CheckMate-003

Published

Topalian SL, et al. "Safety, activity, and immune correlates of anti-PD-1 antibody in cancer". The New England Journal of Medicine. 2012. 366(26):2443-54.
PubMed • Full text • PDF

Clinical Question

Among patients with advanced solid tumors, what is the efficacy and tolerability of the anti-PD1 antibody nivolumab?

Bottom Line

Among patients with advanced solid tumors, nivolumab is well tolerated and yields durable tumor remissions in a subset of patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma.

Major Points

Patients with unresectable, relapsed, or metastatic solid tumors are usually treated with cytotoxic chemotherapy, and despite this, their prognosis is generally poor. This poor prognosis relates to the inability to fully eradicate tumors in these settings, which is driven in part by tumor evasion of the immune system. Early attempts to harness the immune system were modestly successful but only in specific malignancies; for example, high-dose interleukin (IL)-2 appears to cure approximately 8% of selected patients with metastatic renal cell carcinoma. With a growing understanding of immune checkpoint pathways, specific mechanisms by which tumors promote T-cell anergy were discovered; these include interactions with cytotoxic T-lymphocyte antigen 4 (CTLA4), programmed death 1 (PD1), and programmed death ligand 1 (PDL1). The monoclonal antibody ipilimumab was the first FDA-approved targeted immune checkpoint inhibitor, and is currently indicated for the treatment of unresectable or metastatic melanoma based on a phase 3 study published in 2010.

Published in 2012, this phase 1 study by Topalian and colleagues enrolled 296 patients with non-small-cell lung cancer (NSCLC, n=122), melanoma (n=104), renal cell carcinoma (RCC, n=34), colorectal cancer (n=19), and castrate-resistant prostate cancer (n=17). Patients were required to have advanced disease, defined as unresectable, relapsed, refractory, or metastatic disease, and must have received at least one prior systemic therapy. Patients with prior autoimmune disorder or prior checkpoint inhibitor therapy were excluded. All patients were required to have measurable disease by RECIST criteria. Patients received the anti-PD1 monoclonal antibody nivolumab (dose 0.1-10 mg/kg) every 2 weeks for up to 2 years. The primary endpoint was safety, with secondary efficacy endpoints evaluated by imaging every 8 weeks. The maximum tolerated dose (MTD) was not reached; grade ≥3 events were observed in 18% of patients, with 5% of patients discontinuing therapy because of tolerability. Major toxicities included diarrhea (11% of patients) and rash (12%). Objective antitumor responses were seen in patients with melanoma (28%), RCC (27%), and NSCLC (18%), but not in patients with colorectal cancer or castrate-resistant prostate cancer. Long-term follow-up of the melanoma cohort revealed a median overall survival (OS) of 16.8 months, with 2-year OS of 43%. The highest objective response rate was seen at the 3.0 mg/kg dose level, which was associated with objective responses in 41% of patients.

Preliminary results from this study and other studies of checkpoint inhibitors were presented at the American Society of Clinical Oncologists (ASCO) Annual Meeting in 2012 and prompted much excitement in the field. Phase 3 trials are currently under way as part of the industry-sponsored CheckMate series, which compares nivolumab to conventional therapy or incorporates nivolumab into cytotoxic regimens.

Several other PD1 and PDL1 antibodies are currently under development. In September 2014, the anti-PD1 monoclonal antibody pembrolizumab was granted accelerated FDA approval for patients with advanced melanoma whose disease had progressed on ipilimumab and (in the presence of a BRAF V600 mutation) a BRAF inhibitor.

Guidelines

NCCN Guidelines (2015, adapted):

• In metastatic squamous-cell lung cancer, nivolumab is recommended as subsequent therapy for patients who have progressed on or after platinum-based chemotherapy.
• In metastatic or unresectable melanoma, nivolumab and pembrolizumab are recommended for patients with BRAF wild-type disease.

Design

• Randomized phase 1 dose-escalation trial
• N=296 patients with advanced solid tumors
• Setting: An unspecified number of centers
• Enrollment: 2008-2012
• Mean follow-up: Not specified
• Analysis: By assigned group
• Primary outcome: Safety

Population

Inclusion Criteria

• Advanced solid tumor
• Age ≥18 years
• ECOG performance status 0-2
• Disease measurable by RECIST
• Adequate renal, liver, and hematologic function
• 1-5 prior systemic therapies
• If brain metastases present, must be stable

Exclusion Criteria

• Chronic autoimmune diseases
• Prior therapy with other T-cell modulating agents like anti-CTLA4, anti-PD1, and anti-PDL1 therapies
• Chronic immunosuppression
• Chronic infection, including HCV, HBV, or HIV

Baseline Characteristics

• Demographics: Age 63 years, 66% male
• Cancer type:
  • Melanoma: 35%
  • NSCLC: 41% (squamous 39%, non-squamous 60%, unknown 2%)
  • RCC: 11%
  • Prostate cancer (castration resistant): 6%
  • Colorectal cancer: 6%
• ECOG performance status:
  • 0: 43%
  • 1: 53%
  • 2: 2%
  • Unknown: 1%
• Number of prior systemic treatments:
  • 1: 24%
  • 2: 27%
  • 3: 18%
  • ge;4: 29%
  • Unknown: 2%
• Prior therapies: RT 49%, hormonal/immunologic/biologic 25%, chemotherapy 80%, Surgery 79%

Interventions

• Patients were randomized into a nivolumab cohort with dosages ranging from 0.1 to 10 mg/kg.
• Nivolumab was given IV every 2 weeks; one cycle was considered 8 weeks of therapy.
• Patients were treated for up to 2 years, or until toxicity or progressive disease.
• Disease extent was evaluated with CT imaging before each cycle.

Outcomes

Primary Outcome

This trial was designed to evaluate the safety of nivolumab by testing various dosages and establishing a maximum tolerated dose (MTD). An MTD was not reached.

Secondary Outcomes

Objective response rate

Melanoma

0.1 mg/kg: 29% (95% CI 8-58%)

0.3 mg/kg: 19% (95% CI 4-46%)

1 mg/kg: 30% (95% CI 14-50%)

3 mg/kg: 41% (95% CI 18-67%)

10 mg/kg: 20% (95% CI 6-44%)

NSCLC

1 mg/kg: 6% (95% CI 0.1-27%)

3 mg/kg: 32% (95% CI 13-57%)

10 mg/kg: 18% (95% CI 8-34%)

RCC

1 mg/kg: 24% (95% CI 7-50%)

10 mg/kg: 31% (95% CI 11-59%)

Stable disease ≥24 weeks

Melanoma

0.1 mg/kg: 7% (95% CI 0.2-34%)

0.3 mg/kg: 6% (95% CI 0.2-30%)

1 mg/kg: 11% (95% CI 2-29%)

3 mg/kg: 6% (95% CI 0.1-29%)

10 mg/kg: 0

NSCLC

Of note, there was no stable disease ≥24 weeks among those with squamous or unknown NSCLC subtypes.

1 mg/kg: 6% (95% CI 0.1-27%)

3 mg/kg: 11% (95% CI 1-33%)

10 mg/kg: 5% (95% CI 0.6-17%)

RCC

1 mg/kg: 24% (95% CI 7-50%)

10 mg/kg: 31% (95% CI 11-59%)

Progression-free survival at 24 weeks

Melanoma

0.1 mg/kg: 40% (95% CI 13-66%)

0.3 mg/kg: 31% (95% CI 9-54%)

1 mg/kg: 45% (95% CI 26-65%)

3 mg/kg: 55% (95% CI 30-80%)

10 mg/kg: 30% (95% CI 9-51%)

NSCLC

1 mg/kg: 16% (95% CI 0-34%)

3 mg/kg: 41% (95% CI 18-64%)

10 mg/kg: 24% (95% CI 11-38%)

RCC

1 mg/kg: 47% (95% CI 23-71%)

10 mg/kg: 67% (95% CI 43-91%)

Adverse Events

Any grade 3-4 colitis, hepatitis, hypophysitis, thyroiditis, or other event "of special interest"

0-8% (individual grade 3-4 events occurred in <3% of patients)

Funding

• Bristol-Myers Squibb and Ono Pharmaceuticals