September 2014, Part 3
Case Studies in ImmunotherapyUncategorized
Despite recent advances, non–small-cell lung cancer (NSCLC) continues to be the leading cause of cancer-related deaths worldwide, and its cure remains elusive. New drugs targeting EGFR (epidermal growth factor receptor), EML4-ALK, ROS-1, and KRAS mutations have provided considerable benefit and new therapeutic options for patients. However, overall survival for patients with metastatic disease continues to be poor. The need for novel approaches for the treatment of NSCLC has led to the development of various immunotherapeutic options. Agents such as anti–programmed death-1 (anti–PD-1) and anti–programmed death-1 ligand 1 (anti–PD-L1) antibodies have recently garnered significant attention and appear to hold a promising role in the treatment of NSCLC. These successes in NSCLC have helped introduce immunotherapy as a treatment option in other solid tumors such as squamous cell cancer of the head and neck. The 2 cases below highlight the promising role that immunotherapy agents can have in diseases that have traditionally had limited therapy options.
The patient is a 60-year-old man with a 5–pack-year smoking history who quit smoking 31 years prior to presentation (Figure 1). He began complaining of right arm pain in November 2011. A chest computed tomography (CT) scan showed a 4.5-cm lesion in the right upper lobe abutting the pleura. A percutaneous needle biopsy of the lung mass was undertaken, which showed sheets of malignant-appearing cells with glandular features and areas of necrosis. The tumor cells were positive for TTF1, napsin A, cytokeratin (CK) 7, and CD56, and negative for CK20, CK5/6, p63, chromogranin, and synaptophysin consistent with primary adenocarcinoma of the lung. Upon review of his case in a multidisciplinary setting, he was offered chemotherapy with cisplatin and pemetrexed as an initial course of therapy. He had an evaluable response to chemotherapy with evidence of tumor shrinkage, enabling him to be referred for a surgical resection. He underwent a right upper lobectomy. Pathology was consistent with high-grade carcinoma with a prominent neuroendocrine pattern. The tumor was 4.0 cm in greatest dimension and approached the perivascular soft tissue. Mediastinal lymph nodes were negative for any evidence of malignancy. He did not receive chemotherapy in the adjuvant setting.
Six months following the patient’s surgery, surveillance CT scans showed evidence of new lesions in the left lung. Percutaneous biopsy of one of the pulmonary lesions was consistent with recurrent TTF1-positive, CK 7-positive, napsin A-negative, and thyroglobulin-negative cells consistent with adenocarcinoma of the lung. He was negative for EGFR and ALK mutations. Because of his prior experience with chemotherapy, the patient was reluctant to undergo further chemotherapy for his now stage IV disease. He opted to participate in a dendritic cell vaccine study to which he initially had a mixed response followed by progression 3 months after enrollment. Upon progression, he was offered treatment with systemic chemotherapy. However, the patient requested to pursue various trial options, ultimately presenting to our clinic for consideration of an immunotherapy trial with a checkpoint inhibitor.
In July 2013, the patient was evaluated for an anti–PD-1 antibody immunotherapy trial and underwent a biopsy of a pulmonary lesion, which was tested for PD-L1 protein expression. The disease was found to express PD-L1. His CT scans prior to enrollment indicated the presence of multiple bilateral pulmonary nodules, the largest of which was 2.5 cm. There was no evidence of pleural effusion, but the patient had a small pericardial effusion. His first scan 9 weeks after initiating therapy indicated stable disease; all subsequent scans have indicated significant tumor shrinkage. The patient has tolerated therapy well with no significant side effects, except for complaint of bilateral buccal mucosal swelling and sensitivity. He has also developed oral ulcers that have been managed well with oral lidocaine and a steroid solution. He has had no other side effects, and continues to do well on the trial 1 year after enrollment.
This case highlights the exciting advances of immunotherapy in the treatment of NSCLC. Traditionally, immunotherapy has had limited success in treating solid tumors except for melanoma and renal cell cancer.1,2 With recent improvements in the understanding of the functioning of the immune system and its relationship to tumor evasion, novel immunotherapy agents such as anti–PD-1 and anti–PD-L1 antibodies have become available as treatment options. These agents are showing promising results in the treatment of various solid tumors including NSCLC. PD-1 is one of the immune checkpoint inhibitors involved in inhibiting tumor-specific T cells. It is a member of the B7-CD28 superfamily, and is a cell surface receptor with 2 known ligands: PD-L1 (B7-H1) and PD-1 ligand 2 (PD-L2 [B7-DC]).3 Binding of the PD-1 receptor with its PD-L1 ligand causes T-cell inhibition and downregulation of T-cell response, precipitating tumor evasion by the immune system.4
Various PD-1 antibodies are currently available, including nivolumab, pembrolizumab, and AMP-514. The first study to highlight the promising role of an anti–PD-1 antibody in treating solid tumors was published by Topalian and colleagues in 2012.5 In this phase 1 dose-escalation trial of a fully human immunoglobin (Ig) G4-blocking monoclonal antibody against PD-1, nivolumab was administered once every 2 weeks. Patients with melanoma, NSCLC, renal cell cancer, castration-resistant prostate cancer, or colorectal cancer were enrolled. Patients with NSCLC could not receive more than 5 lines of prior therapy. A total of 296 patients were enrolled in the study, 122 of whom had NSCLC. Seventy-six (76/122) of the patients were assessable for response. Of the 76 patients, 14 had objective responses per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. Responses were observed at dosages of 1 mg/kg, 3 mg/kg, and 10 mg/kg with response rates of 6%, 32%, and 18%, respectively. Patients with both squamous and nonsquamous histology benefited from the drug. Six of 18 (33%) patients with squamous cell histology had a response, and 7 of 56 (12%) patients with nonsquamous histology had a response. Upon analysis, PD-L1 tumor expression appeared to correlate with a better response to the drug. Patients without PD-L1 tumor expression had no response, whereas 36% of patients with PD-L1 expression had a response. The drug was well tolerated, with the most common adverse events (AEs) including fatigue, decreased appetite, diarrhea, nausea, cough, dyspnea, constipation, vomiting, rash, pyrexia, and headache. Four patients with NSCLC experienced grade 1 or 2 pneumonitis, and 2 patients died of pneumonitis. Early-grade pneumonitis was controlled with the use of corticosteroids.
Updated survival data on the phase 1 study of nivolumab in NSCLC was presented at the World Conference on Lung Cancer in 2013.6 Responses were noted in 22 of 129 (17%) patients with NSCLC, and were noted to be durable. Twelve of 22 (55%) patients had an ongoing response with median duration of response of 74 weeks. At a follow-up of 20.3 months, survival rates were noted to be 42% at 1 year and 24% at 2 years.
Other anti–PD-1 antibodies, including pembrolizumab, have also shown promising results in the treatment of NSCLC in both previously treated and chemotherapy-naïve patients. Pembrolizumab is a humanized monoclonal IgG4 antibody against PD-1. Initial results of the phase 1 study were presented at the World Conference on Lung Cancer in 2013.7 Pembrolizumab was administered at 10 mg/kg every 3 weeks to patients with NSCLC who were previously treated with 2 systemic regimens. Thirty-eight patients were enrolled. The overall response rate (ORR) by immune-related criteria was 24%, whereas the ORR by RECIST criteria was 21%. The most common AEs were fatigue (16%), rash (16%), and pruritus (16%). Diarrhea was noted in 13% of cases. Activity was also noted in chemotherapy-naïve subgroups. As presented at the American Society of Clinical Oncology (ASCO) annual meeting in 2014, patients with no previous systemic therapy for metastatic disease who received pembrolizumab also seemed to benefit.8 Patients with NSCLC whose tumors expressed PD-L1 were randomized to receive pembrolizumab at 10 mg/kg every 2 or 3 weeks. The first 11 patients were randomized to 2 mg/kg and 10 mg/kg every 3 weeks. Forty-five patients were evaluated for response (2 mg/kg every 3 weeks, N = 6; 10 mg/kg every 3 weeks, N = 23; 10 mg/kg every 2 weeks, N = 16). Preliminary data indicated an ORR of 36%. The responses were 67% in the group receiving 2 mg/kg every 3 weeks, 27% in the group receiving 10 mg/kg every 3 weeks, and 35% in the group receiving 10 mg/kg every 2 weeks. Fifty-two percent of patients experienced a drug-related AE, usually grade 1/2 in severity. Most common AEs were fatigue (14%), pruritus (8%), dermatitis acneiform (6%), diarrhea (6%), and dyspnea (6%). There was a single grade 3 pericardial effusion.
Similar to the anti–PD-1 antibody, the anti–PD-L1 monoclonal antibody blocks the interaction between the PD-1 receptor and its PD-L1 ligand. Various anti–PD-L1 antibody agents are currently available, and are being evaluated for use in various diseases. In a phase 1 trial, BMS-936559, a high-affinity, fully human, PD-L1–specific, IgG4 monoclonal antibody was administered once every 2 weeks to patients with various solid tumors, including NSCLC.9 A total of 207 patients were enrolled in the study, 75 of whom had NSCLC. Patients with NSCLC were included in the dose escalation phase of the trial and were treated with 0.3-, 1-, 3-, and 10-mg/kg dosing. Of the 75 patients with NSCLC, 49 were evaluable for disease activity. There were 5 objective responses seen: 1 of 13 (response rate of 6%) patients with squamous cell, and 4 of 36 (11%) with nonsquamous histology. Six patients (12%) had stable disease at 6 months. The most common treatment-related AEs were fatigue, infusion reactions, arthralgia, rash, nausea, pruritus, headache, and diarrhea. Grade 3 or 4 AEs were noted in 19 of 207 (9%) patients.
Other anti–PD-L1 antibodies such as MPDL3280A are also showing promising activity in NSCLC. Spigel and colleagues reported an ORR of 24% in patients with NSCLC treated with MPDL3280A.10 The drug was administered every 3 weeks to patients with both squamous and nonsquamous histology at doses of 1 mg/kg, 15 mg/kg, or 20 mg/kg. Several cases of rapid tumor shrinkage were observed, as well as a few cases of delayed response after an initial presumed radiographic progression. Patients who were PD-L1–positive showed an ORR of 100% (4/4), whereas patients who were PD-L1 tumor negative showed an ORR of 15%. The drug was well tolerated. Pericardial effusion was noted in 6% of patients. Dehydration (6%), dyspnea (4%), and fatigue (4%) were also noted.
Other anti–PD-L1 antibodies such as MEDI473611 (NCT02117219, NCT02087423) are being evaluated for their role in the treatment of NSCLC. These immunotherapy agents, including the various immune checkpoint inhibitors, are showing promising activity in NSCLC. As outlined in the case above, these agents are well tolerated, and often have durable responses. They offer a novel therapeutic approach in the treatment of a disease that lacks significant options in the metastatic setting.
The patient is a 66-year-old man with a medical history of hypertension and a remote smoking history who initially palpated a mass on the left side of his neck in July 2008 (Figure 2). He was referred to an ear, nose, and throat specialist, and was noted to have a mass overlying and possibly involving his left parotid gland. The patient underwent a fine needle aspiration of the lesion, but pathology was nondiagnostic. He subsequently underwent a neck magnetic resonance imaging, which showed the lesion to be localized to the left parotid. In October 2008, he underwent a left total parotidectomy and left modified radical neck dissection. Pathology from the resection was consistent with a 3.7-cm invasive, high-grade, basaloid squamous cell carcinoma involving the parotid gland and periparotid soft tissue. Evidence of malignancy was seen in the deep parotid tissue as well as in 1 of 5 dissected lymph nodes. There was evidence of perineural invasion by the tumor. The tumor was positive for p63 and KER 5/6, and negative for S100, GFAP, EMA, CEA, and CD117. In the adjuvant setting, the patient received concurrent carboplatin (Paraplatin), docetaxel (Taxotere), and radiation. He completed his course in January 2009, underwent surveillance scans after completion of his concurrent therapy, and did well until February 2011. Surveillance images at that time noted a lesion in the lung and a lytic lesion in the iliac bone. In July 2011, he underwent a percutaneous needle biopsy of the right iliac lesion with pathology again being consistent with metastatic carcinoma consistent with the patient’s history of basaloid squamous cell carcinoma. The tissue was positive for p63, SMA, and pankeratin AE1/AE3, and negative for Vimentin, S100, CD117, CK5/6, and EMA.
Given the stage IV diagnosis, the patient resumed chemotherapy with vinorelbine shortly after the biopsy. After 2 cycles, scans showed disease progression, and therapy was changed to carboplatin and docetaxel with continued progression. He then received bevacizumab and everolimus with no improvement in his disease. Subsequent therapy with cetuximab also did not provide benefit. Upon progression, he was enrolled in a clinical trial with a novel vascular endothelial growth factor inhibitor that provided stabilization of his disease for 4 months, after which his disease began to progress.
In September 2013, the patient presented for consideration of an immunotherapy clinical trial. He was subsequently enrolled in an anti–PD-L1 antibody trial that did not mandate PD-L1 protein expression testing. He underwent a fresh biopsy for the trial, but his PD-L1 protein expression was unknown at the time of his enrollment. Baseline scans prior to initiating the trial indicated evidence of left mastoidectomy and radical left neck surgery. There was evidence of numerous pulmonary nodules and pleural nodularity bilaterally. The largest pulmonary nodule measured 5.1 cm. There was a small right pleural effusion, and there was also evidence of a 5.2-cm lytic and sclerotic lesion involving the right ilium.
The patient began on the anti–PD-L1 antibody with his first infusion in December 2013. His first scans 6 weeks after enrolling into the study indicated evidence of stable disease with minimal shrinkage of his pulmonary lesions. Subsequent scans have shown a dramatic reduction in the size and burden of his pulmonary nodules. His pleural effusion has resolved. The patient has been tolerating the therapy well with no side effects. He is continuing to receive the anti–PD-L1 antibody every 2 weeks with continued evidence of tumor shrinkage
9 months after enrolling in the study.
This case highlights the potential role immunotherapy agents may have in the treatment of various solid tumors. As highlighted in the previous case, initial trials with the anti–PD-1 and anti–PD-L1 antibodies enrolled patients with melanoma, NSCLC, renal cell cancer, castration resistant prostate cancer, colorectal cancer, pancreatic cancer, gastric cancer, and breast cancer.5,9 Melanoma, renal cell cancer, and NSCLC appeared to have significant and durable responses with these immune checkpoint inhibitors. Since these initial trials, additional work has shown these agents to also have promising roles in the treatment of other solid tumors such as bladder cancer and squamous cell cancer of the head and neck.
As presented at the ASCO 2014 annual meeting, the use of the anti–PD-1 antibody pembrolizumab was studied in patients with recurrent or metastatic head and neck cancer.12 In this nonrandomized trial, patients with both human papilloma virus (HPV)-positive and HPV-negative head and neck cancer were enrolled as long as they met the eligibility for PD-L1 expression by trial immunohistochemistry (IHC) cutoff requirements. If patients were deemed PD-L1 positive, they received pembrolizumab intravenously at 10 mg/kg every 2 weeks. PD-L1 expression was defined as ?1% of stained cells in the tumor microenvironment. Sixty patients were enrolled in the study; 23 were HPV-positive, and 37 were HPV-negative. The most common drug-related AEs were pruritus (10%), fatigue (7%), rash (7%), and diarrhea (5%). Of the patients treated, 13.3% had drug-related grade 3 to 5 AEs. These included hyponatremia, lymphopenia, rash, diarrhea, musculoskeletal pain, neck abscess, and atrial fibrillation. Tumor shrinkage was observed in several patients in the study. At the time of the presentation, preliminary data indicated 51% of patients had decreased tumor burden. This response applied to both HPV-positive and HPV-negative patients. Best ORR was 19.6%, and was similar between the HPV-positive and HPV-negative patients. PD-L1 expression appeared to correlate with response. Given the preliminary nature of these data, mature data will be presented at future meetings. Currently, multiple immunotherapy trials are looking into the use of anti–PD-1 antibody, anti–PD-L1 antibody, a combination of the 2 agents, or in combination with other novel immunotherapy agents in the treatment of head and neck cancers. As highlighted in the case above, immunotherapy may play a promising role in the treatment of this otherwise challenging disease.
Bladder cancer is another challenging disease that is difficult to eradicate in the recurrent setting. Despite the efficacy of first-line regimens with platinum-based therapies, nearly all patients experience disease progression and require multiple lines of chemotherapy for treatment. There are currently no approved second-line therapies in the United States for metastatic bladder cancer. The ORRs to second-line therapy have been low.13 Given the paucity of treatment options for metastatic bladder cancer, the anti–PD-L1 antibody MPDL
3280A was evaluated as a potential treatment option in a phase 1 study. As presented at the ASCO 2014 annual meeting, 31 patients with recurrent or metastatic urothelial bladder cancer were treated with MPDL3280A at a dose of 15 mg/kg every 3 weeks for up to 1 year.14 The grades 1 to 4 treatment-related AEs were pyrexia, anemia, decreased appetite, fatigue, and nausea. Grades 3 to 4 AEs occurred in 3.2% of patients. There were no immune-related AEs. The response rate (RR) varied with PD-L1 expression. Patients with an IHC of 3 had an RR of 50%, those with an IHC of 2 had an RR of 40%, those with an IHC of 1 had an RR of 13%, and those with an IHC of 0 had an RR of 8%. With the updated result presented at the meeting, the ORR with this drug was noted to be 52%. Sixteen of 17 responding patients had ongoing responses at the time of data cutoff. Median time to response was 42 days (range, 38-85 days). Based on these promising results, the FDA granted this drug “breakthrough designation.” There is an ongoing phase 2 study with MPDL3280A (NCT02108652) in patients with recurrent and metastatic bladder cancer evaluating patients in the first-line and previously treated settings. Given the data from the phase 1 trial, patients will be allowed to enroll regardless of their PD-L1 protein status.
The introduction of immune checkpoint inhibitors has changed the landscape of the treatment of various solid tumors over the past few years. These agents are offering promising activity in various diseases, often with minimal side effects and with durable responses. The future holds great potential as we expand our knowledge as to how best to use these agents, whether as single agents or in combination with other immunotherapy or chemotherapy agents. Furthermore, studies will elucidate which biomarkers may be useful in predicting the best candidates for immunotherapy. Ongoing clinical trials will help define and expand our current understanding about our use of these drugs while offering promising treatment to patients who previously had limited options for therapy.
- Coppin C, Porzsol T, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005;1:CD001425.
- 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.
- Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704.
- Chen L. Co-inhibitory molecules of B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. 2004;4:336-347.
- Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443-2454.
- Brahmer JR, Horn L, Antonia S, 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 I trial. Paper presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. Abstract MO18.03.
- 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). Paper presented at: IASLC 15th World Conference on Lung Cancer; October 2013; Sydney, Australia. Abstract MO18.02.
- Rizvi NA, Garon EB, Patnaik A, et al. Safety and clinical activity of MK-3475 as initial therapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2014;32:5s(suppl):Abstract 8007.
- Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti–PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455-2465.
- Spigel DR, Gettinger SN, Horn L, et al. Clinical activity, safety, and biomarkers of MPDL3280A, an engineered PD-L1 antibody in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2013;31(suppl):
- Fairman D, Narwal R, Liang M, et al. Pharmacokinetics of MEDI4736, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol. 2014;32:5s(suppl):Abstract 2602.
- Seiwert TY, Burtness B, Weiss J, et al. A phase Ib study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-HPV–associated head and neck (H/N) cancer. J Clin Oncol. 2014;32:5s(suppl):Abstract 6011.
- Sonpavde G, Sternberg CN, Rosenberg JE, et al. Second-line systemic therapy and emerging drugs for metastatic transitional-cell carcinoma of the urothelium. Lancet Oncol. 2010;11:861-870.
- Powles T, Vogelzang NJ, Fine GD, et al. Inhibition of PD-L1 by MPDL3280A and clinical activity in pts with metastatic urothelial bladder cancer (UBC). J Clin Oncol. 2014;32:5s(suppl):Abstract 5011.
Overview Cytokines are familiar to the oncologist as the glycoprotein messengers of the immune system and beyond. Their role in cancer treatment has been firmly established since the late 1980s, when investigators reported that interleukin (IL)-2 administration plus adoptive transfer of lymphokine-activated killer cells were effective treatment for refractory solid [ Read More ]
First Anti–PD-1 Immunotherapy, Pembrolizumab, Receives Accelerated FDA Approval for Advanced Melanoma
On September 4, 2014, the FDA has approved pembrolizumab (Keytruda; Merck), the first anti–programmed death-1 (PD-1) therapy for the treatment of patients with advanced (ie, unresectable or metastatic) melanoma and disease progression after therapy with ipilimumab, or, for a patient with a BRAF V600 mutation, after ipilimumab plus BRAF inhibitor [ Read More ]