Safety of Retreatment With Immunotherapy After Immune-Related Toxicity in Patients With Lung Cancers Treated With Anti-PD-(L)1 Therapy

Transcription

1 Safety of Retreatment With Immunotherapy After Immune-Related Toxicity in Patients With Lung Cancers Treated With Anti-PD-(L)1 Therapy Abstract 9012 Santini FC, Rizvi H, Wilkins O, van Voorthuysen M, Panora E, Halpenny D, Kris MG, Rudin CM, Chaft JE, Hellmann MD

2 Overview of Cohort Retrospectively Identified Patients Who Had Treatment Delay or Discontinuation Due to irae Patients with NSCLC treated at MSKCC with anti PD-L1 (+/- anti CTLA-4) between 4/2011 to 5/2016 (n = 482) Treatment with delay >1 week between planned doses of immunotherapy? Yes, delay during treatment (n = 99) No delay during treatment (n = 383) Treatment delay due to other causes (n = 61): Infection Pleural catheter placement Radiation Schedule Disease progression or death (n = 294) Ongoing treatment (n = 57) Treatment held due to irae, but later retreated after resolution of the irae (n = 38) Treatment discontinued due to definite irae (n = 32) CTLA-4, cytotoxic T-lymphocyte-associated protein 4; irae, immune-related adverse event; MSKCC, Memorial Sloan Kettering Cancer Center; NSCLC, non-small cell lung cancer; PD-L1, programmed death-ligand 1

3 Clinical Characteristics of Patients Experiencing irae That Led to Delay/Retreatment or Discontinuation of Treatment Patients With NSCLC Who Received Immunotherapy at MSKCC from 4/2011 to 5/2016 Discontinued 46% Clinical Characteristics of Patients Experiencing irae That Led to Either Delay/Retreatment or Discontinuation of Treatment Retreated Discontinued No. of patients P Value Histology.06 Adenocarcinoma 23 (61) 28 (87.5) 85% irae* Retreated 54% Squamous 11 (29) 4 (12.5) LCNEC + NOS 4 (10) 0 (0) Immunotherapy treatment data.21 Anti-PD-1 19 (50) 22 (69) Anti-PD-L1 5 (13) 4 (12) Combinations with anti-ctla4 14 (37) 6 (19) Line of therapy (66) 8 (25) 2 10 (26) 10 (31) *Immune-related adverse event that led to treatment delay or discontinuation CR, complete response; LCNEC, large cell neuroendocrine carcinoma; NOS, not otherwise specified; PD-1, programmed cell death protein-1; PR, partial response; SD, stable disease 3 3 (8) 14 (44) Disease status at the detection of irae 1.13 CR or PR 12 (32) 9 (28) SD 9 (24) 2 (6) No scans yes 16 (42) 18 (56) Not available 1 (2) 3 (10) 1 Patients with concurrent irae and disease progression were excluded from this analysis as they were not eligible for potential retreatment, which was the main purpose of the study.

4 Description and Severity of irae Requiring Delay/Treatment or Discontinuation Retreated Discontinued Patients who presented with high grade (3-4) toxicity, used intravenous corticosteroids with prolonged taper and were hospitalized, were more likely to have treatment discontinued TNF, tumor necrosis factor P Value Grade of the first irae.01 Grades 1 and 2 24 (63) 11 (34) Grades 3 and 4 14 (37) 21 (66) Type of irae.41 Colitis 7 (18) 5 (16) Pneumonitis 6 (16) 8 (25) Musculoskeletal 5 (13) 1 (3) Skin 5 (13) 7 (22) Pancreas 4 (11) 0 (0) Liver 3 (8) 5 (16) Central nervous system 2 (5) 1 (3) Endocrine 2 (5) 1 (3) Nephritis 2 (5) 2 (6) Other 2 (6) 2 (6) Hospitalization due to irae 8 (22) 18 (56).003 Time interval to irae No. infusions before the irae Retreated Discontinued P Value Days, median (range) 84 (14-579) 93 (2-452).49 No., median (range) 4.5 (1-42) 5.5 (1-27).69 Corticosteroid used 29 (86) 30 (97).01 Intravenous 3 (10) 12 (40) Oral 23 (80) 16 (53) Other 3 (10) 2 (6) Steroid taper >4 weeks 10 (34) 16 (67).02 Anti-TNF used in the first toxicity 0 (0) 3 (9).054 Grade of irae following treatment.007 Resolved/improved grade 0/1 37 (97) 22 (76) Grade 2 1 (3) 7 (24) Death related to irae 0 (0) 6 (19)

5 Patients who were retreated after a serious immune-related adverse event (n = 38) Same irae No irae No subsequent irae 24% Description of irae requiring delay/retreatment Patients Who Had the Toxicity Below As the Culprit irae Rate of irae Occurrence (Same/New irae) After Retreatment Pneumonitis 33% (2/6) 50% 26% Rash 40% (2/5) Colitis 57% (4/7) Arthralgia/Myalgia 80% (4/5)

6 Patients Who Were Retreated After a Serious irae (n = 38) Characteristics of the First irae Two features associated with recurrent toxicity following retreatment: Hospitalization during the first irae Duration of treatment before the first irae less than 3 months Of note, patients with either low grade (1-2) or high grade (3-4) toxicities as their first toxicity were equally likely to have recurrent/new irae or no subsequent irae Grade First irae Hosp Corticosteroid Grade 1 or Grade 2 Treatment Duration Before irae Grade 3 or Grade 4 IV Oral Taper >4w <3 Months >3 Months New or same irae, 12 (50) 7 (50) 7 (87) 2 (67) 11 (48) 7 (70) 15 (63) 4 (29) No. subsequent irae, 12 (50) 7 (50) 1 (13) 1 (33) 12 (52) 3 (30) 9 (37) 10 (71) P value

7 Outcomes of Recurrent/New ireas in Patients Retreated Following an Initial irae Same irae New irae Total 9 (24) 10 (26) Grades of the recurrent irae Corticosteroid used Grades 1 and 2 3 (33) 8 (80) Grades 3 and 4 6 (67) 2 (20) Oral 6 (67) 4 (40) Intravenous 2 (22) 2 (20) Steroid taper >4 weeks 5 (62) 5 (50) Anti-TNF 0 (0) 2 (20) Grade of irae following treatment Resolved/improved, Grades 0 and 1 8 (89) 8 (80) Stabilized, Grade 2 1 (11) 0 (0) Did not improve; deaths related to irae 0 (0) 2 (20) Pneumonitis colitis Of the 19 people who did develop a recurrent irae, nearly all were manageable, with 16/19 (84%) improving to grade 0-1 with treatment 2 treatment-related death occurred despite high dose corticosteroids, anti-tnf and other immunosuppressors Mortality rate of the retreated cohort due to irae was 5%

8 Duration of Immunotherapy in the Retreated Population Patients (n = 38) Three patients had onset of objective response following resumption of treatment, representing: 8% (3/38) of all retreated patients Years Solid lines represent duration of immunotherapy Arrows represent ongoing therapy

9 Outcome Among Patients With Early Response Informing Decision Related to Retreatment Progression-Free Survival (PFS) Estimate Overall Survival (OS) Estimate Probability P = Months Retreated Discontinued Probability P = Months Retreated Discontinued Among patients who achieved PR or CR prior to onset of irae, PFS and OS were similar in the retreatment vs discontinued cohort

10 Conclusions In patients with iraes that improve, retreatment with anti PD-L1 therapy resulted in recurrent or new iraes in half of patients Note that retreated patients were identified retrospectively and tended to have less severe events characterized by fewer hospitalization and less steroids Among those who were retreated, hospitalization and early onset of irae were associated with increased risk of recurrent/new irae The majority of patients who developed recurrent/new irae were successfully managed, but 2 deaths occurred Limited responses occurred following retreatment Among those with CR/PR prior to onset of first irae, PFS and OS were similar in the retreatment and discontinuation cohorts