Validation of Immunotherapy for Lung Cancer
Validation of Immunotherapy for Lung Cancer
Topalian SL, Hodi FS, Brahmer JR, et al
N Engl J Med. 2012;366:2443-2454
Although this year's American Society of Clinical Oncology (ASCO®) conference didn't feature any presentations that were practice-changing in the management of lung cancer, it did include several encouraging results from early studies that offer great promise for the future. One of the studies that I considered most provocative is this study by Topalian and colleagues, which focused on the safety and clinical activity of immunotherapy with an anti-PD-1 antibody and which was recently published in the New England Journal of Medicine, reflecting its potential importance.
Although passive immunotherapy with antibodies against relevant oncologic targets has led to remarkable benefits in the treatment of lymphoma, breast cancer, and some other cancers, treatments directed against T-cells have remained more challenging to harness into efficacy. Ipilimumab, an antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), is approved by the US Food and Drug Administration as an effective therapy in melanoma, but it is associated with a very challenging toxicity profile and remains investigational against other cancers. The unrealized promise of immunotherapy as a durably effective, minimally toxic anticancer intervention has largely remained elusive.
Programmed death-1 (PD-1) protein is a T-cell receptor similar to CTLA-4, interacting with 2 ligands, PD-L1 and PD-L2, to inhibit T-cell-mediated immune responses; PD-L1 is found in tumors associated with inhibition of tumor-infiltrating lymphocyte response and response to PD-1 blockade.The anticancer strategy of blockade of this interaction can release the inhibitory effect on the host immune system.
Topalian and colleagues focused on BMS-936558, a fully human, PD-1-specific antibody that was administered intravenously on an every-2-week schedule, in 8-week cycles, to patients with advanced melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma, castration-resistant prostate cancer, or colon cancer. The primary endpoints were assessment of safety and the adverse effect profile associated with dose escalation (from 1 to 3 to 10 mg/kg) in the phase 1 portion; secondary endpoints were assessment of antitumor activity and pharmacokinetics.
After no dose-limiting toxicity was reported at any level, enrollment was expanded in disease-specific cohorts, the largest being patients with NSCLC (n = 122). Of note, most patients had been heavily pretreated, with 47% of those enrolled having received at least 3 previous lines of treatment.
A total of 15 of the 296 patients (5%) discontinued treatment because of an adverse event. The most common adverse effects, regardless of causality, were fatigue, anorexia, diarrhea, nausea, cough, dyspnea, constipation, vomiting, rash, fever, and headache. Most of these adverse events were of low severity. Treatment-related adverse events of grade 3 or 4 were reported in 41 of 296 patients (14%). The most notable adverse events were pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. There were 3 treatment-related deaths (1%); these were attributed to pneumonitis, which occurred in 2 patients with NSCLC and 1 with colorectal cancer.
When efficacy results were restricted to patients with NSCLC, objective responses were seen in 14 of 76 patients with measurable disease (18%): 6 of 18 patients with squamous NSCLC (33%), 7 of 56 (12%) of patients with nonsquamous NSCLC, and 1 of 2 patients with disease of unknown histology. The duration of response was noteworthy, in that 8 of 14 (57%) of these responses lasting 24 weeks, with several going beyond 1 year. An additional 5 patients with nonsquamous NSCLC had stable disease lasting 24 weeks or more. The progression-free survival rate at 24 weeks for all patients with NSCLC and measurable disease was 26%.
There are obvious study limitations that influence how we should appropriately interpret a phase 1-2 trial with several dozen patients treated across a range of doses and that achieved a rather modest response rate. However, there is good reason why these results merited publication in the New England Journal of Medicine and invited a highly visible presentation at ASCO.
The study's findings are noteworthy for several reasons. First, these were generally heavily pretreated patients, in whom we very rarely see tumor shrinkage sufficient to reach a threshold for objective response. Second, many of these patients had very long-lasting responses or nonprogression, a critical goal in the palliative setting that rivals and may well eclipse the significance of tumor shrinkage. Third, treatment was generally very well tolerated in a setting in which it can be very challenging to continue to administer anticancer therapy. Finally, any therapy that is associated with responses, particularly in patients with squamous cell NSCLC, is especially welcome, given the very limited options available for this large minority of patients with NSCLC.
Speaking with several of the investigators directly, many expressed to me palpable enthusiasm for this line of research, citing both the efficacy and tolerability of anti-PD-L1 antibody therapy for their own patients. Many commented that even patients who failed to demonstrate an objective response experienced impressively prolonged stable disease, including patients who had progressed readily through several other lines of treatment.
Although not highlighted in this summary, the fact that this agent was also associated with significant activity in melanoma and renal cell carcinoma is also encouraging and contributes to a new momentum for immunotherapies in a broader range of solid tumors. These early results clearly merit larger studies that should find an enthusiastic reception among oncologists and cancer patients, ideally leading to a new treatment option for NSCLC and perhaps other solid cancers.
Abstract
Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer
Topalian SL, Hodi FS, Brahmer JR, et al
N Engl J Med. 2012;366:2443-2454
Background
Although this year's American Society of Clinical Oncology (ASCO®) conference didn't feature any presentations that were practice-changing in the management of lung cancer, it did include several encouraging results from early studies that offer great promise for the future. One of the studies that I considered most provocative is this study by Topalian and colleagues, which focused on the safety and clinical activity of immunotherapy with an anti-PD-1 antibody and which was recently published in the New England Journal of Medicine, reflecting its potential importance.
Although passive immunotherapy with antibodies against relevant oncologic targets has led to remarkable benefits in the treatment of lymphoma, breast cancer, and some other cancers, treatments directed against T-cells have remained more challenging to harness into efficacy. Ipilimumab, an antibody against cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), is approved by the US Food and Drug Administration as an effective therapy in melanoma, but it is associated with a very challenging toxicity profile and remains investigational against other cancers. The unrealized promise of immunotherapy as a durably effective, minimally toxic anticancer intervention has largely remained elusive.
Programmed death-1 (PD-1) protein is a T-cell receptor similar to CTLA-4, interacting with 2 ligands, PD-L1 and PD-L2, to inhibit T-cell-mediated immune responses; PD-L1 is found in tumors associated with inhibition of tumor-infiltrating lymphocyte response and response to PD-1 blockade.The anticancer strategy of blockade of this interaction can release the inhibitory effect on the host immune system.
Study Summary
Topalian and colleagues focused on BMS-936558, a fully human, PD-1-specific antibody that was administered intravenously on an every-2-week schedule, in 8-week cycles, to patients with advanced melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma, castration-resistant prostate cancer, or colon cancer. The primary endpoints were assessment of safety and the adverse effect profile associated with dose escalation (from 1 to 3 to 10 mg/kg) in the phase 1 portion; secondary endpoints were assessment of antitumor activity and pharmacokinetics.
After no dose-limiting toxicity was reported at any level, enrollment was expanded in disease-specific cohorts, the largest being patients with NSCLC (n = 122). Of note, most patients had been heavily pretreated, with 47% of those enrolled having received at least 3 previous lines of treatment.
A total of 15 of the 296 patients (5%) discontinued treatment because of an adverse event. The most common adverse effects, regardless of causality, were fatigue, anorexia, diarrhea, nausea, cough, dyspnea, constipation, vomiting, rash, fever, and headache. Most of these adverse events were of low severity. Treatment-related adverse events of grade 3 or 4 were reported in 41 of 296 patients (14%). The most notable adverse events were pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. There were 3 treatment-related deaths (1%); these were attributed to pneumonitis, which occurred in 2 patients with NSCLC and 1 with colorectal cancer.
When efficacy results were restricted to patients with NSCLC, objective responses were seen in 14 of 76 patients with measurable disease (18%): 6 of 18 patients with squamous NSCLC (33%), 7 of 56 (12%) of patients with nonsquamous NSCLC, and 1 of 2 patients with disease of unknown histology. The duration of response was noteworthy, in that 8 of 14 (57%) of these responses lasting 24 weeks, with several going beyond 1 year. An additional 5 patients with nonsquamous NSCLC had stable disease lasting 24 weeks or more. The progression-free survival rate at 24 weeks for all patients with NSCLC and measurable disease was 26%.
Viewpoint
There are obvious study limitations that influence how we should appropriately interpret a phase 1-2 trial with several dozen patients treated across a range of doses and that achieved a rather modest response rate. However, there is good reason why these results merited publication in the New England Journal of Medicine and invited a highly visible presentation at ASCO.
The study's findings are noteworthy for several reasons. First, these were generally heavily pretreated patients, in whom we very rarely see tumor shrinkage sufficient to reach a threshold for objective response. Second, many of these patients had very long-lasting responses or nonprogression, a critical goal in the palliative setting that rivals and may well eclipse the significance of tumor shrinkage. Third, treatment was generally very well tolerated in a setting in which it can be very challenging to continue to administer anticancer therapy. Finally, any therapy that is associated with responses, particularly in patients with squamous cell NSCLC, is especially welcome, given the very limited options available for this large minority of patients with NSCLC.
Speaking with several of the investigators directly, many expressed to me palpable enthusiasm for this line of research, citing both the efficacy and tolerability of anti-PD-L1 antibody therapy for their own patients. Many commented that even patients who failed to demonstrate an objective response experienced impressively prolonged stable disease, including patients who had progressed readily through several other lines of treatment.
Although not highlighted in this summary, the fact that this agent was also associated with significant activity in melanoma and renal cell carcinoma is also encouraging and contributes to a new momentum for immunotherapies in a broader range of solid tumors. These early results clearly merit larger studies that should find an enthusiastic reception among oncologists and cancer patients, ideally leading to a new treatment option for NSCLC and perhaps other solid cancers.
Abstract
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