Multicenter phase II study of romidepsin plus lenalidomide for patients with previously untreated peripheral T-cell lymphoma (PTCL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7514-7514
Author(s):  
Jia Ruan ◽  
Jasmine M. Zain ◽  
Brett Palmer ◽  
Borko Jovanovic ◽  
Xinlei Mi ◽  
...  
Keyword(s):  
Response Assessment ◽  
Initial Therapy ◽  
Primary Objective ◽  
Cytotoxic Chemotherapy ◽  
Novel Agents ◽  
Margin Of Error ◽  
Grade 3 ◽  
Intensive Approach ◽  
Clinical Trial Information

7514 Background: PTCL are aggressive malignancies associated with poor prognosis when treated with cytotoxic chemotherapy. Novel agents, such as HDAC inhibitor romidepsin and immunomodulatory agent lenalidomide, have shown clinical activities as single agents and in combination in R/R PTCL. We hypothesize that upfront treatment with these agents is an effective and well-tolerated option to defer chemotherapy, particularly in patients who are not candidates for intensive approach. We report the findings of the first chemo-free combination of romidepsin plus lenalidomide as initial treatment for PTCL (ClinicalTrials.gov-NCT02232516). Methods: Patients with untreated PTCL who were over 60 or noncandidates for chemotherapy based on comorbidity CIRS score were eligible. Treatment was initiated with romidepsin 10 mg/m2 IV on d 1, 8, 15, and lenalidomide 25 mg PO on d 1-21 of 28-day cycle for up to 1 year, unless discontinued prior due to POD, toxicities, or withdrawal of consent. The primary objective was to evaluate ORR per Cheson criteria. Secondary objectives included safety, PFS, OS, DOR, and delay to chemotherapy. The sample size was 20 evaluable patients, which allows to estimate the underlying true response rate with the margin of error of an approximate 95% confidence interval equal to 0.22, assuming the true ORR = 0.5. Results: The study enrolled 29 subjects at 3 US centers, including 16 (55%) AITL, 11 (38%) PTCL-NOS, 1 ATLL and 1 EATCL. The median age was 75 (range 49-84), and M:F ratio was 1:1. Nineteen (66%) had stage III/IV disease, 23 (79%) had elevated LDH, and 9 (31%) had IPI 3-5. Treatment was well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (45%), thrombocytopenia (34%) and anemia (28%). Grade 3-4 non-hematologic toxicities included hyponatremia (45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%), hyperglycemia (14%), hypokalemia (14%), dehydration (10%), lung infection (10%) and sepsis (10%). At a median follow-up of 8 months, 20 subjects were evaluable with at least one response assessment, and received a median treatment of 6 cycles. The ORR was 75% (95%CI: 50.9%, 91.3%) with CR at 30% (11.9%, 54.3%). For AITL, the ORR was 85% (54.6%, 98.1%) with CR at 38% (13.9%, 68.4%). Median DOR was 4.2 months for all responders, and 14.3 months for CR patients. The estimated 1-yr PFS was 54.3% with 3-yr PFS at 36.2%, and the estimated 1-yr OS was 76.0% with 3-yr OS at 51.3%. Two subjects moved onto consolidative ASCT in remission, and 4 received additional cytotoxic chemotherapy after progression. Conclusions: This study provides the first demonstration that chemo-free biologic combination of romidepsin and lenalidomide is feasible and effective as initial therapy for PTCL patients who are not candidates for cytotoxic chemotherapy. These data justify further evaluation of such novel agents as a frontline strategy. Clinical trial information: NCT02232516.

Long-term trend of quality-adjusted time without symptoms or toxicities (Q-TWiST) of nivolumab+ipilimumab (N+I) versus sunitinib (SUN) for the first-line treatment of advanced renal cell carcinoma (aRCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6568-6568
Author(s):  
Robert J. Motzer ◽  
Toni K. Choueiri ◽  
Jessica May ◽  
Youngmin Kwon ◽  
Nifasha Rusibamayila ◽  
...  
Keyword(s):  
Good Health ◽  
Group Differences ◽  
Parametric Bootstrapping ◽  
Clinical Benefits ◽  
Grade 3 ◽  
Relative Gains ◽  
Clinical Trial Information ◽  
Over Time

6568 Background: After a minimum follow-up of 48 months (mos), the CheckMate 214 trial (phase 3, NCT02231749) continued to demonstrate a significant overall (OS) and progression-free (PFS) survival benefit for N+I vs. SUN in aRCC patients (pts) with intermediate (I) or poor (P) International Metastatic RCC Database Consortium (IMDC) risk factors (median OS: 48.1 vs. 26.6 mos, HR: 0.65, 95% confidence interval [95% CI]: 0.54, 0.78; 48-mos PFS: 32.7% vs. 12.3%, HR: 0.74, 95% CI: 0.62, 0.88) (Albiges et al. ESMO Open 2020). To further understand the clinical benefits and risks of N+I vs. SUN, we evaluated the Q-TWiST over time using up to 57 mos of follow-up in CheckMate 214. Methods: OS was partitioned into 3 states: time with any grade 3 or 4 adverse events (TOX), time without symptoms of disease or toxicity (TWiST), and time after progression (REL). The Q-TWiST is a metric that combines the quantity and quality (i.e., “utility”) of time spent in each of the 3 states TWiST, TOX, and REL. Prior research (Revicki et al, Qual Life Res, 2006) has established that relative gains in Q-TWiST (i.e., Q-TWiST gain divided by OS in SUN) of ≥ 10% and ≥ 15% can be considered as “clinically important” and “clearly clinically important”, respectively. Non-parametric bootstrapping was used to generate 95% CIs. To observe changes in quality-adjusted survival gains over time, absolute and relative Q-TWiST were calculated up to 57 mos at intervals of 12-mos. Results: With 57-mos follow-up, compared to SUN pts, N+I pts (N = 847) had significantly longer time in TWiST state (+7.1 mos [95% CI: 4.2, 10.4]). The between-group differences in TOX state (0.3 mos [95% CI: -0.2, 0.8]) and REL state (-1.2 mos [95% CI: -4.1, 1.5]) were not statistically significant. The Q-TWiST gain in the N+I vs. SUN arms was 6.6 mos (95% CI: 4.1, 9.4), resulting in a 21.2% relative gain. Q-TWiST gains progressively increased over the follow-up period and exceeded the “clinically important” threshold around 27 mos (Table). These gains were driven by steady increases in TWiST gains from 0.4 mos (after 12 mos) to 7.1 mos (after 57 mos). Conclusions: In CheckMate 214, N+I resulted in a statistically significant and “clearly clinically important (≥ 15%)” longer quality-adjusted survival vs. SUN, which increased over the longer follow-up time. Q-TWiST gains were primarily driven by time in “good” health (i.e., TWiST), which largely resulted from the long-term PFS benefits seen for N+I vs. SUN. Clinical trial information: NCT02231749. [Table: see text]

Long-Term Outcomes of Patients with Systemic Light Chain Amyloidosis (AL) Treated At Diagnosis with Risk-Adapted Stem Cell Transplant and Consolidation with Novel Agents.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3150-3150 ◽  
Author(s):  
Raymond L. Comenzo ◽  
Daniel E Fein ◽  
Hani Hassoun ◽  
Christina Bello ◽  
Joanne F Chou ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Light Chain ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Initial Therapy ◽  
Novel Agents ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematologic Response

Abstract Abstract 3150 Background: AL is a plasma cell dyscrasia characterized by the pathologic production of monoclonal light chains which misfold, deposit in various organs, including the heart, and can cause early death. High dose melphalan with stem cell transplant (SCT) results in high hematologic response rates and is a standard treatment for eligible patients. Achieving a complete hematologic response (CR) to SCT results in extended event-free and overall survival (OS), up to 8 and 13 years respectively in one large series. (Blood 2011; 118:4346) We have studied the addition of novel agents as consolidation following risk-adapted SCT (RA-SCT) in order to improve hematologic response (HR) rates and therefore outcomes. (Br J Haem 2007;139:224; Amyloid 2010;17:80a) In this report we examine the long-term outcomes of patients who received initial therapy with RA-SCT followed by consolidation for hematologic response less than CR (HR < CR). Methods: We performed a retrospective study to assess the HR rates, incidence of hematologic progression and overall survival (OS) of AL patients enrolled at diagnosis on two consecutive phase II trials using RA-SCT with consolidation for HR < CR (NCT01527032 and NCT00458822). OS was calculated from date of transplant to date of death or last follow up. Median event free survival (EFS) and OS were estimated by the method of Kaplan Meier. Cumulative incidence function was used to estimate the incidence of progression and death. Results: Between 2002 and 2011, 83 patients were enrolled and underwent RA-SCT on these trials and, following RA-SCT, those with HR < CR received consolidation with thalidomide and dexamethasone (TD) in the first and bortezomib and dexamethasone (BD) in the second trial. Thirty-six patients had cardiac involvement (43%) and all patients had free light chain measurements employed to score hematologic response and progression using consensus criteria (Am J Hematol 2005;79:319; Blood 2010;116:1364a). The frequency of CR following SCT was 24% and increased to 48% with post-SCT consolidation. The CR rates increased at 1 year compared to 3 months post-SCT from 21% to 36% with TD and from 28% to 62% with BD. With a median follow up of 5.1 years, the EFS is 4.5 years (95% CI: 2.6 to not reached) and the OS of all patients has not been reached (Figure 1). Sixteen patients died prior to hematologic progression and 26 patients have progressed with a cumulative incidence of hematologic progression of 8%, 18%, and 29% at 1, 2 and 3 years, respectively (Figure 2). Thirty-one percent (8/26) of relapsed patients have not required second-line therapy while among those who have, 78% (14/18) have responded including 44% (8/18) with CR. The median OS following hematologic progression was 5 years (95% CI: 2.6–5.8). Conclusions: Half of the AL patients on initial therapy trials employing RA-SCT and consolidation for HR < CR achieved CR with 36% of pts on the TD and 62% on the BD consolidation trial in CR at 1 year post-SCT respectively. At 3 years post-SCT the cumulative incidence of relapse was 29% and a third of relapsed patients did not require therapy, likely due to the very sensitive serum free light chain assay that detects low level hematologic progression in the absence of organ progression. Almost 80% of patients requiring second-line therapy responded, over half with CR, and median OS after relapse was 5 years. These results indicate that initial therapy with RA-SCT and consolidation is an effective initial treatment strategy for patients with AL in the era of novel agents. With over 5 years of follow up the median OS has not been reached. Disclosures: Comenzo: Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Use of the investigational agent MLN9708, an oral proteasome inhibitor, in the treatment of relapsed or refractory light-chain amyloidosis. Hassoun:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Giralt:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landau:Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Research Funding.

Nontransplant Treatment Outcomes with Generic Novel Agents in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5382-5382
Author(s):  
Chandran K Nair ◽  
Vineetha Raghavan ◽  
Atanu Bhattacharjee ◽  
Satheesh Babu ◽  
Sangeetha Nayanar
Keyword(s):  
Treatment Outcomes ◽  
Stem Cell Transplant ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Cell Transplant ◽  
Free Survival ◽  
Entire Cohort ◽  
Grade 3 ◽  
Stage 1

Abstract Introduction Introduction of novel agents (Immunomodulators-thalidomide/lenalidomide and proteasome inhibitors-bortezomib) has really changed the treatment outcomes in myeloma patients. This is applicable to patients both eligible and ineligible for autologous stem cell transplant. In developing countries, like India, access to the generic forms makes it easy for patients to have treatment with all types of novel agents. In this study, we did a retrospective audit of the treatment outcomes with the generic forms of novel agents in a group of transplant ineligible patients. Methodology All newly diagnosed myeloma cases from January 2011 to December 2014, who did not undergo stem cell transplant, were included for the study. Criteria for diagnosis and treatment response were according to the latest IMWG guidelines. Baseline demographic data and details regarding CRAB criteria, Performance Status (PS), comorbidities, type and duration of treatment, and toxicity were recorded. Toxicity was graded according to CTCAE v 4. Only the maximum grade of a particular toxicity per patient has been reported. Dates of death if applicable was noted, and if patients were alive, date of last follow up was documented. Survival was analysed by non-parametric methods (Kaplan Meier and Cox proportional hazard model) and the variables considered were 'treatment completed' versus 'not completed', 'response' (PR or more) versus 'no response', 'maintenance received' versus 'not received', 'age ≤65 years' versus 'age >65 years', and international staging system (ISS) ' stage 1' versus 'stage 2 or 3'. Analysis was performed with R v 3.2.0 (http://cran.r-project.org.) Results One hundred and nineteen patients (53 males, 66 females) with median age of 62 years (range 44-85) were included as per eligibility criteria. Eighty four (70%) patients had IgG, and 21 (17.6%) had IgA, and 14 (11.7%) had light chain myeloma. Twenty two (18.4%) patients were in ISS stage 1, 36 (30%) were in stage 2 and 39 (32.7%) were in stage 3, with data missing in 22 patients. Fifty seven (47.9%) patients were having comorbidity. Ninety seven patients (81%) were having PS ≤ 2 and 21(17.6%) had PS >2. Lenalidomide based regimen was given in 29 patients, thalidomide based in 65 and bortezomib based in 25 patients. Overall response (PR or more) was documented in 74 (72%), out of 102 evaluable patients. VGPR or more was documented in 56 (55%), and PR in 18(17.6%) patients. Seventy three (61%) patients had some form of toxicity. Grade 3 nonhematologic toxicity occurred in 7 patients (peripheral neuropathy in 2, diarrhea in 2 and DVT in 3), grade 4 in none. Grade 3-4 hematologic toxicity occurred in 8 patients (grade 3 anemia and thrombocytopenia in 3 each, and grade 4 thrombocytopenia in 2 patients). Median follow up duration was 22 months. Estimated 3 year OS for entire group was 60% (95 % CI 47-77%) (Figure 1). Median PFS was 22 months (95 % CI 19- 25) (Figure 2). Variables significantly predicting OS were, treatment completed or not (47 Vs 32 months, HR= 0.372, P= 0.011) and age ≤ 65 versus age >65(47 Vs 31 months, HR= 4.15, P<0.001). Similarly for PFS the significant variables were response or not (24 Vs 7 months, HR= 4.89, P<0.001) and ISS stage 1 Vs stage 2 or 3 (25 Vs 19 months, HR=2.39, P=0.021). Conclusion Treatment with the generic forms of novel agents leads to comparable response rates and survival in patients with myeloma. So, use of these agents with lower cost seems justifiable in the real world practice where it may be difficult to access the innovators for the exuberant cost. Figure 1. Overall survival for the entire cohort Figure 1. Overall survival for the entire cohort Figure 2. Progression free survival for the entire cohort Figure 2. Progression free survival for the entire cohort Disclosures No relevant conflicts of interest to declare.

Results of a phase II trial of docetaxel (DOC), bevacizumab (BEV), and androgen deprivation therapy (ADT) for biochemical relapse (BCR) after definitive local therapy for prostate cancer (PC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 54-54
Author(s):  
Rana R. McKay ◽  
Kathryn P. Gray ◽  
Julia H. Hayes ◽  
Glenn J. Bubley ◽  
Jonathan E. Rosenberg ◽  
...  
Keyword(s):  
Specific Antigen ◽  
Local Therapy ◽  
Primary Treatment ◽  
Entire Cohort ◽  
Psa Response ◽  
Secondary Endpoints ◽  
Psa Progression ◽  
Grade 3 ◽  
Clinical Trial Information

54 Background: Despite primary treatment for localized PC, 20-30% of men experience a BCR, detected by a rise in prostate-specific antigen (PSA). Though 30% of these patients develop metastatic disease, the optimal treatment of men with BCR has yet to be determined. In this trial, we evaluate the efficacy of DOC, BEV, and ADT for men with BCR after local therapy for PC. Methods: 41 men with a BCR and PSA doubling time of ≤10 months (mos) were enrolled. Patients received 4 cycles of DOC (75 mg/m2) every 3 weeks, 8 cycles of BEV (15 mg/kg) every 3 weeks, 18 mos of a luteinizing-hormone releasing hormone (LHRH) agonist, and 15 mos of bicalutamide (50 mg daily) beginning after completion of DOC. The primary endpoint was the proportion of patients free from PSA-progression 1 year after completion of ADT. Secondary endpoints included PSA response, testosterone recovery, and toxicity. Results: Median follow-up was 27.6 mos. Median age at diagnosis was 58 years. Median PSA at diagnosis was 6.7 ng/mL, with the majority of patients (59%) having Gleason 7 disease. Most patients underwent radical prostatectomy +/- radiation therapy (n=36). At baseline, 33 men (81%) had a normal testosterone (> 240 ng/dL). The table describes the PSA responses for the entire cohort. 10 men (28%) had a normal testosterone 6 mos after completing ADT. 17 men (47%) had a normal testosterone 12 mos after completing ADT, of whom 5 (29%) had a PSA <0.2 ng/mL at that time. There were 15% grade 1, 34% grade 2, 39% grade 3, and 12% grade 4 adverse events (AEs). The most frequent grade 3-4 AEs included neutropenia (24%), febrile neutropenia (11%), and hypertension (9%). Conclusions: DOC, BEV, and ADT for BCR resulted in complete responses in 16 men (44%) 1 year after completion of therapy. Longer follow-up is needed to determine the efficacy of this regimen. Clinical trial information: NCT00658697. [Table: see text]

Irinotecan (Iri) and buparlisib (B) in previously treated patients (pts) with metastatic colorectal cancer (mCRC).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 655-655 ◽  
Author(s):  
Joaquina Celebre Baranda ◽  
Greg Reed ◽  
Stephen K. Williamson ◽  
Raymond P. Perez ◽  
Maxine L. Stoltz ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Complete Analysis ◽  
Dose Titration ◽  
Human Trial ◽  
Ffpe Samples ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

655 Background: The PIK3CA pathway has oncogenic role in mCRC. Buparlisib is an oral pan-class PIK3CA inhibitor. It is currently being studied in combination trials for various malignancies. The primary objective of this phase I trial was to identify the maximum tolerated dose (MTD) for Iri plus B in pts with previously treated mCRC, with or without previous Iri therapy. We also performed PK analysis of each drug alone and in combination, determined clinical response to the combination, and evaluated achieval FFPE samples for somatic mutations in a panel of cancer associated genes, including PIK3CA for clinical correlation. Methods: A 3+3 dose titration method was used. Iri was administered intravenously every 14 days (one cycle) and B orally daily. Pts received the first dose of Iri on Cycle1 Day1. B was started 24 hours after the first dose of Iri. Safety and toxicity assessments were performed every cycle. Results: Twenty patients were enrolled: 4 in cohort 0 (Iri 120 mg/m2 + B 50 mg/d), 11 in cohort 1 (Iri 150 mg/m2 + B 50 mg/d), 5 in cohort 2 (Iri 150 mg/m2 + B 80 mg/d). The most common Grades 3/4 adverse events were neutropenia and abdominal pain. The MTD was Iri 150 mg/m2 + B 50 mg/d. The DLTs include male genital mucositis, grade 3 diarrhea, and asymptomatic grade 3 hyponatremia. In cohort 1, one pt experienced grade 2 delirium and a pt in cohort 2 had grade 3 psychosis. Of the 4 pts who received 4 cycles of therapy 2 had stable and 2 had progressive disease. No objective responses were seen. There is no significant change in the PK of Iri between Cycles 1 and 2. B at 50 mg had no consistent effect on the disposition of Iri given at 120 mg/m2 and 150 mg/m2. The Cmax and AUC for B show clear dose proportionality. Using targeted re-sequencing, a 48-gene panel that included AKT1, BRAF, KRAS, and PTEN was performed. The complete analysis of the correlative study will be presented in the meeting. Conclusions: This first human trial established that Buparlisib (50 mg qd) and Iri (150 mg/m2 q14d) are tolerable in combination. However, it is too early to determine the activity of this combination in the treatment of mCRC. Clinical trial information: NCT01304602.

Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4046-4046 ◽  
Author(s):  
Ian Chau ◽  
Johanna C. Bendell ◽  
Emiliano Calvo ◽  
Rafael Santana-Davila ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Median Duration ◽  
Gastroesophageal Junction ◽  
Survival Rates ◽  
Kidney Injury ◽  
Primary Objective ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

4046 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.

Efficacy and safety of lorlatinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) with one or more prior ALK tyrosine kinase inhibitor (TKI): A phase I/II study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9006-9006 ◽  
Author(s):  
Alice Tsang Shaw ◽  
Sai-Hong Ignatius Ou ◽  
Enriqueta Felip ◽  
Todd Michael Bauer ◽  
Benjamin Besse ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Efficacy And Safety ◽  
Resistance Mutations ◽  
Small Cell Lung ◽  
Cns Metastases ◽  
Grade 3 ◽  
Clinical Trial Information

9006 Background: Lorlatinib is a selective, potent, brain-penetrant, next generation ALK/ROS1 TKI active against most known resistance mutations. In Ph I of this Ph I/II study, lorlatinib showed robust clinical activity in ALK+ or ROS1+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were heavily pre-treated. In Ph II of this study, efficacy was explored based on prior ALK TKI tx as well as safety across all patients treated at the recommended Ph II dose. Methods: In this ongoing Ph II study (NCT01970865), pts with ALK+ or ROS1+ NSCLC, ± asymptomatic untreated or treated CNS mets, were enrolled into 6 expansion cohorts (EXP) based on prior tx (EXP 1-5, ALK+) and rearrangement status (EXP 6, ROS1+). Pts received lorlatinib 100mg QD. Primary objective was ORR and intracranial ORR (IC-ORR) by independent central review (ICR). Results: Efficacy (ALK+ pts with prior tx): At data cut-off (15 Aug 2016), 82 ALK+ pts were enrolled in cohorts EXP 2-5, received C1 no later than 31 Mar 2016 and were evaluated for ORR (ITT population); 52 were evaluated for IC-ORR and 35 were evaluated for IC-ORR response based on target lesions only (≥5mm; no prior radiotherapy or progression post prior radiotherapy). Confirmed response rates by ICR are reported in the table below. Safety (all pts): 116 ALK/ROS1+ pts were evaluated for safety at data cut-off. Most common tx-related AEs (TRAEs) and grade 3/4 TRAEs were hypercholesterolemia (90%, 17%) and hypertriglyceridemia (72%, 17%). Dose interruptions and reductions due to TRAEs were reported in 29% and 20% of pts, respectively. 14% of pts had tx-related SAEs. 5 pts (4%) discontinued tx due to TRAEs and there were no tx-related deaths. 74/116 pts (64%) remain on tx. Conclusions: Lorlatinib showed compelling clinical activity, with substantial IC activity, in ALK+ pts who received ≥1 prior ALK TKI, many of whom were heavily pre-treated. Clinical trial information: NCT01970865. [Table: see text]

Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 506-506 ◽  
Author(s):  
Rita Nanda ◽  
Minetta C. Liu ◽  
Christina Yau ◽  
Smita Asare ◽  
Nola Hylton ◽  
...  
Keyword(s):  
Single Agent ◽  
Complete Response ◽  
Bayesian Probability ◽  
Immune Mediated ◽  
Predictive Probability ◽  
Grade 3 ◽  
High Risk Breast Cancer ◽  
Risk Breast Cancer ◽  
Clinical Trial Information

506 Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]

Efficacy and safety of nivolumab (NIVO) plus ipilimumab (IPI) in patients with melanoma (MEL) metastatic to the brain: Results of the phase II study CheckMate 204.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9507-9507 ◽  
Author(s):  
Hussein Abdul-Hassan Tawbi ◽  
Peter A. J. Forsyth ◽  
Alain Patrick Algazi ◽  
Omid Hamid ◽  
F. Stephen Hodi ◽  
...  
Keyword(s):  
Objective Response ◽  
Complete Response ◽  
Median Number ◽  
Disease Assessment ◽  
Response Data ◽  
Grade 3 ◽  
Favorable Safety ◽  
The Brain ◽  
Clinical Trial Information

9507 Background: Brain metastases (BMts) are a major cause of morbidity/death in MEL. We report the first efficacy data in MEL patients (pts) with BMts who received NIVO+IPI in study CheckMate 204. Methods: In this multicenter US trial (NCT02320058), MEL pts with ≥1 measurable BMt 0.5-3.0 cm and no neurologic symptoms or steroid Rx received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, then NIVO 3 mg/kg Q2W until progression or toxicity. Pts with severe adverse events (AEs) during NIVO+IPI could receive NIVO when toxicity resolved; stereotactic radiotherapy (SRT) was allowed for brain oligo-progression if an assessable BMt remained. The primary endpoint was intracranial (IC) clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] > 6 months). The planned 90-pt accrual is complete; we report efficacy and updated safety for 75 pts with disease assessment before the Nov 2016 database lock. Results: Median age was 59 yrs (range 22–79). Median number of induction doses was 3; 26 pts (35%) received 4 NIVO+IPI doses and 38 pts (51%) began NIVO maintenance. Response data are reported at a median follow-up of 6.3 months (Table). The IC objective response rate (ORR) was 56% (95% CI: 44–68); 19% of pts had a complete response. IC and extracranial responses were largely concordant. Rx-related grade 3/4 AEs occurred in 48% of pts, 8% neurologic, including headache and syncope. Only 3 pts (4%) stopped Rx for Rx-related neurologic AEs. One pt died of immune-related myocarditis. Conclusions: In CheckMate 204, prospectively designed to investigate NIVO+IPI in MEL pts with BMts, NIVO+IPI had high IC antitumor activity with objective responses in 56% of pts, CR in 19%, and no unexpected neurologic safety signals. The favorable safety and high anti-melanoma activity of NIVO+IPI may represent a new Rx paradigm for pts with asymptomatic MEL BMts and could change practice to avoid or delay whole brain RT or SRT. Clinical trial information: NCT02320058. [Table: see text]

First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9094-9094 ◽  
Author(s):  
Vassiliki Papadimitrakopoulou ◽  
Shirish M. Gadgeel ◽  
Hossein Borghaei ◽  
Leena Gandhi ◽  
Amita Patnaik ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
First Line ◽  
End Point ◽  
Background Data ◽  
Risk Of Progression ◽  
Grade 3 ◽  
Clinical Trial Information ◽  
Nonsquamous Nsclc ◽  
Radiologic Progression

9094 Background: Data from the randomized, phase 2 cohort G of KEYNOTE-021 (NCT02039674) showed that adding pembro to first-line CP in patients (pts) with advanced nonsquamous NSCLC significantly improved the primary end point of ORR (55% vs 29%, P = 0.0016) and the key secondary end point of PFS (HR 0.53, P= 0.0102) compared with CP alone and had a manageable safety profile (grade 3-4 treatment-related AEs, 39% vs 26%; treatment-related AEs leading to discontinuation, 10% vs 13%). We present updated efficacy for cohort G based on 5 mo additional follow-up. Methods: 123 pts with stage IIIB/IV, chemotherapy-naive, nonsquamous NSCLC and no EGFR mutation or ALK translocation were randomized to 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m2 Q3W ± 24 mo of pembro 200 mg Q3W; maintenance pemetrexed was permitted in both arms. Eligible pts in the CP arm who had radiologic progression could crossover to pembro monotherapy. Response was assessed per RECIST v1.1 by blinded, independent central review. All Pvalues are nominal. Results: As of Dec 31, 2016, median follow-up was 14.5 mo (range, 0.8-24.0). 36 of 48 pts (75.0%) in the CP arm who discontinued CP received subsequent anti–PD-1 or PD-L1 therapy. There was 1 additional response in each arm, and ORR was 56.7% (95% CI 43.2%-69.4%) with pembro + CP vs 30.2% (95% CI 19.2%-43.0%) with CP ( P = 0.0016). Median DOR was not reached for pembro + CP (range, 1.4+ to 18.6+ mo) and was 16.2 mo (range, 2.8 to 20.7+) for CP alone. PFS remained longer with pembro + CP (HR 0.49, 95% CI 0.29-0.83, P = 0.0035; median [95% CI] NR [9.7 mo-NR] vs 8.9 mo [6.2-10.3]; 12-mo estimate, 56% vs 34%). With 16 deaths in the pembro + CP arm and 23 deaths in the CP arm, HR for OS was 0.69 (95% CI 0.36-1.31, P= 0.13). Median OS was not reached in either arm; at 12 mo, estimated OS was 76% in the pembro + CP arm and 69% in the CP alone arm. Conclusions: With 5 mo additional follow-up, first-line pembro + CP continues to provide a substantial, clinically relevant improvement in efficacy over CP alone in pts with advanced nonquamous NSCLC, including an almost doubled ORR, halved risk of progression or death, and a trend toward improved OS despite a 75.0% crossover rate in the CP arm. Clinical trial information: NCT02039674.

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