Targeted Programmed Cell Death in Lung Cancer Treatment
Published Online: March 19, 2014
Marj P. Zimmerman, MS, BSPharm, and Stanton R. Mehr
Despite new and improved therapies, lung cancer remains the second most common type of cancer in men and women (not including skin cancer), and is the leading cause of cancer-related death for both men and women (Table 1).1 The 5-year survival rate for all stages is 16.3%, which is lower than many other types of cancer. Most patients are not diagnosed in the early stages of the disease, so more than half the patients die within 1 year of being diagnosed.2 In 2010, an estimated $12.1 billion was spent on treating lung cancer.3 However, research is ongoing to uncover and better understand potential treatments for lung cancer.
Recently, immunotherapeutic approaches involving the body’s T-cell immune system were effectively implemented in lung cancer therapy. T-cell activity is regulated by a balance of costimulatory and inhibitory signals, known as checkpoints. The body’s self-regulation through these checkpoints enables it to respond to infections and prevent tumor progression, as well as to prevent autoimmune-type responses.4
Ipilimumab, which has been approved for use in patients with advanced melanoma, is known to have antitumor activity mediated via T cells.5 Knowing that T-cell function is suppressed in lung cancer, researchers explored the effectiveness of ipilimumab for treating lung cancer. Early trials have indicated that this immune checkpoint inhibitor, administered in combination with chemotherapy, can improve progression-free survival (PFS) in patients with advanced lung cancer.6
Another key checkpoint pathway that is mediated via T cells is the programmed death-1 (PD-1) pathway. Together with its ligands PD-L1 and PD-L2, the PD-1 receptor, a doorway through which T cells either recognize and attack tumor cells normally or diation treatment), pointing to a need if the pathway is inhibited, allow tumor cells to foil the immunotherapeutic system and grow unrecognized and without sparking a natural T-cell reaction. What makes this such a promising area is the fact that many solid tumor types express PD-L1. In fact, PD-L1 expression is often associated with a worse prognosis, because it is a sign that the patients’ own immune system is likely not helping to combat tumor growth. However, recent research efforts indicate that by blocking the PD-L1 ligands, the body’s T cells can be forced to recognize tumor cells, and the natural programmed cell death mechanism can then take over.7
Research has found that blocking the PD-1 pathway inhibits binding to both PD-L1 and PD-L2 ligands. There is potential to selectively block the PD-L1 receptor, which affects the CD80 pathway that is necessary for T-cell activation and survival.4,7 The more specific targeting is preferable, as studies have indicated that targeting PD-L1 may lead to fewer toxicities (including pneumonitis) than targeting the overall PD-1 pathway.7,8
Several PD-1 and PD-L1 agents are currently being tested in clinical trials. Since several tumor types express these targets, the early investigational studies involve multiple solid tumor types. Once a drug candidate demonstrates PD-1 pathway activity, the clinical trials tend to home in on specific tumor types. Ongoing studies should indicate whether anti-tumor activity is greatest with the PD-1 targeted agents versus those targeting PD-L1 alone.
PD-1 Targeted Agents in Development
Nivolumab. Nivolumab, a fully human IgG4-PD-1 immune checkpoint inhibitor, is currently in phase III trials. Nivolumab binds to the PD-1 receptors expressed on activated T-cells, which in turn inhibits the binding of PD-1 to both PD-L1 and PD-L2 ligands.9
Results of an expanded nonrandomized controlled phase I trial were pre-sented at the World Conference on Lung Cancer in October 2013.10 A total of 129 patients with non-small cell lung cancer (NSCLC) who had been previously treated (74 with non-squamous cell cancer, 54 with squamous cell cancer, and 1 with unknown histology) were given an intravenous infusion of nivolumab every 2 weeks for 4 doses in an 8-week treatment cycle. Treatment with 1, 3, or 10 mg/kg was administered for a maximum of 12 cycles or until patients had a complete response (CR), unacceptable toxicity, progressive disease (PD), or withdrew consent.
Patients were not tested for PD-L1-receptor expression. Twenty-two patients (17%) had either a complete response or partial response (PR), as measured by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The highest objective response rate (ORR; ORR = CR + PR) was seen with the 3 mg/kg dose across all of the NSCLC disease types. There was no differentiation with regard to response based on tumor cell type. Of the patients responding to therapy, 50% (11/22) saw improvement at 8 weeks. The median overall survival (OS) was 9.6 months across all doses and 14.9 month with the 3 mg/kg dose across tumor types. The 1-year OS rate was 42%, while the 2-year OS was 14%.
Adverse events of any grade were observed in 41% (53/129) of the patients, with the most common relating to dermatologic (16%), gastrointestinal (12%), and pulmonary (7%) problems. Grade 3 or 4 adverse advents were seen in 5% (6/129) of the patients; 3 patients (2%) had pneumonitis. Pneumonitis was the cause of 2 early deaths.10
Phase III clinical trials are in progress for nivolumab for NSCLC (both squamous cell and non–squamous cell), melanoma, and renal cell carcinoma. The drug is being investigated as monotherapy and in combination with other drugs used to treat cancer. In 1 phase I trial, nivolumab and ipilimumab are being administered in combination for the treatment of advanced stage NSCLC.
As of January 27, 2014, Bristol-Myers Squibb, the company developing the 2 molecules, did not have plans to initiate late-stage trials with this combination (nivolumab and ipilimumab) for treating NSCLC.11
Lambrolizumab. Mechanistically, lambrolizumab is similar to nivolumab. It differs only in that it is a humanized IgG4 rather than a fully human monoclonal antibody.4 Phase III trials are currently in progress with this drug. Interim data from a phase Ib expansion study were presented at the World Conference on Lung Cancer in October 2013. Patients with previously treated NSCLC were administered 10 mg/kg lambrolizumab via intravenous infusion every 3 weeks. PD-L1 expression was evaluated before the study was initiated, though it was not used to determine treatment. The ORR in the 38 patients diagnosed with squamous and non-squamous disease was 24%. Using RECIST criteria, the ORR was 21% (N = 9). Most of the responses were seen at the first planned assessment at week 9.
The median duration of response had not been reached after 6 to 9 months of study. Adverse events were observed in 51% of the study participants, with the most common being fatigue, rash, and pruritis (6 patients each), with 12% experiencing diarrhea. One case of grade 3 pulmonary edema was reported; no patient died as a result of treatment.12
The presence of this PD-L1 expression was a statistically significant predictor of response—all confirmed responses were in patients with tumors that strongly expressed PD-L1.12 A press release by Merck provided additional information13: high levels of PD-L1 expression resulted in a response rate of 57% or 67% (depending upon the assay utilized), whereas patients with zero or low levels of PD-L1 expression had a response rate of only 4% to 9%. Further studies will help fully understand the relationship between PD-L1 expression and response to therapy.
Pidilizumab. Pidilizumab is currently in a phase I trial, where it is being evaluated for multiple tumor types. This agent is different from nivolumab and lambrolizumab in that it a humanized IgG1 monoclonal antibody. An early study with this agent in patients with advanced hematologic malignancies showed no pulmonary adverse effects.14
A small study has indicated that there may be a difference in the adverse event profile between IgG4 antibodies and IgG1 antibodies.
Other agents. Two other PD-1 agents are in phase I development: (1) AMP514/MEDI0680, a collaboration between Amplimmune and Medimmune, and (2) AMP224, a collaboration between Amplimmune and GlaxoSmithKline.15 No early clinical trial results have been released to date.
PD-L1 Targeted Agents in Development
MPDL3280A. MPDL3280A, being developed by Genentech, is an anti-PD-L1 monoclonal antibody that enhances the anti-tumor T-cell response. In a trial of 53 patients with either squamous or non–squamous-cell NSCLC having prior therapy (surgery, radiotherapy, or systemic chemotherapy), the agent was given intravenously every 3 weeks for up to a year (median duration, 106 days).16 Dosages administered were ≤1 mg, 10 mg, 15 mg, and 20 mg/kg. The ORR across dosages was 24% (9/37 patients evaluated for efficacy), and the PFS at 24 weeks was 48%.
Overall, 34% of patients experienced grade 3 or 4 adverse events, including dehydration, dyspnea, and fatigue (all 4%), and pericardial effusion (6%). Severe pneumonitis or diarrhea was not reported.
The study also evaluated the correlation between PD-L1 tumor marker status and efficacy finding that those patients with a positive PD-L1 tumor status having an ORR of 100% while those with a negative PD-L1 tumor status of 15%. There was a PD rate of 0% in the PD-L1–positive tumor status group and a PD rate of 58% in the PD-L1–negative tumor status group.16
Smoking seemed to be a predictor of outcome: the response rate was 25% in the former or current smokers group and 14% in the group of patients who had never smoked.17 MPDL32801A is currently in phase II development; a trial in patients with locally advanced or metastatic NSCLC that was initiated in May 2013 has an estimated completion date of May 2015.
MEDI4736. Early clinical results for another PD-L1 monoclonal antibody were presented at the European Cancer Congress 2013 held August 31-September 2013. The preliminary results for the phase I trial of MEDI4736 showed that 8 patients receiving a median of 6 doses indicated tumor shrinkage as early as 7 weeks. No adverse events grade 3 or above were reported and there were no reports of pneumonitis or colitis of any grade.18
The drug is currently in phase I clinical development for patients with advanced solid tumors as well as for NSCLC. One study is evaluating the combination of MEDI4736 with tremelimumab, a CTLA-4 antibody for patients with NSCLC. These phase I clinical trials are not anticipated to be completed until November 2015 and October 2017, respectively.
BMS-936559/MDX1104. Bristol-Myers Squibb’s agent is a high-affinity, fully human PD-L1 monoclonal antibody that inhibits the PD-L1 pathway. The drug was given to 207 patients with various cancer types in a phase 1 trial.9 The efficacy population included 160 patients, with a subset of 49 patients with NSCLC.
Three doses (1, 3, and 10 mg/kg) were given every 14 days in 6-week cycles for up to 16 cycles. Therapy was discontinued if the patient had a CR or if there was confirmed disease progression.
Five patients had an objective response at 24 weeks, and 6 patients had a PFS rate of 31% at 24 weeks. The response rate was 8% and 16%, respectively, in the patients receiving 3 and 10 mg/kg of drug. Across all tumor types, 91% of the patients were observed to have adverse events, with 9% experiencing a grade 3 or 4 adverse event. Twelve patients discontinued treatment owing to adverse drug events.9 Although an apparently low level of response, this is of interest because no response was expected by the investigators—until then, NSCLC had been considered to be nonimmunogenic and therefore poorly responsive to immune-based treatments.
This agent is currently in phase I studies for multiple tumor types as well as in patients with HIV who have viral load levels below the limit of detection.
The PD-1 inhibitors and PD-L1–targeted agents are in various stages of development, but application to the US Food and Drug Administration is not expected for any of these products until at least 2015. Very early results demonstrate some specific response when this pathway is blocked, and more data (both initial and supportive) are needed to quantify their expected efficacy in patients who express PD-L1 receptors.
One might expect PD-L1 overexpression to be a reliable biomarker for patients who would benefit from such targeted treatment. However, PD-L1 has not been conclusively found to predict response, and investigators studying Merck’s lambrolizumab12 indicated that further study is needed to better understand the role of PD-L1 as a biomarker.
Additional studies will continue to evaluate the efficacy and safety of these drugs as well as the potential to find a highly predictive biomarker that will accurately identify patients in whom the agents will be most efficacious.
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10. Brahmer JR, Horn L, Antonia SJ, et al. Nivolumab (anti-PD-1: BMS-936558; ONO-4538) in patients with non-small cell lung cancer (NSCLC): overall survival and long-term safety in a phase 1 trial. Presented at the World Conference on Lung Cancer, Sydney, Australia, October 29, 2013, Abstract M-18.03.
11. Carroll J. Is Bristol-Myers fading back in its hot race with Merck for PD-1 lead? Fierce Biotech. www.fiercebiotech.com/story/bristol-myers-fading-back-its-hot-race-merck-pd-1-lead/2014-01-27. Published January 27, 2014. Accessed January 28, 2014.
12. Garon EB, Balmanoukian A, Hamid O, et al. Preliminary clinical safety and activity of MK-3475 monotherapy for the treatment of previously treated patients with non-small cell lung cancer (NSCLC). Presented at the World Conference on Lung Cancer, Sydney, Australia, October 29, 2013. Abstract #M-18.02.
13. Interim data from Phase 1B trial of an investigational anti-PD-1 immunotherapy in patients with previously-treated NSCLC announced by Merck. NewsMedical. www.news-medical.net/news/20131031/Interim-data-from-Phase-1Btrial-of-an-investigational-anti-PD-1-immunotherapy-in-patients-with-previously-treated-NSCLCannounced-by-Merck.aspx. Published October
31, 2013. Accessed January 24, 2014.
14. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res. 2008;14:3044-3051.
15. Product Development. Amplimmune www.amplimmune.com/proddev.html. Accessed February 3, 2014.
16. Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety, and biomarkers of MPDL83280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic
non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31(suppl):abstract 8008.
17. Soria JD, Cruz C, Bahleda, 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). Presented at the European Cancer Congress, Amsterdam, The Netherlands, September 29, 2013. Abstract 3408.
18. Khleif S, Lutzky J, Segal N, et al. MEDI4736, an anti-PD-L1 antibody with modified Fc domain: preclinical evaluation and early clinical results from a phase 1 study in patients with advanced solid tumors. Presented at the European Cancer Congress, Amsterdam, The Netherlands, September 29, 2013. Abstract 802.