Any-grade Treatment-emergent Adverse Events Research Articles

Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

Bintrafusp Alfa With CCRT Followed by Bintrafusp Alfa Versus Placebo With CCRT Followed by Durvalumab in Patients With Unresectable Stage III NSCLC: A Phase 2 Randomized Study

IntroductionPreclinical evaluation of bintrafusp alfa (BA) combined with radiotherapy revealed greater antitumor effects than BA or radiotherapy alone. In a phase 1 study, BA exhibited encouraging clinical activity in patients with stage IIIB or IV NSCLC who had received previous treatment. MethodsThis multicenter, double-blind, controlled phase 2 study (NCT03840902) evaluated the safety and efficacy of BA with concurrent chemoradiotherapy (cCRT) followed by BA (BA group) versus placebo with cCRT followed by durvalumab (durvalumab group) in patients with unresectable stage III NSCLC. The primary end point was progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by the investigator. On the basis of the recommendation of an independent data monitoring committee, the study was discontinued before the maturity of overall survival data (secondary end point). ResultsA total of 153 patients were randomized to either BA (n = 75) or durvalumab groups (n = 78). The median progression-free survival was 12.8 months versus 14.6 months (stratified hazard ratio = 1.48 [95% confidence interval: 0.69–3.17]), in the BA and durvalumab groups, respectively. Trends for overall response rate (29.3% versus 32.1%) and disease control rate (66.7% versus 70.5%) were similar between the two groups. Any-grade treatment-emergent adverse events occurred in 94.6% versus 96.1% of patients in the BA versus durvalumab groups, respectively. Bleeding events in the BA group were mostly grade 1 (21.6%) or 2 (9.5%). ConclusionsBA with cCRT followed by BA exhibited no efficacy benefit over placebo with cCRT followed by durvalumab in patients with stage III unresectable NSCLC.

Parsaclisib, a PI3Kδ inhibitor, in relapsed and refractory follicular lymphoma (CITADEL-203): a phase 2 study

Parsaclisib, a potent and highly selective PI3Kδ inhibitor, has shown clinical benefit in patients with relapsed or refractory (R/R) B-cell malignancies. This phase 2 study (CITADEL-203; NCT03126019, EudraCT 2017-001624-22) assessed efficacy and safety of parsaclisib monotherapy in patients with R/R follicular lymphoma (FL). Patients ≥18 years of age with histologically confirmed R/R FL (grade 1-3a) and prior treatment with ≥2 systemic therapies received parsaclisib 20mg once daily (QD) for 8 weeks then parsaclisib 20mg once weekly (weekly dosing group [WG]) or parsaclisib 20mg QD for 8 weeks then parsaclisib 2.5mg QD (daily dosing group [DG]); DG was selected for further assessment. Primary endpoint was objective response rate (ORR). At data cut-off (January 15, 2021), 126 patients had been treated (WG: n=23; DG: n=103). ORR (95% confidence interval [CI]) was 77.7% (68.4-85.3) with a complete response rate (95% CI) of 19.4% (12.3-28.4) in DG; median (95% CI) duration of response was 14.7 months (10.4-not estimable [NE]), median progression-free survival was 15.8 months (11.0-NE), and median overall survival was not reached. The most common any-grade treatment-emergent adverse events (TEAEs) among all treated patients included diarrhoea (n=48, 38.1%), nausea (n=31, 24.6%), and cough (n=28, 22.2%); the most common grade ≥3 TEAEs were diarrhoea (n=15, 11.9%), neutropenia (n=13, 10.3%), and colitis (n=7, 5.6%). Dose interruption, reduction, and discontinuation from TEAEs occurred in 46.8% (n=59), 17.5% (n=22), and 23.8% (n=30) of patients, respectively. Treatment with parsaclisib demonstrated rapid and durable responses, and a manageable safety profile in patients with R/R FL. Incyte Corporation.

A phase Ib/II study to assess the safety and preliminary efficacy of PM8002 in combination with nab-paclitaxel in patients with triple-negative breast cancer.

e13091 Background: PD-L1 and VEGF play important roles in immune escape and tumor angiogenesis and enhance cancer growth and metastasis. PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A. Here, we present our results from a Phase Ib/II study of PM8002 in combination with nab-paclitaxel in subjects with locally advanced or metastatic triple negative breast cancer without previous systematic treatment. Methods: Sixty subjects with locally advanced or metastatic triple-negative breast cancer (with no previous systematic treatment), shall be enrolled into Phase Ib and II studies for testing the safety and efficacy of PM8002 in combination with nab-paclitaxel. Six subjects were enrolled during Phase Ib with safety as the primary endpoint, with the remaining subjects enrolled for the Phase II study to evaluate both safety and efficacy with ORR as the primary endpoint. Each cycle contains 28 days. All subjects received PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Tumor responses were evaluated every 8 weeks. Results: As of February 03, 2023, a total of 25 subjects had received at least 1 dose of PM8002 in combination with nab-paclitaxel, including 6 subjects for Phase Ib and 19 subjects for Phase II. For Phase Ib, all 6 subjects received a full dose of PM8002 and nab-paclitaxel during the first cycle and no adverse events of special interest were observed during the 28-day period. Any-grade treatment emergent adverse events (TEAEs) occurred in 17 subjects (68.0%, 17/25); 3 subjects (12.0%, 3/25) with ≥ Grade 3 TEAEs. TEAEs related to PM8002 occurred in 12 subjects (48.0%, 12/25); 2 subjects (8.0%, 2/25) with ≥ Grade 3 TEAEs. Two subjects (8.0%, 2/25) discontinued PM8002 administration due to treatment-related adverse reactions (TRAEs), such as ascites and hypertension, both may be related to PM8002 and nab-paclitaxel. The most common TRAEs with PM8002 and nab-paclitaxel were anemia (16.0%, 4/25), fever (12.0%, 3/25) and neutropenia (12.0%, 3/25). Any-grade immune-related adverse events (irAEs) occurred in 2 subjects (8.0%, 2/25), such as hyperthyreosis; there was no ≥ Grade 3 irAEs occurred. Thirteen subjects completed at least one efficacy evaluation. Objective response rate (ORR) per RECIST 1.1 was 69.2%, including 9 partial responses (PRs), with 9 PRs occurring during the first evaluation. Three subjects achieved stable disease, with a total disease control rate (DCR) of 92.3%. Twenty-two subjects are still on treatment. Conclusions: PM8002 in combination with nab-paclitaxel showed acceptable safety and encouraging antitumor activity in locally advanced or metastatic triple-negative breast cancer. The Phase II study is still ongoing, and we are actively enrolling subjects to complete the study. Clinical trial information: ChiCTR2200060400 .

An age-specific pooled analysis of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-positive (HER2+) metastatic breast cancer (mBC) from DESTINY-Breast01, -02, and -03.

1006 Background: T-DXd is approved for use in pts with HER2+ unresectable or mBC after a prior anti-HER2-based regimen in the metastatic or (neo)adjuvant setting, based on the randomized phase 3 DESTINY-Breast03 study (Cortes et al. N Engl J Med 2022). Older pts with HER2+ mBC tend to have worse efficacy and safety outcomes, regardless of treatment (Evans et al. Cancer Res 2021). Outcomes of older pts treated with T-DXd have not been thoroughly examined. Here we report age-specific (<65 vs ≥65 years) efficacy and pooled safety analyses of T-DXd from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03. Methods: DESTINY-Breast01 (data cutoff [DCO], March 26, 2021) and DESTINY-Breast02 (DCO, June 30, 2022) enrolled pts whose disease progressed on trastuzumab emtansine (T-DM1); DESTINY-Breast02 compared T-DXd to chemotherapy of physician’s choice. DESTINY-Breast03 (DCO, July 25, 2022) included pts previously treated with trastuzumab and taxane; pts received either T-DXd or T-DM1. Results: At baseline, there were 44 (23.9%), 85 (20.9%), and 49 (18.8%) pts ≥65 years of age who received T-DXd in DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03, respectively. At DCO, median pooled treatment duration with T-DXd was 13.1 mo (range, 0.7-44.0) for pts <65 and 12.4 mo (range, 0.7-45.1) for pts ≥65. Key efficacy data are shown in the Table. Any-grade treatment-emergent adverse events (TEAEs), grade ≥3 TEAEs, and serious AEs were observed in 99.6%, 53.6%, and 24.3% of pts <65 and 100%, 65.5%, and 32.2% of pts ≥65, respectively. There were 125 (18.7%) and 45 (25.4%) TEAEs associated with T-DXd discontinuation in pts aged <65 and ≥65, respectively. Any-grade adjudicated drug-related interstitial lung disease/pneumonitis occurred in 11.8% of pts <65 and 17.5% of pts ≥65; grade 5 events occurred in 0.9% and 0.6% of pts <65 and ≥65, respectively. Additional efficacy and safety data will be presented. Conclusions: Results from this pooled analysis further demonstrate that T-DXd has a favorable benefit-risk profile in pts ≥65 years, with slightly increased toxicity, as expected. Clinical trial information: NCT03248492 , NCT03523585 , NCT03529110 . [Table: see text]

P.104 Treatments and outcomes for patients with spinal muscular atrophy (SMA) type 2: Findings from RESTORE registry

We aimed to describe real-world treatment patterns/outcomes for patients with SMA type 2 (SMA2). RESTORE is an ongoing SMA patient registry. We analyzed changes in motor milestones and disability scores and assessed treatment-emergent adverse events (TEAEs) for patients who received ≥1 disease-modifying therapy (DMT; gene therapy [onasemnogene abeparvovec (OA)] or SMN2 modulator [nusinersen/risdiplam]). As of Nov. 23, 2021, RESTORE included 48 patients with SMA2, and 29 (60.4%) were female. Eight (16.7%), 37 (77.1%), 2 (4.2%) and 1 (2.1%) had 2, 3, 4 and ≥4 SMN2 gene copies, respectively. Median age at SMA diagnosis was 14.0 months and at first DMT administration, 16.0 months. Median interval between diagnosis and first DMT was 1 month. Median age at first DMT differed between groups (p=0.0033): OA monotherapy, 16.5 months (n=24); nusinersen monotherapy, 25 months (n=10); risdiplam monotherapy, 8 months (n=1); switching from other DMT to OA, 12 months (n=11); and receiving add-on therapy to OA, 15.5 months (n=2). Of 26 patients with ≥2 motor milestone assessments (≥1 post-DMT administration), all but 4 (OA only [n=3], nusinersen only [n=1]) maintained or achieved new milestones: 13 (59.1%) received OA monotherapy; 6 (27.3%) switched from nusinersen to OA; 1 (4.5%) received add-on to OA; and 2 (9.1%) received nusinersen only. Median HFMSE score change was 5.5 (n=10), with median monthly change of 0.6 (n=10) for all patients, and 11.0 (n=5), with median monthly change of 0.7 (n=6) for patients receiving OA monotherapy. Any-grade TEAEs were recorded for 12/24 (50%) patients who received OA monotherapy, 7/11 (63.6%) who switched from nusinersen to OA, and 1/2 (50%) who received add-on treatment to OA. Of patients who received OA, 3 required non-oral feeding support and 2 required BiPAP ventilation. AEs in RESTORE are consistent with OA experience. No new safety signals were identified. OA is effective and has an acceptable safety profile for patients with SMA2.

1005P Indirect treatment comparisons of relative efficacy for aumolertinib vs osimertinib in EGFR-positive non-small cell lung cancer (NSCLC)

Aumolertinib (aumo), a third-generation (3rd gen) EGFR inhibitor (EGFRi), is being developed as a first-line treatment (1L tx) for patients with advanced EGFR mutation-positive (EGFR+) NSCLC. Osimertinib (osi) is a widely used 3rd gen EGFRi for 1L tx of EGFR+ NSCLC. Although both aumo and osi have demonstrated superior safety and efficacy to earlier generation EGFRis in clinical trials, no direct comparison of efficacy and safety has been done. The objective of this analysis was to compare progression-free survival (PFS), overall survival (OS), and any-grade treatment-emergent adverse events (AG-TEAE) for aumo vs osi utilizing an anchored indirect treatment comparison (ITC).

Bosutinib in Japanese patients with newly diagnosed chronic-phase chronic myeloid leukemia: final 3-year follow-up results of a phase 2 study

Bosutinib has been evaluated for treatment of chronic-phase chronic myeloid leukemia (CP-CML) in several clinical studies, including in Japan. This open-label, single-arm, phase 2 study evaluated the efficacy and safety of bosutinib at a starting dose of 400 mg once daily in Japanese patients (n = 60) with newly diagnosed CP-CML. The minimum follow-up period was 3 years and median duration of treatment was 35.9 months. At study completion, 60% of patients were still on treatment. Cumulative rates of major molecular response (MMR), molecular response4 (MR4), and MR4.5 at any time were 70.0%, 53.3%, and 48.3%, respectively. No patient who achieved MMR or MR4 had a confirmed loss of response. No patient experienced on-treatment transformation to accelerated/blast phase or died within 28 days of the last bosutinib dose. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100% (grade ≥ 3: 81.7%) of patients. The most common TEAEs were diarrhea (86.7%), increased alanine aminotransferase (55.0%), and increased aspartate aminotransferase (46.7%). No new safety signals emerged during the follow-up period. Bosutinib continues to demonstrate a favorable benefit/risk profile and is an important treatment option for Japanese patients with newly diagnosed CP-CML. Optimal management of TEAEs during initial treatment with bosutinib should be prioritized.Trial Registration: ClinicalTrials.gov ID: NCT03128411.

LIO-1: Initial phase 2 experience of lucitanib + nivolumab in patients with metastatic or recurrent cervical cancer (NCT04042116; ENGOT-GYN3/AGO/LIO) (034)

<b>Objectives:</b> Lucitanib is a potent, selective inhibitor of the tyrosine kinases VEGFR1-3, PDGFRα/ß, and FGFR1-3 that is being investigated in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab in four recurrent gynecologic malignancies (cervical, endometrial, ovarian, and ovarian/endometrial clear-cell cancers) in an ongoing phase II study, using a Simon's two-stage design. To maximize lucitanib exposure and potential clinical benefit of the combination, individualized lucitanib dose titration is utilized. We presented initial data from the cervical cancer cohort. <b>Methods:</b> Patients with metastatic or recurrent cervical cancer of squamous carcinoma, adenocarcinoma, or adenosquamous carcinoma histology, who received ≥1 prior platinum-based chemotherapy regimen, with or without bevacizumab, were enrolled. Prior treatment with a PD-1 or programmed cell death ligand-1 (PD-L1) inhibitor was prohibited. All patients-initiated treatment with lucitanib 6 mg orally once daily (QD) + nivolumab 480 mg intravenously every 28 days. Lucitanib dose was escalated from 6 mg to 8 mg and up to 10 mg QD in patients who met safety-based titration criteria. Tumor response was assessed by investigators per RECIST v1.1. Data cut-off was September 1, 2021. <b>Results:</b> Twenty patients have been treated to date (median treatment duration: 85 days, range: 1-343+); 15 (75%) remain on treatment (13 remain on the combination and two on nivolumab monotherapy). Eleven (55%) patients received ≥2 prior anticancer regimens; nine (45%) had prior bevacizumab. To date, 17 (85%) patients have completed ≥1 cycle; two patients have escalated lucitanib to a dose of 8 mg, and three to the maximum dose of 10 mg. The most frequent anygrade treatment-emergent adverse events (TEAEs) have been hypertension (<i>n</i>=13, 65%), decreased appetite (<i>n</i>=11, 55%), asthenia/fatigue (<i>n</i>=10, 50%), and nausea (<i>n</i>=10, 50%). The most frequent grade ≥3 TEAE has been hypertension (<i>n</i>=4, 20%). Three (15%) patients discontinued lucitanib due to a related TEAE (colonic fistula, hypertension, and proteinuria). As of the data cut-off, 17 patients had at least one post-baseline tumor assessment, with four confirmed partial responses (PRs), eight patients with stable disease (7 remain ongoing), and five patients with the best response of progressive disease reported. The durations of PR range from 1.8+ to 9.3+ months. Of the four responding patients, three had received prior bevacizumab. <b>Conclusions:</b> Promising signs of antitumor activity in patients with metastatic or recurrent cervical cancer were noted in this initial analysis. Toxicity has been manageable and is consistent with that previously reported for lucitanib and nivolumab, and other agents of both classes. Having met Simon's two-stage stage I requirements (≥3 confirmed responses), study accrual continues in stage II of the cervical cancer cohort. Additional and more mature data, including biomarker analyses, will be presented at the meeting.

Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis.

Bosutinib has been investigated in multiple clinical trials globally, including Japan, for treatment of chronic myeloid leukemia (CML). A pooled analysis of seven Pfizer-sponsored clinical trials evaluated the safety of bosutinib in Japanese (n = 138) vs non-Japanese (n = 1210) patients with CML. First-line bosutinib was administered in 54.3% vs 41.4% of patients, and second-line or later bosutinib in the remainder. Median treatment duration was 1.4 vs 2.3years, and median relative dose intensity 78.1% vs 90.0%. Any-grade treatment-emergent adverse events (TEAEs) occurred in 100.0% vs 98.9% (grade ≥ 3: 81.9% vs 75.2%). In both groups, the most common TEAEs relevant to bosutinib were gastrointestinal (92.8% vs 84.7%), liver function (72.5% vs 34.8%), rash (63.8% vs 37.4%), and myelosuppression (55.1% vs 50.7%). TEAEs led to dose reduction in 65.2% vs 50.6%, dose interruption in 78.3% vs 68.8%, and permanent treatment discontinuation in 30.4% vs 25.4% of patients. The safety profile of bosutinib in Japanese patients was generally consistent with that in non-Japanese patients, despite a higher incidence of gastrointestinal, liver function, and rash events. TEAEs were largely manageable with dose modifications and supportive care in both groups. These data may help optimize TEAE management and outcomes in Japanese patients receiving bosutinib for CML. Trial registration ClinicalTrials.gov: NCT02130557, NCT03128411, NCT00574873, NCT00261846, NCT01903733, NCT00811070, NCT02228382.

Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies

AbstractPhosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other tumor types [n = 25]) who were treated with the recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.

SUBGROUP ANALYSES OF ELDERLY PATIENTS AGED 70 YEARS IN MAGNIFY: A PHASE 3B INTERIM ANALYSIS OF INDUCTION R2 FOLLOWED BY MAINTENANCE IN RELAPSED/REFRACTORY INDOLENT NON-HODGKIN LYMPHOMA

Lenalidomide combined with rituximab (R 2 ) has shown complimentary clinical activity and is a tolerable regimen in both untreated and relapsed or refractory (R/R) patients (pts) with indolent non-Hodgkin lymphoma. Pts with advanced age at diagnosis are considered to be high risk, supporting post-hoc subgroup analyses by age, with a focus on pts aged ≥ 70 years from the MAGNIFY study. MAGNIFY is a multicenter, phase 3b trial (NCT01996865) in pts with R/R follicular lymphoma (FL) grades 1–3b, transformed FL (tFL), marginal zone lymphoma (MZL), and mantle cell lymphoma (MCL). Lenalidomide 20 mg on d 1–21 of a 28-d cycle + rituximab 375 mg/m 2 /wk cycle 1 and then every 8 wk starting with cycle 3 (R 2 ) is given for 12 cycles followed by 1:1 randomization in pts with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R 2 vs rituximab maintenance for 18 mo. The primary end point is progression-free survival (PFS) by 1999 International Working Group (IWG) criteria. Secondary end points include safety, CR rate, duration of response DOR, duration of CR DOCR, time-to-response TTR, time-to-next antilymphoma therapy, and overall survival. Data presented here focus on induction R 2 in efficacy-evaluable FL grade 1–3a and MZL pts (FL grade 3b, tFL, and MCL not included) receiving ≥ 1 treatment with baseline/postbaseline assessments. Post-hoc analyses were performed by analyzing data from pts aged ≥ 70 years at time of study entry. As of August 28, 2020, 394 pts have enrolled and 152 (39%) were aged ≥ 70 years. Baseline characteristics including histology, disease status, and prior treatments of pts ≥ 70 and the overall population were similar. Median PFS in the ≥ 70 subgroup was 40.1 months (95% CI, 28.6–NR). Overall response rate (ORR) and CR/CRu were 75% and 39%, with a median duration of response that was not reached (95% CI, 29.4–NR). Efficacy results for the overall population were similar; median PFS = 41.2 mo (95% CI, 38.7–NR), ORR = 75%, CR = 44%, and median DOR = NR (95% CI, 38.6–NR). In pts ≥ 70 the most common (≥ 20%) any-grade treatment emergent adverse events (TEAEs) were fatigue (44%), neutropenia (41%), diarrhea (34%), constipation (34%), and nausea (27%). Neutropenia (35%) was the only grade 3/4 TEAE occurring in > 10% of pts (febrile neutropenia occurred in 3 pts [2%]). TEAEs led to lenalidomide dose reduction in 71 pts (47%) and discontinuation in 42 pts (28%). Eighty-two pts ≥ 70 (54%) completed all 12 cycles of induction treatment, and 75 (49%) have entered the maintenance phase. Sixty-two pts ≥ 70 (41%), prematurely discontinued both lenalidomide and rituximab, due to TEAEs (n = 28; 18%), progressive disease (n = 14; 9%), patient withdrawal (n = 12; 8%), death (n = 4; 3%), and other reasons (n = 4; 3%). Neutropenia was the only TEAE leading to discontinuation of lenalidomide in more than 2 pts (n = 10; 7%). Similar to findings in the overall population, R 2 treatment in advanced-age pts with R/R FL and MZL resulted in encouraging efficacy, and with close attention to dose reduction there is a tolerable safety profile. These results suggest that R 2 should be considered as a therapeutic option for advanced-age pts with R/R FL and MZL.

A multicenter, open-label, randomized, phase III study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab versus treatment of physician's choice in patients with advanced endometrial cancer

<h3>Objectives:</h3> Results from a phase 1b/2 study showed lenvatinib (LEN) + pembrolizumab (pembro) has efficacy in patients (pts) with advanced endometrial carcinoma following prior treatment. Here, we describe the phase III study results of LEN + pembro vs treatment of physician's choice (TPC) following platinum-based therapy in pts with advanced endometrial cancer (aEC). <h3>Methods:</h3> Pts were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m² IV Q3W or paclitaxel at 80 mg/m² IV QW [3 weeks on; 1 week off]). Eligible pts had aEC with 1 prior platinum-based chemotherapy regimen or up to 2 prior platinum-based chemotherapy regimens, if 1 was given in the neoadjuvant/adjuvant setting. Randomization was stratified by DNA mismatch repair (MMR) status (centrally determined); pts with proficient (p)MMR tumors were further stratified by ECOG PS, geographic region, and prior history of pelvic radiation. Primary endpoints were PFS by blinded independent central review per RECIST v1.1 and OS. Key secondary endpoints included objective response rate (ORR) and safety. A graphical approach for multiplicity to control for type 1 error was used to test PFS for pts with pMMR aEC, then pts irrespective of MMR tumor status (ie, all comers), followed by OS (pMMR aEC, then all comers) and ORR (pMMR aEC, then all comers). Efficacy analyses were conducted in randomized pts; safety analyses were conducted in pts who received treatment. <h3>Results:</h3> A total of 827 Pts (pMMR, n=697; dMMR, n=130) received LEN + pembro (n=411) or TPC (n=416). Median follow-up was 12.2 mo for pts randomized to LEN + pembro and 10.7 mo for pts randomized to TPC (data cutoff October 26, 2020). PFS was significantly improved with LEN + pembro vs TPC in pMMR aEC (median 6.6 vs 3.8 mo; HR 0.60) and in all-comers (median 7.2 vs 3.8 mo; HR 0.56). OS was significantly longer with LEN + pembro vs TPC in pMMR aEC (median 17.4 vs 12.0 mo; HR 0.68) and in all-comers (median 18.3 vs 11.4 mo; HR 0.62). ORR was significantly greater with LEN + pembro vs TPC in pMMR aEC (30.3% vs 15.1%) and in all-comers (31.9% vs 14.7%). Additional results are in the table. Median treatment duration was 231 days with LEN + pembro and 104.5 days with TPC. Overall, any-grade treatment-emergent adverse events (TEAEs) occurred at similar rates across treatment arms. Grade ≥3 TEAEs occurred in 89% of pts with LEN + pembro and 73% of pts with TPC. In the LEN + pembro arm, 30.8% pts discontinued LEN, 18.7% discontinued pembro, and 14.0% discontinued both study treatments due to a TEAE; the most common TEAEs were hypertension (64%), hypothyroidism (57%), diarrhea (54%) and nausea (50%). <h3>Conclusions:</h3> LEN + pembro demonstrated statistically significant and clinically meaningful improvements in PFS, OS, and ORR vs TPC both in pts with aEC that was pMMR and in pts with aEC irrespective of MMR status. The safety profile of LEN + pembro was manageable and consistent with previously reported studies.

Abstract CT124: Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor

Abstract Background: The PARP inhibitor rucaparib is approved in the US for pts with recurrent ovarian or metastatic castration-resistant prostate cancer. This phase 1 study (NCT03499444) evaluated safety, pharmacokinetics (PK), and antitumor activity (per RECIST v1.1) of rucaparib in Japanese pts. Methods: Pts were enrolled in a 3+3 dose-escalation phase to establish the recommended dose (RD) in Japanese pts; dose-limiting toxicities (DLTs) were assessed in the first 21 days. Pts must have had an advanced solid tumor that had progressed on standard treatment. A dose-expansion phase enrolled pts at the RD to further assess safety, PK, and efficacy. Results: The visit cutoff was Oct 20, 2020; 29 pts received rucaparib, including 15 in the dose-escalation phase (400 mg BID, n=3; 500 mg BID, n=6; and 600 mg BID, n=6) and 14 in the dose-expansion phase at the RD of 600 mg BID. Median (range) time on treatment was 5.1 (1.3-16.4) months overall and 5.3 (1.4-16.4) months for 600 mg BID pts (n=20).One DLT was reported (treatment interruption &amp;gt;7 days due to grade 1/2 nausea, vomiting, diarrhea, fatigue; 500 mg BID cohort). Across all doses, the most frequent any-grade treatment-emergent adverse events (TEAEs) were alanine aminotransferase/aspartate aminotransferase increased (82.8%), anemia (82.8%), and nausea (69.0%); the most frequent grade ≥3 TEAE was anemia (51.7%). Among 600 mg BID pts, 25.0% (5/20) had a TEAE leading to treatment interruption or dose reduction, most commonly due to anemia (20.0%; 4/20).Steady-state PK was evaluated for the 400, 500, and 600 mg BID cohorts (Table).Most pts with measurable disease had a best response of stable disease (63.0%; 17/27); the confirmed objective response rate was 18.5% (5/27) overall and 21.1% (4/19) among 600 mg BID pts (Table).Conclusions: Rucaparib 600 mg BID had a manageable safety profile for Japanese pts with advanced solid tumors, with a PK profile similar to that of Western pts. These results support further exploration of rucaparib in Japanese pts. 400 mg BID(n=3)500 mg BID(n=6)600 mg BID(n=20)Overall(N=29)Baseline characteristicsAge, median (range), years67.0 (45.0-68.0)61.5 (44.0-73.0)59.5 (43.0-74.0)61.0 (43.0-74.0)Female, n (%)3 (100)6 (100)16 (80.0)25 (86.2)ECOG PS 0, n (%)a3 (100)4 (66.7)15 (75.0)22 (75.9)Tumor type, n (%)Ovarian2 (66.7)1 (16.7)9 (45.0)12 (41.4)Primary peritoneal1 (33.3)2 (33.3)2 (10.0)5 (17.2)Pancreatic004 (20.0)4 (13.8)Breast02 (33.3)1 (5.0)3 (10.3)Other01 (16.7)4 (20.0)5 (17.2)Steady-state PK dataCmax, mean (CV%), ng/mL1,690 (38.7)3,650 (61.9)b2,800 (37.0)cNCtmax, median (range), h1.48 (1.47-2.45)3.95 (2.47-9.95)b2.50 (0.93-9.83)cNCCmin, mean (CV%), ng/mL1,590 (38.7)2,380 (78.5)2,130 (44.4)NCAUClast, mean (CV%), h × ng/mL14,400 (36.6)30,200 (64.7)b23,800 (39.9)cNCCL/F, mean (CV%), L/h26.1 (45.2)22.1 (68.5)d24.3 (34.6)eNCAUC0-12, mean (CV%), h × ng/mL17,200 (35.8)33,900 (78.9)d28,100 (40.8)eNCEfficacy dataORR, n/N (%) [95% CI]1/3 (33.3) [0.8-90.6]0/5 (0) [0.0-52.2]4/19 (21.1) [6.1-45.6]5/27 (18.5) [6.3-38.1]aAll other pts had ECOG PS 1.bn=5.cn=18.dn=3.en=13.AUC0-12, area under the concentration-time curve up to 12 h; AUClast, area under the concentration-time curve up to last time point (10 h) with a quantifiable concentration; CL/F, apparent total clearance of drug after oral administration; Cmax, maximum concentration; CV, coefficient of variation; ECOG PS, Eastern Cooperative Oncology Group performance status; NC, not calculated; ORR, objective response rate; PK, pharmacokinetics; tmax, time to maximum concentration. Citation Format: Kenji Tamura, Koji Matsumoto, Kan Yonemori, Kosei Hasegawa, Jenn Habeck, Eric Jones, Jim Xiao, Aaron Enke, Keiichi Fujiwara. Evaluation of rucaparib in Japanese patients (pts) with a previously treated advanced solid tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT124.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS)

BackgroundATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC).MethodsPatients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks.ResultsOf 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6–1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1–10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration.ConclusionsRucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer.Trial registrationThis trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017–004166-10).

Phase 1b/2 SEASTAR trial: Safety, pharmacokinetics, and preliminary efficacy of the poly(ADP)-ribose polymerase (PARP) inhibitor rucaparib and angiogenesis inhibitor lucitanib in patients with advanced solid tumors.

3102 Background: Lucitanib is an oral, potent tyrosine kinase inhibitor that selectively inhibits VEGFR1–3, PDGFRα/β, and FGFR1–3. In preclinical studies, antitumor activity of rucaparib is enhanced by lucitanib through antiproliferative, antiangiogenic, and immunological mechanisms. We hypothesize that combining lucitanib and rucaparib is tolerable and can induce a higher hypoxic state and homologous recombination repair deficiency that may lead to greater sensitivity to PARP inhibition. Methods: Patients with advanced solid tumors who had ≥1 prior line of therapy were eligible. Patients with BRCA1/2-mutated ovarian cancer must have received prior PARP inhibitor. Rucaparib and lucitanib were escalated using a 3+3 phase 1b dose-escalation design from starting doses of 300 mg BID and 4 mg QD, respectively. Dose-limiting toxicities (DLTs) were assessed during the first 28 days of treatment. Plasma samples were collected for pharmacokinetic analyses. Genomic alterations were identified by local testing, or through central testing of plasma or tumor tissue. Results: As of February 1, 2021, 16 patients were treated with rucaparib + lucitanib and included in the analyses (Table). Patients had a median of 4 prior therapies; 1 patient had prior PARP inhibitor (olaparib) treatment. Median time on treatment was 58.5 days, with 2 patients ongoing as of the data cutoff date. A DLT of grade 3 proteinuria was seen in Cohort 1; no other DLTs have been reported. Across all cohorts, the most common any-grade treatment-emergent adverse events were nausea (n=9; grade ≥3, n=1), hypertension (n=8; grade ≥3, n=2) and ALT/AST increased (n=7; grade ≥3, n=3). Initial pharmacokinetic data indicated no drug interactions between the 2 agents. To date, 1 patient in Cohort 1 with PALB2-mutated advanced endometrial cancer had a confirmed partial response per RECIST v1.1, lasting 30 weeks; 6 patients had RECIST v1.1 stable disease (SD), including 1 patient each in Cohorts 1 and 3 with SD for ≥16 weeks. In addition, 1 patient in Cohort 2 with BRCA2-mutated castration-resistant prostate cancer continued to receive treatment despite initial progressing bone metastases, resulting in a prostate-specific antigen response (≥50% change) lasting 16 weeks and a best change in sum of target lesions of −46.3%. Conclusions: Initial findings suggest that rucaparib + lucitanib has an acceptable safety profile. The safety and efficacy of the combination are being further evaluated. Clinical trial information: NCT03992131. [Table: see text]

Abstract PD13-07: Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer

Abstract Background: Patients (pts) with metastatic triple-negative breast cancer (mTNBC) who have brain metastases represent a poor prognosis cohort with a high unmet clinical need. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). SN-38 can cross the blood-brain barrier and is a drug partner in central nervous system (CNS) disease regimens (PMID: 18784279; PMID: 26080460). Although antibody-based therapy raises concerns regarding CNS penetration, activity with SG has been seen in intracranial xenograft models (Brenner Neurooncol Adv 2019). In a subgroup analysis from ASCENT, the efficacy and safety of SG were evaluated in pts with stable brain metastases. Methods: In the phase 3 ASCENT study (NCT02574455), 529 pts with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Brain MRIs were required in pts with known brain metastases who were eligible if they had stable CNS disease for ≥4 wk by MRI. Per protocol, stable disease was defined as ≥2 wk from discontinuation of antiseizure medication and corticosteroid dose (≤20 mg prednisone equivalent) that was stable or decreasing for ≥2 wk before randomization. In these pts, brain MRIs were required throughout the study. The primary endpoint was progression-free survival (PFS) per independent central review (RECIST v1.1) in brain metastases-negative pts. Secondary endpoints included PFS per investigator assessment, PFS in the full population (in pts with/without brain metastases) by central review, objective response rate (ORR), overall survival (OS), and safety. Results: Overall, 61 of 529 (12%) enrolled pts had stable brain metastases at screening and were randomized to SG (n=32) or TPC (n=29). Median age was 53 y for SG and 51 y for TPC; all pts were female and had a median of 5 prior anticancer regimens. In this subset, median PFS was 2.8 mo (95% CI, 1.5-3.9) for SG vs 1.6 mo (95% CI, 1.3-2.9) for TPC by central review, and median OS was 6.8 mo (95% CI, 4.7-14.1) for SG vs 7.5 mo (95% CI, 4.7-11.1) for TPC. ORR for SG vs TPC, respectively, was 3% (1/32) vs 0% by central review, with a clinical benefit rate of 9.4% vs. 3.4%. Stable disease was achieved in 15 (47%) pts with SG vs 9 (31%) pts with TPC. In 53 pts who received at least 1 dose of treatment (SG, n=30; TPC, n=23), any-grade treatment-emergent adverse events (&amp;gt;20% with SG) for SG vs TPC were fatigue (63% vs 52%), diarrhea (50% vs 13%), neutropenia (43% vs 35%), nausea (43% vs 26%), decreased appetite (30% vs 17%), decreased neutrophil count (33% vs 22%), anemia (23% vs 35%), alopecia (23% vs 13%), and constipation (23% vs 22%). There were no treatment-related deaths. Two pts treated with SG are continuing study treatment for 16.2 and 6.3 mo as of the data cutoff date. Conclusions: Data interpretation in this population with poor prognosis is limited by the small sample size. In this exploratory analysis of pts with brain metastases from the phase 3 ASCENT study, SG was numerically better than TPC for tumor response and PFS but not OS. The safety profile was similar to that of the population without brain metastases for both study arms. SG is currently under clinical investigation for pts undergoing elective craniotomy for breast cancer with brain metastases or recurrent glioblastoma (NCT03995706) based on promising preclinical and intracranial clinical data. Citation Format: Véronique Diéras, Robert Weaver, Sara M. Tolaney, Aditya Bardia, Kevin Punie, Adam Brufsky, Hope S. Rugo, Kevin Kalinsky, Tiffany Traina, Leonard Klein, Delphine Loirat, Filipa Lynce, Brooke Daniel, Foluso Ademuyiwa, Sara A. Hurvitz, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Lisa Carey. Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-07.

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Subgroup Analyses of Elderly Patients Aged ≥ 70 Years in MAGNIFY: A Phase IIIb Interim Analysis of Induction R2 Followed By Maintenance in Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

Final Analysis of the Ro-CHOP Phase III Study (Conducted by LYSA): Romidepsin Plus CHOP in Patients with Peripheral T-Cell Lymphoma

Final Analysis of the Ro-CHOP Phase III Study (Conducted by LYSA): Romidepsin Plus CHOP in Patients with Peripheral T-Cell Lymphoma

A Phase I Study of CC-90002, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndromes (MDS): Final Results

A Phase I Study of CC-90002, a Monoclonal Antibody Targeting CD47, in Patients with Relapsed and/or Refractory (R/R) Acute Myeloid Leukemia (AML) and High-Risk Myelodysplastic Syndromes (MDS): Final Results