Pembrolizumab in microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) cancers: Updated analysis from phase 2 KEYNOTE-158 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2565-2565
Author(s):  
Michele Maio ◽  
Paolo Antonio Ascierto ◽  
Ludmila Manzyuk ◽  
Daniel Motola-Kuba ◽  
Nicolas Penel ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Tissue Sample ◽  
Guillain Barre Syndrome ◽  
Phase 2 ◽  
Contributing Factors ◽  
Open Label ◽  
Multiple Tumor ◽  
Guillain Barré Syndrome ◽  
Grade 3 ◽  
Guillain Barré

2565 Background: Approval of pembrolizumab for the treatment of unresectable or metastatic MSI-H/dMMR solid tumors that have progressed on prior therapy was supported by data from KEYNOTE-158 (NCT02628067). At the data cutoff of Dec 6, 2018, the ORR was 34.3% among 233 patients (pts) with MSI-H/dMMR solid tumors enrolled in all cohorts of KEYNOTE-158, 77.6% had duration of response (DOR) ≥24 mo, median PFS was 4.1 mo, and median OS was 23.5 mo. We present results from 351 pts enrolled in KEYNOTE-158 cohort K at the data cutoff of Oct 5, 2020. Methods: Cohort K of this phase 2, open-label study enrolled adults with any previously treated advanced noncolorectal MSI-H solid tumor, measurable disease per RECIST v1.1, and ECOG PS of 0–1. MSI-H/dMMR status was assessed locally from a tumor tissue sample and defined as ≥1 of 4 MMR proteins absent by immunohistochemistry or as ≥2 allelic loci size shifts of 5 microsatellite markers by PCR. Pts received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD, unacceptable toxicity, investigator decision, or withdrawal of consent. The primary endpoint was ORR per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints were DOR and PFS per RECIST v1.1 by BICR, OS, and safety. Efficacy was assessed in all pts who received ≥1 dose of treatment with ≥6 mo follow-up; safety was assessed in all treated pts. Results: 351 pts were enrolled in KEYNOTE-158 cohort K across multiple tumor types, including endometrial (22.5%), gastric (14.5%), small intestine (7.4%), ovarian (7.1%), cholangiocarcinoma (6.3%), and pancreatic (6.3%). 41.0% had 1 prior line of therapy; 55.6% had ≥2 prior lines. Median time from first dose to database cutoff (Oct 5, 2020) was 37.5 (range, 0.2–55.6) mo; 16.0% were continuing treatment. The ORR among the 321 eligble pts was 30.8% (CR, 27; PR, 72); median DOR was 47.5 mo (Table). Treatment-related AEs occurred in 64.7% of pts (grade 3–5, 12.0%), led to discontinuation in 6.6%, and led to death in 3 pts (myocarditis, pneumonia, and Guillain-Barre syndrome). Immune-mediated AEs and infusion reactions occurred in 20.2% of pts (grade 3–4, 4.3%) and led to death in 2 pts with no other contributing factors (myocarditis [AE start, day 26; death, day 33] and Guillain-Barre syndrome [AE start, day 22; death, day 41]). Conclusions: Pembrolizumab demonstrated a high ORR (30.8%), durable clinical benefit, and a manageable safety profile in this heavily pretreated advanced MSI-H/dMMR noncolorectal pan-tumor population. Clinical trial information: NCT02628067. [Table: see text]

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Carlos A. Gomez-Roca ◽  
Eduardo Yanez ◽  
Seock-Ah Im ◽  
Eduardo Castanon Alvarez ◽  
Hélène Senellart ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Phase 2 ◽  
Open Label ◽  
Previously Treated ◽  
Grade 3

3564 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (̃2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mo (range, 5.9-13.1). ORR was 22% (95% CI, 9–40; table). Grade 3–5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. Clinical trial information: NCT03797326. [Table: see text]

LEAP-005: A phase 2 multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the gastric cancer cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4030-4030
Author(s):  
Hyun Cheol Cheol Chung ◽  
Zarnie Lwin ◽  
Carlos A. Gomez-Roca ◽  
Federico Longo ◽  
Eduardo Yanez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Advanced Gastric Cancer ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Phase 2 ◽  
Open Label ◽  
Previously Treated

4030 Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients. Clinical trial information: NCT03797326.

LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the colorectal cancer cohort.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 94-94
Author(s):  
Carlos Gomez-Roca ◽  
Eduardo Yanez ◽  
Seock-Ah Im ◽  
Eduardo Castanon Alvarez ◽  
Helene Senellart ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Final Visit ◽  
Open Label ◽  
Previously Treated ◽  
Grade 3

94 Background: Pembrolizumab (pembro), an anti-PD-1 antibody, is approved for the treatment of patients (pts) with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair (MMR) deficient colorectal cancer, both as first-line treatment and after progression following treatment with fluoropyrimidine, oxaliplatin, and irinotecan. The combination of lenvatinib, a multiple receptor tyrosine kinase inhibitor, and anti-PD-1 treatment showed synergistic antitumor activity in preclinical models. LEAP-005 (NCT03797326) is evaluating the efficacy and safety of lenvatinib plus pembro in pts with previously treated advanced solid tumors. We present findings from the colorectal cancer cohort. Methods: In this nonrandomized, open-label, phase 2 study, adult pts (aged ≥18 y) with histologically/cytologically documented metastatic and/or unresectable colorectal cancer, non–MSI-H/pMMR tumor per local determination, previous treatment with oxaliplatin and irinotecan in separate lines of therapy, measurable disease per RECIST v1.1, ECOG PS of 0‒1, and a tissue sample evaluable for PD-L1 expression were eligible. Pts received lenvatinib 20 mg QD plus pembro 200 mg Q3W for up to 35 cycles of pembro (~2 y) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 y in pts with clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 wks, then Q12W to week 102, and Q24W thereafter. Results: 32 pts with colorectal cancer received treatment with lenvatinib plus pembro (median age, 56 y [range, 36-77]; male, 81%; 3L, 91%); median time from first dose to data cutoff (April 10, 2020) was 10.6 mos (range, 5.9-13.1) ORR was 22% (95% CI, 9-40; Table). Grade 3-5 treatment-related AEs occurred in 16 (50%) pts. Treatment-related AEs led to treatment discontinuation in 3 pts (grade 2 ischemic stroke [n = 1], grade 3 increased liver transaminases [n = 1], grade 5 intestinal perforation [n = 1]). Efficacy Results. Clinical trial information: NCT03797326. NR, not reached aConfirmation was not required for best overall response of SD, but a final visit response of SD or better must have occurred ≥6 wks after starting study treatment Conclusions: In pts with previously treated advanced non–MSI-H/pMMR colorectal cancer, lenvatinib plus pembro demonstrated promising antitumor activity and a manageable safety profile. Enrollment in the colorectal cohort was expanded to 100 pts. [Table: see text]

Guillain-Barre Syndrome Following Azacitidine for Treatment of Myelodysplastic Syndrome.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4861-4861
Author(s):  
Phoebe E. Harvey ◽  
Mary Lynn R. Nierodzik ◽  
Jennifer Wu
Keyword(s):  
Case Report ◽  
Lower Extremity ◽  
Myelodysplastic Syndrome ◽  
Guillain Barre Syndrome ◽  
Lower Extremity Weakness ◽  
Guillain Barré Syndrome ◽  
Demyelinating Process ◽  
Grade 3 ◽  
Guillain Barré ◽  
Ecog Ps

Abstract Abstract 4861 Background In this case report we describe a 65-year-old woman with myelodysplastic syndrome who was started on azacitidine and subsequently developed Guillain-Barre Syndrome (GBS). To our knowledge, there are no other reported cases of azacitidine-associated GBS. Case Report This patient was diagnosed in 2004 when a bone marrow biopsy done for anemia showed erythroid, myeloid and megakaryocytic dysplasia. Cytogenetics were normal. Her baseline hemoglobin was 7g/dL. Despite combined growth factor support and thalidomide, this patient remained transfusion-dependent, requiring packed red blood cells (PRBCs) every 3 weeks. Her only other medical problem was well-controlled diabetes without renal impairment or neuropathy. Liver function was normal. Her medications included deferasirox, glyburide, metformin and pioglitazone. At baseline she had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0. This patient received a 7-day course of subcutaneous azacitidine, after which she required a total of 7 units PRBCs for grade 3 anemia. She did not experience any other complications such as viral illness or diarrheal infection. There were no changes in medications. Thirty-four days after starting azacitidine she experienced acute onset of bilateral lower extremity weakness starting distally and moving proximally. The next day she developed bilateral weakness in her distal upper extremities. On initial evaluation she was found to have symmetric bilateral upper and lower extremity weakness. Strength in the distal and proximal extremities (both upper and lower) was 1/5 and 3/5, respectively. Lower extremity deep tendon reflexes were absent. Sensation remained intact, and cranial nerve exam was normal with preserved respiratory muscle strength. A non-contrast head CT and cervical spine MRI without contrast were normal. CSF studies revealed elevated protein in the absence of cells. Lumbosacral MRI with contrast showed a non-specific, faint enhancement of the anterior lumbosacral nerve roots. An EMG indicated an acute demyelinating process. She was diagnosed with GBS and received a 5-day course of intravenous immunoglobulin with notable improvement in upper extremity strength within 1 week. At baseline after recovery from acute presentation, she was wheelchair-bound with an ECOG PS of 3. Discussion This is the first reported case of azacitidine-associated GBS. Azacitidine is a DNA hypomethylating agent that was FDA-approved in 2004 for the treatment of myelodysplastic syndrome. A common side effect is grade 3-4 myelosuppression. The common non-hematologic side effects are nausea and vomiting. Severe adverse non-hematologic reactions to azacitidine are uncommon (Sullivan, et al, AJHP 2005;62:1567-73). In 1975 neuromuscular toxic syndrome was described in 17 leukemic patients after they received combination therapy containing azacitidine (Levi JA, Wiernik PH Cancer Chemother Rep 1975;59:1043-45). A case report in 1985 documented a child with acute rapidly reversible CNS toxicity (coma preceded by somnolence/myalgias) days after receiving an erroneously high dose of 5-azacytidine for acute leukemia (Weisman, et al, J Pediatr Hematol Oncol 1985;7:86-88). No other azacitidine-associated adverse neurologic events, and specifically no reports of a demyelinating process, have been published. While the association between GBS and certain infections and immunizations has been well documented (Hughes RA, Cornblath DR Lancet 2005;366:1653-66), there is data to suggest that GBS can be medication-induced. Zimeldine has been described as the probable link to the development of GBS in 10 patients (Fagius, et al, JNNP 1985;48:65-69). In our patient, the temporal relationship between starting treatment and the development of neurologic symptoms, along with the lack of other known GBS-inciting factors, form a strong basis for an associational relationship between azacitidine and the development of GBS. It is therefore important that clinicians are aware of this potential severe adverse effect. Disclosures No relevant conflicts of interest to declare.

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial

2018 ◽  
Vol 17 (6) ◽  
pp. 519-529 ◽  
Author(s):  
Sonoko Misawa ◽  
Satoshi Kuwabara ◽  
Yasunori Sato ◽  
Nobuko Yamaguchi ◽  
Kengo Nagashima ◽  
...  
Keyword(s):  
Guillain Barre Syndrome ◽  
Phase 2 ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Phase 2 Trial ◽  
Guillain Barré Syndrome ◽  
Guillain Barré

LEAP-005: A phase II multicohort study of lenvatinib plus pembrolizumab in patients with previously treated selected solid tumors—Results from the gastric cancer cohort.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 230-230
Author(s):  
Hyun Cheol Chung ◽  
Zarnie Lwin ◽  
Carlos Gomez-Roca ◽  
Federico Longo ◽  
Eduardo Yanez ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Antitumor Activity ◽  
Advanced Gastric Cancer ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Tumor Imaging ◽  
Tissue Sample ◽  
Phase 2 ◽  
Open Label ◽  
Previously Treated

230 Background: Lenvatinib, an anti-angiogenic multiple receptor tyrosine kinase inhibitor, in combination with the anti‒PD-1 antibody pembrolizumab, has demonstrated promising antitumor activity with manageable safety in the first- or second-line in a phase 2 trial of patients with advanced gastric cancer. LEAP-005 (NCT03797326) is a phase 2, multicohort, nonrandomized, open-label study evaluating efficacy and safety of lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors; here, we present findings from the gastric cancer cohort of LEAP-005. Methods: Eligible patients were aged ≥18 years with histologically or cytologically confirmed metastatic and/or unresectable gastric cancer, received at least 2 prior lines of therapy, had measurable disease per RECIST v1.1, ECOG PS of 0‒1, and provided a tissue sample evaluable for PD-L1 expression. Patients received lenvatinib 20 mg once daily plus pembrolizumab 200 mg Q3W for up to 35 cycles of pembrolizumab (approximately 2 years) or until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. Treatment with lenvatinib could continue beyond 2 years in patients experiencing clinical benefit. Primary endpoints were ORR (per RECIST v1.1 by blinded independent central review) and safety. Secondary endpoints included disease control rate (DCR; comprising CR, PR, and SD), duration of response (DOR), PFS, and OS. Tumor imaging was performed Q9W from treatment initiation for 54 weeks, then Q12W to week 102, and Q24W thereafter. Results: 31 patients were enrolled in the gastric cancer cohort; 87% were male, 58% were aged < 65 years, and 71% had PD-L1 combined positive score (CPS) ≥1. Median time from first dose to data cutoff (April 10, 2020) was 7.0 months (range, 1.9‒11.9); 19 patients (61%) had discontinued treatment. ORR was 10% (95% CI, 2‒26); 1 patient had CR (3%), and 2 had a PR (6%). 12 patients (39%) had SD. Median DOR was not reached (range, 2.1+ to 2.3+ months). DCR was 48% (95% CI, 30‒67). Median PFS was 2.5 months (95% CI, 1.8‒4.2). Median OS was 5.9 months (95% CI, 2.6‒8.7). 28 patients (90%) had treatment-related AEs, including 13 patients (42%) with grade 3‒5 AEs. 1 patient had a treatment-related AE that led to death (hemorrhage). 8 patients (26%) had immune-mediated AEs: hypothyroidism (n = 5), hyperthyroidism (n = 2), and pneumonitis (n = 1). There were no infusion-related reactions. Conclusions: In patients with advanced gastric cancer who received 2 prior lines of therapy, lenvatinib plus pembrolizumab demonstrated promising antitumor activity and a manageable safety profile. Based on these data, enrollment in the gastric cancer cohort has been expanded to 100 patients. Clinical trial information: NCT03797326.

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