Real-World and Phase 1 Safety Studies of Immuno-Oncology Agents in NSCLC and Glioblastoma

Evidence-Based Oncology, The American Society of Clinical Oncology Annual Meeting, 2015, Volume 21, Issue SP10

Two posters summarized the safety of nivolumab in lung cancer and in glioblastoma, at the ASCO annual meeting.

Safety Study of Nivolumab in Community Oncology Centers

The fully humanized PD-1 inhibitor nivolumab is currently approved to treat melanoma patients who have progressed on ipilimumab and patients with squamous non-small cell lung cancer (NSCLC) who have progressed on platinum-based chemotherapy.

A poster presented on the second day of the annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago presented results from a phase 3/4b safety study of nivolumab in 824 previously treated NSCLC patients, primarily conducted in community-based oncology centers. A majority (72%) of patients had the non-squamous form of the disease; the rest (28%) had squamous NSCLC. Patients received intravenous nivolumab (3 mg/kg for 60 min) once every 2 weeks, either until progressive disease or unacceptable toxicity (cohort A) or for 1 year with the possibility of retreatment upon disease progression (cohort B). The primary objective was to estimate the incidence of high-grade (3-5) select treatment-related adverse events (AEs). The trial also explored efficacy and evaluated objective response rate, progression-free survival, and overall survival (OS).

Results. At week 9, of the 531 evaluable patients, 12% demonstrated a partial response per RECIST v1.1, with no complete response observed. The authors claim that the efficacy follow-up period was relatively short, with an average on-study time for these data of only about 10.4 weeks. Treatment-related select AEs (SAEs) observed included cardiac disorders, endocrine disorders, gastrointestinal (GI) disorders, general disorders, hepatic disorders, musculoskeletal disorders, nervous system disorders, skin disorders, and respiratory and metabolic disorders. A majority of patients presented with skin disorders and GI disorders.

Conclusions. The authors conclude that safety and tolerability are consistent with prior nivolumab experience, and no neIIw safety signals have been identified in this trial. Drug-related toxicities are manageable in a community practice setting using previously developed management algorithms. The frequency of treatment-related SAEs and SAEs of interest were similar between patients with performance status (PS) 0 to 1 and those with PS 2. Early data from this large multicenter trial suggests that patients with pretreated advanced NSCLC benefit from nivolumab therapy, regardless of histology type, performance status, EGFR/ALK mutation status, number of prior therapies, or smoking status.1

Checkmate-143 Evaluates Safety and Efficacy of Nivolumab, Alone or in Combination With Iplilimumab in Glioblastoma

Glioblastoma (GBM), a malignant brain cancer in adults, continues to present a grim prognosis despite current first-line therapies. Median OS with first-line treatment of surgery, radiotherapy, and temozolomide is 15 to 17 months; the 3-year survival rate is a dismal 10% to 15%, and the 5-year survival is even lower, at 1% to 5%. Treatments for relapsed patients have limited success and are clinically aggressive for the patient, resulting in poor quality of life.

The rationale behind this CHECKMATE-143 trial, according to the authors, is the reduced risk of gliomas and longer survival observed in individuals with elevated immunoglobulin E levels. Since inhibition of PD-1 and CTLA-4 has yielded impressive results in melanoma and in lung cancer, the authors evaluated the combination of nivolumab (PD-1 inhibitor) and ipilimumab (CTLA-4 inhibitor) in patients with recurrent glioblastoma. Preclinical studies with nivolumab prolonged survival in a glioblastoma mouse model, and combining both agents increased tumor infiltration of T-effector cells.

The abstract, presented on the third day of the annual meeting of ASCO in Chicago, included safety, tolerability, and preliminary efficacy results from phase 1 of the trial. Patients were randomized 1:1 to receive nivolumab 3 mg/kg once every 2 weeks or nivolumab 1 mg/kg + ipilimumab 3 mg/kg once every 3 weeks for 4 doses followed by nivolumab 3 mg/kg once every 2 weeks. The primary end points were safety and tolerability.

Eligibility criteria were:

· First recurrence of grade IV primary glioblastoma

· No prior bevacizumab treatment

· Interval of at least 12 weeks after end of prior radiotherapy and a confirmation of recurrent tumor or MRI-confirmation of enhancement outside of radiotherapy treatment field

· Karnofsky performance status ≥70.

Exclusion criteria were:

· >1 glioblastoma recurrence

· Presence of extracranial metastatic or leptomeningeal disease

· Known or suspected autoimmune disease

· Previous treatment with vascular endothelial growth factor or anti-angiogenic agents

· Cardiovascular disease.

Results. The study included 20 patients, 10 in each arm, with similar demographic and disease characteristics. Assessments were made after the last patient in each arm had completed 4 doses of the study medication, and AEs were collected for at least a 100 days following the last dose. Of the 20 patients, 14 (6 in the nivolumab-alone arm) died. The authors did not report any unexpected side effects, and safety profiles mirrored other tumor types. Most common treatment-related AEs included diarrhea, fatigue, and increased lipase. Treatment-related serious AEs were observed in 2 and 7 patients in the monotherapy and the combination arms, respectively. The combination regimen resulted in more treatment-related discontinuation (4/10) compared with none on the monotherapy arm, after the first 4 doses.

Preliminary efficacy evaluation from this trial showed a partial response in 1 patient receiving monotherapy and stable disease in 4 patients in each treatment arm.

Conclusions. The authors concluded that nivolumab monotherapy was well tolerated in this recurrent glioblastoma population, with no treatment-related grade 3 to 4 AEs observed and no treatment-related discontinuations within the first 4 doses of treatment. The combination of ipilimumab and nivolumab, on the other hand, was associated with a higher incidence of treatment-related grade 3 (n = 7/10) and grade 4 AEs (n = 2/10). Treatment-related effects observed on histopathology and neuroimaging suggest biologic activity at the tumor site. The safety profile and preliminary clinical activity of nivolumab monotherapy observed in this phase 1 study led to the initiation of phase 3 of CHECKMATE-143 to assess efficacy compared with bevacizumab in patients with recurrent glioblastoma.2


1. Bauer TM, McCleod M, Chandler JC, et al. An ongoing phase IIIb/IV safety trial of nivolumab (NIVO) in patients (pts) with advanced or metastatic non-small-cell lung cancer (NSCLC) who progressed after receiving 1 or more prior systemic regimens. J Clin Oncol. 2015;33(suppl): abstract 3013.

2. Sampson JH, Vlahovic G, Sahebjam S, et al. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. J Clin Oncol. 2015;33(suppl): abstract 3010.