substantially reduced and delayed by the addition of a MEKi to BRAFi therapy. Clinical trial information: NCT01072175. [Table: see text]
Identification of changing melanocytic lesions in patients on BRAF inhibitor therapy.
Authors: Yagerman Sarah , Flores Eileen , Marghoob Ashfaq A. , Lacouture Mario E.
Published: March 2020

9018

Background: Patients treated with BRAF inhibitors (BRAFi) have been observed to develop new primary melanomas. In addition, these patients often develop new nevi and involuting nevi. It remains a challenge to detect clinically subtle and histopathologically early melanomas in a background of such increased nevus volatility. In this study, we sought to quantify and describe the new, changing, and involuting melanocytic lesions observed in these patients. Methods: A retrospective chart and image analysis was conducted for all BRAFi treated patients referred to the Dermatology service at Memorial Sloan-Kettering Cancer Center. Initial overview and follow-up images were compared in MIRROR Body Mapping image system, DermaGraphiX software (Canfield Imaging Systems, Fairfield, NJ). A total count of new, changing, and involuting melanocytic lesions was determined in four anatomic areas: upper back, lower back, chest, and abdomen. Dermoscopy images of all changing lesions that were biopsied were evaluated for dermoscopic pattern and for the presence or absence of any melanoma specific features. Results: Average photography follow-up was 261 days (n=21). The average number of combined new and changing melanocytic lesions was 13.1, 16.4, 9.5, and 6.1 for the upper back, lower back, chest, and abdomen respectively. The average number of involuting melanocytic lesions was 8.0, 4.0, 4.3, and 3.4 for the upper back, lower back, chest, and abdomen respectively. Of all new and changed lesions, 38 were biopsied revealing 31 benign melanocytic lesions and 7 melanomas (18% of lesions biopsied). All 7 melanomas revealed at least one melanoma specific structure, with the most significant dermoscopic discriminate being negative network. Conclusions: Given the setting of highly volatile melanocytic changes in BRAFi treated patients and that 18% of biopsied lesions were melanomas; we propose the use of total body photography and dermoscopy as a method for the identification and monitoring of secondary atypical pigmented lesions.
Gene expression profile of primary cutaneous melanomas to distinguish between low and high risk of metastasis.
Authors: Lawson David H. , Russell Maria , Wilkinson Jeffrey , Amaria Rodabe Navroze , Gonzalez Rene , Gerami Pedram , Lyle Stephen , Jackson Gilchrist L. , Greisinger Anthony , Johnson Clare , Oelschlager Kristen M. , Stone John F , Maetzold Derek , Cook Robert W. , Delman Keith A.
Published: March 2020

9022

Background: Wide variability exists in metastatic rates of primary cutaneous melanoma (CM), even within TNM stage groupings. We developed an RT-PCR based gene expression profile (GEP) test to predict distant metastases in early stage CM. Methods: RNA was isolated from formalin-fixed, paraffin embedded biopsies or wide excisions of primary CM from patients with stage 1-4 CM (87% stage 1-2) converted to cDNA and analyzed using RT-PCR. All analyses were done using JMP Genomics and WinSTAT. Radial Basis Machine (RBM) modeling was used to predict metastasis-free survival (MFS) for the training set of 149 samples. Independent validation was performed on an additional 107 CM samples. RBM reports a binary Class 1 (low risk) and Class 2 (high risk). Results: Analysis of the training set resulted in a model with 85% receiver operating characteristic (ROC) and sensitivity of 82%. Prediction of metastatic risk for the validation set resulted in a 90% ROC and sensitivity of 89%. 30 of 33 stage 1-3 cases with a known metastatic event were accurately called Class 2. Kaplan-Meier analysis showed 5-year MFS rates of 88% and 25% for predicted Class 1 and Class 2, respectively, in the training set (p<0.0001, overall MFS=60%). Similarly, MFS was 95% and 26% for Class 1 and Class 2, respectively, in the independent validation set (p<0.0001, overall MFS=67%). Univariate Cox regression analysis of the validation set revealed that GEP, AJCC stage, Breslow thickness, and ulceration were each predictors of metastatic risk (HR=27.2, 11.4, 3.0, and 11.6, respectively, p<0.002 for each). Multivariate analysis showed GEP and AJCC stage were independent predictors of risk (HR=8.4 and 6.4 respectively, p<0.007 for both). Conclusions: This GEP signature provides an accurate stratification of metastatic risk in the training and validation samples independent of all other histologic factors. This test may serve as a prognostic tool for outcomes in patients with melanoma and for stratifying patients for clinical trials.
A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF wild-type melanoma.
Authors: O'Day Steven , Gonzalez Rene , Kim Kevin , Chmielowski Bartosz , Kefford Richard , Long Georgina , Loquai Carmen , Cowey Charles Lance , Hauschild Axel , Hainsworth John D. , Hersey Peter , Boyle Frances , Evans T. R. Jeffry , Hamid Omid , Meneses Nicole , Andresen Corina , Ren Min , O'Brien James P. , Flaherty Keith
Published: March 2020

9026

Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Melanoma responses in the phase I study led to this multicenter phase II trial of lenvatinib in separate cohorts of BRAF mutant and BRAF wild-type (wt) melanoma to provide an estimate of efficacy and to identify molecular correlates of clinical benefit. Primary analyses of clinical outcomes for the BRAF wt cohort are reported here; the BRAF mutant cohort will be presented at a later date. Methods: Eligible patients (pts) had stage IV or unresectable stage III BRAF wt melanoma with ≥1 prior treatment (26/96 [27%] pts received ≥3 treatments) and no prior VEGF-targeted therapy. Lenvatinib 24 mg once daily with dose reduction for toxicity was administered until disease progression or unmanageable toxicities. Primary endpoint was response rate by independent review (IRR) using RECIST 1.1. Archival tumor tissue and baseline and posttreatment serum samples were collected for molecular analysis. Results: 93 pts were treated (median [m] age: 64 y; male: 69%; 95% AJCC stage IV). Confirmed partial responses (PRs) were observed in 8 pts (9%) with a clinical benefit rate (CR+PR+durable SD ≥23 wks) of 32% by IRR. mPFS was 3.7 mos (95% CI, 2.5-4.0) by IRR and mOS was 9.5 mos (95% CI, 8.3-12.9); 46% pts required dose reduction for management of toxicity; 12% were withdrawn from therapy due to toxicity. Treatment-related adverse events reported in ≥20% pts included hypertension 59% (34% Gr 3/4), fatigue 58% (16% Gr 3/4), nausea 44% (3% Gr 3/4), diarrhea 43% (2% Gr 3/4), decreased appetite 38%, vomiting 29% (2% Gr 3), dysphonia 27%, and proteinuria and headache 26% each (4% and 1% Gr 3/4). Serum biomarker analysis showed baseline levels of serum angiogenic factors, such as angiopoietin-2, correlated with OS. More extensive biomarker analyses are reported in an accompanying abstract. Conclusions: Lenvatinib administered to pts with advanced BRAF wt melanoma was associated with frequent but manageable toxicity. Clinical benefit was seen in some pts. Predictive biomarkers for response to lenvatinib, such as the serum level of angiogenic factors, may be useful for future clinical trials. Clinical trial information: NCT01136967.
Lenvatinib combined with dacarbazine versus dacarbazine alone as first-line treatment in patients with stage IV melanoma.
Authors: Maio Michele , Hassel Jessica Cecile , Del Vecchio Michele , Testori Alessandro , Ascierto Paolo Antonio , Marshall Ernie , Glen Hiliary , Lorigan Paul , Meek Elaine , Liou Song , Hodge Jeff Paul , Bologna Fabrina , Dave Harish P.
Published: March 2020

9027

Background: Lenvatinib (E7080; LEN) is an oral, receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ . In a phase I study qd dosing of >/= 20mg LEN demonstrated PRs and prolonged SD in patients (pts) with advanced melanoma. Dacarbazine (DTIC) upregulates the proangiogenic factor VEGF and has been shown to confer resistance in melanoma cell lines (Lev, JCO 2004; 22:2092-2100). Treatment of melanoma pts with LEN + DTIC may potentiate the therapeutic effects of DTIC. Methods: This was a phase II study in pts with metastatic melanoma randomized 1:1 to receive LEN (20 mg QD) + DTIC (1000 mg/m2 Q 21 d) or DTIC (1000 mg/m2Q 21 d). Pts were stratified by LDH level and stage IV subclass. Eligible pts were ECOG PS 0/1 and had no prior systemic therapies. BRAF status was determined from circulating tumor DNA. The primary endpoint was PFS by independent assessment. Results: In a modified ITT analysis,a total of 78 of 81 pts were evaluable for efficacy; 59% were male, 59% were Stage IV M1c, 22% had elevated LDH, 29% had prior adjuvant therapy and 49% BRAF wild-type (wt). Most common AEs in the LEN + DTIC arm were hypertension (48%), nausea (38%), constipation (33%), and diarrhea (31%). Most common Grade 3/4 AEs in LEN + DTIC were hypertension (26%) and neutropenia (10%). There were no deaths due to an AE. Median PFS increased in LEN + DTIC compared to DTIC alone (see Table). An improvement in median PFS was observed in BRAFwt pts on the combination. Conclusions: A 2.7-fold increase in the median PFS was observed in pts administered LEN + DTIC compared to single agent DTIC. A 2.5 fold increase in the median PFS was observed in the combination arm in pts with BRAFwt melanoma. The AE profile observed with the LEN + DTIC was consistent with observed LEN monotherapy studies. These data suggest further evaluation of LEN + DTIC in BRAFwt melanoma is warranted. Clinical trial information: NCT01133977. [Table: see text]
Phase II study of low-dose peginterferon alfa-2b antiangiogenic therapy in patients with metastatic melanoma overexpressing basic fibroblast growth factor: An Eastern Cooperative Oncology Group study (E2602).
Authors: Go Ronald S. , Lee Sandra J. , Shin Donghoon , Callister Steven M , Jobe Dean A , Conry Robert Martin , Tarhini Ahmad A. , Kirkwood John M.
Published: March 2020

9038

Background: FGF-2 plays an important role in the pathogenesis and progression of melanoma. In particular, FGF-2 and its receptor are expressed in melanoma cells. We investigated the use of graded dosages Peg-IFN in patients with stage IV melanoma overexpressing FGF-2. Primary objective: suppression of plasma FGF-2 to normal levels (< 7.5 pg/mL). Secondary objectives: clinical efficacy of Peg-IFN and its association with angiogenic factor levels (FGF-2 and vascular endothelial growth factor /VEGF). Methods: Patients were eligible if they had stage IV melanoma from any primary site. Prior systemic therapies (< 4) were allowed including IFN. Plasma FGF-2 was measured at baseline (Step 1) and patients with levels > 15 pg/mL allowed to receive study treatment (Step 2). Peg-IFN was given weekly at starting dose of 0.5 mcg/kg/wk with increments every 3 weeks (maximum dose: 5 mcg/kg/wk) based on serial FGF-2 levels. Results: 207 patients entered into Step 1 and 45 (22%) overexpressed FGF-2 with a median level of 22 pg/dL (range, 15-216). 29 eligible patients enrolled into Step 2 and received treatment. The median age was 64 years and most had > 2 prior therapies. FGF-2 decreased in 28 (97%) patients with suppression to normal level in 10 (35%). The median time to FGF-2 suppression was 30 days (range, 14-116). The best clinical responses were PR (7%) and stable disease (17%). The median PFS and OS were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely to have a response or stable disease compared to those who did not (50% vs 11%; P=.03). Landmark analysis at 63 days showed similar OS between those who achieved FGF-2 suppression and those who did not (7.8 vs 7.7 months; P=.31). VEGF decreased in 27 patients (93%) during treatment and the levels paralleled those of FGF-2 over time. We did not find a compensatory rise in VEGF level among those with FGF-2 suppression. Conclusions: Graded dose Peg-IFN suppresses FGF-2 and has activity against metastatic refractory melanoma. Complete suppression of plasma FGF-2 was observed in 35% of the patients and correlated with clinical response but not OS. Clinical trial information: NCT00049530.
Open-label, multicenter safety study of vemurafenib in patients with BRAFV600 mutation–positive metastatic melanoma.
Authors: Larkin James M. G. , Del Vecchio Michele , Ascierto Paolo Antonio , Schachter Jacob , Garbe Claus , Neyns Bart , Mandala Mario , Lorigan Paul , Miller Wilson H , Guminski Alexander David , Berking Carola , Rutkowski Piotr , Queirolo Paola , Hauschild Axel , Arance Ana Maria , Brown Michael Paul , Mitchell Lada , Veronese Maria Luisa , Blank Christian U.
Published: March 2020

9046

Background: Vemurafenib (VEM), a BRAF kinase inhibitor, has demonstrated high response rates and improved progression-free and overall survival in pts with BRAFV600mutation–positive metastatic melanoma (mM). We present interim results from predefined subgroups from a large multicenter, open-label safety study of VEM in pts with mM (NCT01307397). Methods: Pts with BRAFV600mutation–positive histologically confirmed mM received VEM (960 mg BID) as first-line therapy or subsequent to previous therapies. Assessments for safety and efficacy were made every 28 days. Results: As of Feb 29, 2012, 2,265 pts have received VEM. Pts had a median age of 54.0 (13-95) yrs and median time since diagnosis of mM of 6.2 (0-351.9) mos. 59% had received prior systemic therapy. Median time of exposure to VEM as of the cut-off date was 3 (0.03-11.24) mos for the overall population and majority of subgroups, and approximately 2.5 mos for pts with ECOG ≥2 and age ≥75 yrs. 1537 (68%) pts were still receiving VEM at the cut-off date. 728 (32%) pts discontinued, most frequently because of PD (538/728 pts; 74%). Adverse events (AEs) were reported for 87% of all patients, with arthralgia (32%) and rash (26%) the most frequent. The incidences of AEs in the subgroups are summarized (Table). Although efficacy analyses are limited by the short duration of follow-up, six-month OS rate was 76% (95% CI 72-79%) and median PFS was 4.1 mos (95% CI 3.9-4.5 mos). Postbaseline tumor assessments were available for 63% and 30% of pts at wk 8 and 16, respectively. At wk 8 CR: 2%, PR: 57%, SD: 30%, PD: 6%. At wk 16 CR: 3%, PR: 46%, SD: 31%, PD: 15%. Conclusions: Although the overall safety profile of VEM in this study was consistent with previous clinical data, interim analyses of subgroups suggest that very elderly pts may be at higher risk of G3 AEs. Clinical trial information: NCT01307397. [Table: see text]
Pharmacodynamic effect of ipilimumab on absolute lymphocyte count (ALC) and association with overall survival in patients with advanced melanoma.
Authors: Postow Michael Andrew , Chasalow Scott D. , Yuan Jianda , Kuk Deborah , Panageas Katherine S. , Cheng Michael , Shahabi Vafa , Berman David Mark , Wolchok Jedd D.
Published: March 2020

9052

Background: Ipilimumab (Ipi) is a fully human monoclonal antibody that augments antitumor T-cell responses. Ipi has been shown to improve overall survival (OS) in 2 phase (ph) III trials of advanced melanoma, as monotherapy at 3 mg/kg in previously treated patients (pts) (MDX010-20) or at 10 mg/kg with dacarbazine in previously untreated pts (CA184-024). In preclinical and clinical studies, inhibition of CTLA-4 by Ipi resulted in increases in activation and proliferation of peripheral T cells and increases in ALC. Baseline ALC may be a prognostic biomarker in several cancer types. The current analyses aim to increase understanding of changes in ALC with Ipi treatment and association of these changes with OS. Methods: Data were from 6 studies of Ipi with chemotherapy (CT) (ph I 078; N=59) or without CT (ph III MDX010-20; ph II trials 004, 007, 008, and 022; N=1203), and Ipi monotherapy in an Expanded Access Program (N=117) or with commercially available Ipi (N=71) or BRAF inhibitors (N=39). ALC was measured at baseline, prior to each dose during induction (weeks 1, 4, 7, and 10) and at the end of induction (week 13). Cox proportional hazards models were used to estimate and test associations between ALC measures and OS. Results: In all studies, mean ALC increased significantly over time in pts who received Ipi, with or without CT (P<.0001 to P=.03). There was no significant mean increase in ALC in pts who received gp100 or BRAF-inhibitor monotherapy. In study MDX010-20, pts with a greater rate of change in ALC from baseline to week 7 tended to have longer OS (P=.0003). A similar association was found between OS and ALC ≥1000/µL after 2 Ipi doses. However, pts in MDX010-20 had an OS benefit from Ipi relative to gp100, regardless of rate of change in ALC (P=.14). Conclusions: In these analyses, consistent with inhibition of CTLA-4, Ipi induced an increase in mean ALC, even with the addition of CT. A positive association between rate of ALC increase and OS was observed, but this was not specifically predictive of OS benefit from Ipi. Therefore, ALC cannot currently be used to guide clinical management with Ipi. However, further prospective investigation may be warranted.