July 2015, Vol. 2, No. 4
Checkpoint Modulation for Lung Cancer
Numerous clinical studies are under way investigating the blockade of inhibitory “checkpoint pathways” to enhance the antitumor immune response
One promising approach to treating lung cancer involves augmenting the existing antitumor immune responses through blockade of inhibitory checkpoint pathways (ie, natural mechanisms that serve to limit the immune response).1 Checkpoint blockade is often described as “taking the brakes off” the immune system.
Two examples of immune checkpoint pathways include the programmed death-1 (PD-1) pathway and the cytotoxic T-lymphocyte antigen 4 (CTLA-4) pathway. Immune checkpoint blockade with monoclonal antibodies directed at the inhibitory immune receptors PD-1 (or one of its ligands, PD-L1) or CTLA-4 are under investigation in lung cancer (Table 1).2,3
Monoclonal antibodies against PD-1 are designed to prevent interaction between PD-1 and PD-L1, potentially restoring the function of tumor-specific T cells and augmenting the T-cell response.4
Nivolumab, which was approved by the FDA for the treatment of metastatic melanoma in 2014, was approved on March 4, 2015, for the treatment of patients with metastatic squamous non–small cell lung cancer (NSCLC) that had progressed on or after platinum-based chemotherapy. The approval was based on the results from 2 phase 3 studies, CheckMate -017 (NCT01642004) and CheckMate -063 (NCT01721759).
CheckMate -017 was an open-label, randomized, phase 3 study (N = 272) that evaluated nivolumab (3 mg/kg intravenously over 60 minutes every 2 weeks) (n = 135) versus standard of care, docetaxel (75 mg/m2 intravenously administered every 3 weeks) (n = 137), in patients with metastatic squamous NSCLC that had progressed during or after a prior platinum doublet–based chemotherapy regimen. This trial included patients regardless of their tumor PD-L1 status. The primary end point was overall survival (OS). In January 2015, the trial was stopped based on an assessment conducted by the independent data monitoring committee, which concluded that the study had met its end point, demonstrating superior OS in patients receiving nivolumab compared with those receiving docetaxel. Patients who received nivolumab lived a median of 3.2 months longer than those who received docetaxel. Median OS was 9.2 months (95% CI, 7.3-13.3) for nivolumab and 6 months (95% CI, 5.1-7.3) for docetaxel. The hazard ratio (HR) was 0.59 (95% CI, 0.44-0.79; P = .00025; Figure 1). The prespecified interim analysis was conducted when 199 events (86% of the planned number of events for final analysis) were observed (86 in the nivolumab arm and 113 in the docetaxel arm).5,6
The safety and efficacy of nivolumab to treat patients with squamous NSCLC were supported by a single-arm trial (CheckMate -063) with 117 participants who had progressive disease after receiving a platinum-based therapy and ?1 additional systemic regimens. The study was designed to measure objective response rate (ORR). After a minimum follow-up of at least 10 months for all patients, ORR was 15% (17 of 117 patients; 95% CI, 9-22), all of which were partial responses (PRs). The median time to onset of response was 3.3 months (range, 1.7-8.8 months) after the start of nivolumab treatment. Thirteen of the 17 patients (76%) with PRs had ongoing responses with a duration ranging from 1.9+ to 11.5+ months; 10 of these 17 patients (59%) had durable responses of 6 months or longer.5,6
Nivolumab is being investigated in a number of phase 2 and phase 3 clinical studies (Table 2).
Pembrolizumab is a PD-1–blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor.7 Pembrolizumab was approved by the FDA in September 2014 for the treatment of advanced melanoma and was granted breakthrough therapy designation in October 2014 for the treatment of NSCLC.
At the 2014 European Society for Medical Oncology Congress in Madrid, Spain, data were presented from 282 patients with treatment-naive or previously treated advanced NSCLC enrolled in randomized and nonrandomized cohorts of the phase 1 KEYNOTE-001 study, which is also investigating the use of pembrolizumab in other types of cancer.8 Pembrolizumab was given at 2 mg/kg every 3 weeks (q3w), 10 mg/kg q3w, or 10 mg/kg every 2 weeks (q2w) until disease progression, death, or unacceptable toxicity. The overall response rate was assessed using RECIST v1.1 by central review and by immune-related response criteria (irRC) by investigator review. The investigators also measured expression of PD-L1 by immunohistochemistry (IHC).
Mature data were available for 262 patients (5.4-months median follow-up). Grade 3 to 5 drug-related adverse events (AEs) occurred in 24 patients (9%), most commonly pneumonitis (n = 5; 3 grade 3, 2 grade 4). The overall response rate (RECIST/irRC) in patients with measurable disease at baseline was 21%/23% overall (26%/47% treatment naive, 20%/18% previously treated) and was similar in patients with squamous (18%/25%) and nonsquamous (23%/23%) histology. The overall response rate was 33%/67% at 2 mg/kg q3w (n = 6), 21%/22% at 10 mg/kg q3w (n = 141), and 21%/22% at 10 mg/kg q2w (n = 115). The overall response rate was 23%/25% in patients with ?1% PD-L1 staining and 9%/13% in patients with negative PD-L1 staining. In treatment-naive patients, progression-free survival (PFS) was 27 weeks, with a 24-week PFS rate of 51%. In the same group, the median OS was not yet reached, and the 6-month OS rate was 86%. In previously treated patients, the median PFS was 10 weeks, and the 24-week PFS rate was 26%. The median OS was 8.2 months, and the 6-month OS rate was 59%. In the pooled population (treatment naive plus previously treated), the median PFS was 13 weeks, and the 24-week PFS rate was 30%; the median OS was 8.2 months, and the 6-month OS rate was 64%.
The data for PD-L1 staining using the clinical trial IHC assay were available for nearly half of the patients. In these patients, the overall response rate was higher in patients with strong PD-L1 expression (?50% staining) than in patients with weak/negative PD-L1 expression. The PFS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/negative tumors (HR, 0.52). The OS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/negative tumors (HR, 0.59), suggesting that patients with strong PD-L1 tumor expression may derive particular benefit from pembrolizumab.
Ongoing studies with pembrolizumab in NSCLC are listed in Table 3.
Another promising strategy is to inhibit PD-L1 on the tumor cell surface.2
MPDL3280A is an antibody targeting PD-L1 (the binding partner of checkpoint molecule PD-1). In February 2015, the FDA granted breakthrough therapy designation for MPDL3280A for the treatment of patients with PD-L1–positive NSCLC that has progressed during or after platinum-based chemotherapy.9 The designation, which is designed to expedite the development and review of MPDL3280A, is based on early-stage data with the immunotherapy in patients with PD-L1–positive NSCLC, as determined by an investigational diagnostic.
At the 2013 European Cancer Congress, results were presented from a phase 1 study of MPDL3280A in patients with metastatic NSCLC, including tumors with squamous and adenocarcinoma histology.10 The data presented were from a cohort of 85 patients with metastatic NSCLC who were part of a larger study of MPDL3280A that included patients with other solid tumors. Of the 85 patients with NSCLC, 55% were heavily pretreated with ?3 prior systemic therapies, and the majority (81%) were smokers or former smokers.
MPDL3280A was generally well tolerated; the majority of AEs were grade 1 or 2 and did not require intervention. A total of 12.6% of patients experienced a treatment-related grade 3 or 4 AE, including fatigue (2%), dyspnea (0.7%), nausea (0.4%), and vomiting (0.4%). No cases of grade 3 to 5 pneumonitis or diarrhea were reported, and no dose-limiting toxicities were identified.
The ORR was 23% in the 53 NSCLC patients who received MPDL3280A as a single agent by October 1, 2012; 17% of responders were stable over 24 weeks. The 24-week PFS rate was 44% in patients with squamous cell NSCLC and 46% in those with nonsquamous cell NSCLC.
The investigators measured expression of PD-L1 by IHC and found that, for patients treated with MPDL3280A, ORR increased as PD-L1 expression increased (Figure 2). ORR was particularly pronounced in the population with the highest level of PD-L1 expression (IHC 3; defined as tumors containing ?10% PD-L1–positive tumor-infiltrating immune cells) at 83% (5 of 6 patients; 95% CI, 40.2%-99.1%).
In addition, the investigators analyzed whether smoking status predicted for a differential effect, and they found that smokers responded much better than nonsmokers: former/current smokers had an ORR of 26% (n = 43) versus 10% in never-smokers (n = 10).
A list of ongoing studies of MPDL3280A is shown in Table 4. All studies of MPDL3280A are prospectively evaluating PD-L1 expression. Some studies, including the phase 3 OAK study and the phase 2 POPLAR study, are evaluating the agent regardless of tumor PD-L1 status; other studies, including 2 phase 2 studies (FIR and BIRCH), are evaluating the agent only in patients whose tumors are characterized as PD-L1 positive.
MEDI4736, another PD-L1 antibody, is under investigation in a multicenter, open-label phase 1/2 study (NCT01693562) in patients with advanced solid tumors, including 155 patients with NSCLC. At the 2014 American Society of Clinical Oncology Annual Meeting, preliminary safety results from 13 patients with NSCLC in dose escalation cohorts were presented.11 Treatment-related AEs occurred in 43% of patients, all of which were grade 1 or 2, and none led to discontinuation of study drug. No pneumonitis or colitis was reported in dose escalation. Of 13 patients, 3 patients (24%) achieved a PR, with 2 additional patients achieving more modest tumor shrinkage not meeting the irRC criteria (46% and 48% decreases). Tumor shrinkage was reported as early as the first assessment (at 6 weeks), and benefit was durable; 4 of 13 patients remained on study (10+, 10+, 11.1+, and 14.9+ months) as of the data cutoff. Assessment of clinical activity by PD-L1 expression and smoking history is ongoing. A list of ongoing studies of MEDI4736 is shown in Table 5.
Monoclonal antibodies against CTLA-4 are designed to block the binding of CTLA-4 to its ligands (CD80/CD86) resulting in enhancement of activation and proliferation of tumor-specific T cells, thereby allowing an effective immune response against the tumor.12,13
Ipilimumab, a fully human monoclonal antibody, specifically blocks the binding of CTLA-4 to its ligands (CD80/CD86). This drug has shown significant improvement in OS in patients with previously treated and untreated metastatic melanoma14,15 and was approved by the FDA for the treatment of patients with unresectable or metastatic melanoma in 2011.16
Ipilimumab has been investigated in a randomized, double-blind, phase 2 study that assessed the monoclonal antibody in combination with first-line chemotherapy in patients with advanced NSCLC (stage IIIb/IV; n = 204) or extensive-stage small cell lung cancer (SCLC) (n = 130).17,18 Because the sequence of the administration of chemotherapy and immunotherapy may affect outcome, 2 alternate regimens of drug administration were used in these studies. In the concurrent regimen, ipilimumab was administered concurrently with paclitaxel and carboplatin, which allowed ipilimumab to be present at the earliest phase of chemotherapy-induced antigen release. In the phased regimen, paclitaxel and carboplatin were given before ipilimumab, which allowed antigen release to occur before ipilimumab addition. Results showed that in previously untreated patients with NSCLC, the combination of ipilimumab with paclitaxel and carboplatin as a phased, but not as a concurrent, regimen significantly improved PFS. Similarly, in the extensive-stage SCLC group, ipilimumab in combination with paclitaxel/carboplatin appeared to show clinical activity in patients with previously untreated disease when administered as a phased, but not as a concurrent, regimen.
Tremelimumab, another antibody targeting CTLA-4, has mostly been studied in melanoma.19 In phase 1/2 studies, tremelimumab induced durable objective responses in a subset of patients with advanced melanoma; however, in a phase 3 melanoma study, the agent did not produce a statistically significant advantage in OS compared with first-line standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma.20
In Italy, the efficacy, safety, and immunologic activity of tremelimumab has been investigated in an open-label, single-arm phase 2 study in 29 patients with unresectable malignant mesothelioma and progressive disease after a first-line platinum-based regimen.21 The primary end point was the proportion of patients who achieved an objective response (complete or partial response), with a target response rate of 17% according to the modified RECIST for pleural malignant mesothelioma or standard RECIST 1.0 for peritoneal malignant mesothelioma. Results showed that no patients had a complete response, and 2 patients (7%) had a durable PR (one lasting 6 months and the other lasting 18 months); 1 PR occurred after initial progressive disease. Thus, the study did not reach its primary end point. However, disease control was noted in 9 patients (31%), with a median PFS of 6.2 months (95% CI, 1.3-11.1) and a median OS of 10.7 months (range, 0.0-21.9). Twenty-seven patients (93%) had ?1 grade 1 or 2 treatment-emergent AEs (mainly cutaneous rash, pruritus, colitis, or diarrhea), and 4 patients (14%) had ?1 grade 3 or 4 treatment-emergent AEs (2 gastrointestinal, 1 neurological, 2 hepatic, and 1 pancreatic).
Tremelimumab is currently being investigated in a placebo-controlled phase 2 study (NCT01843374) for patients with unresectable pleural or peritoneal malignant mesothelioma.
- Zielinski C, Knapp S, Mascaux C, Hirsch F. Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer. Ann Oncol. 2013;24:1170-1179.
- Creelan BC. Update on immune checkpoint inhibitors in lung cancer. Cancer Control. 2014;21:80-99.
- Brahmer JR. Immune checkpoint blockade: the hope for immunotherapy as a treatment of lung cancer? Semin Oncol. 2014;41:126-132.
- Weber J. Immune checkpoint proteins: a new therapeutic paradigm for cancer—preclinical background: CTLA-4 and PD-1 blockade. Semin Oncol. 2010;37:430-439.
- Opdivo [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2015.
- US Food and Drug Administration. FDA News Release. FDA expands approved use of Opdivo to treat lung cancer. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436534.htm. Accessed March 16, 2015.
- Keytruda [package insert]. Whitehouse Station, NJ: Merck & Co, Inc; 2015.
- Garon EB, Rizvi N, Balmanoukian AS, et al. Antitumour activity of pembrolizumab and correlation with PD-L1 expression in a pooled analysis of patients with advanced NSCLC. Paper presented at: ESMO 2014; September 26-30, 2014; Madrid, Spain. Abstract LBA43.
- Genentech. FDA grants breakthrough therapy designation for Genentech’s investigational cancer immunotherapy MPDL3280A (anti-PDL1) in non-small cell lung cancer [press release]. www.gene.com/media/press-releases/14583/2015-02-01/fda-grants-breakthrough-therapy-designat. February 1, 2015. Accessed March 16, 2015.
- Soria JC, Cruz C, Bahleda R, et al. Clinical activity, safety and biomarkers of PD-L1 blockade in non-small cell lung cancer (NSCLC): additional analyses from a clinical study of the engineered antibody MPDL3280A (anti-PDL1). Paper presented at: 2013 European Cancer Congress; September 27-October 1, 2013; Amsterdam, The Netherlands. Abstract 3408.
- Brahmer JR, Rizvi NA, Lutsky J, et al. Clinical activity and biomarkers of MEDI4736, an anti-PD-L1 antibody, in patients with NSCLC. J Clin Oncol. 2014;32(suppl). Abstract 8021.
- Kavanagh B, O’Brien S, Lee D, et al. CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion. Blood. 2008;112:1175-1183.
- Maker AV, Attia P, Rosenberg SA. Analysis of the cellular mechanism of antitumor responses and autoimmunity in patients treated with CTLA-4 blockade. J Immunol. 2005;175:7746-7754.
- Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711-723.
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517-2526.
- Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2013.
- Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-2054.
- Reck M, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer:
results from a randomized, double-blind, multicenter phase 2 trial. Ann Oncol. 2013;24:75-83.
- Ribas A, Hanson DC, Noe DA, et al. Tremelimumab (CP-675,206), a cytotoxic T lymphocyte associated antigen 4 blocking monoclonal antibody in clinical development for patients with cancer. Oncologist. 2007;12:873-883.
- Ribas A, Kefford R, Marshall MA, et al. Phase III randomized clinical trial comparing tremelimumab with standard-of-care chemotherapy in patients with advanced melanoma. J Clin Oncol. 2013;31:616-622.
- Calabrò L, Morra A, Fonsatti E, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14:1104-1111.
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