Lung cancer is the number one cause of cancer mortality globally and has an estimated incidence of 1.3 million new cases every year. Approximately 80–85% of the newly diagnosed cases of lung cancer are non-small cell lung cancer ( NSCLC ) ( adenocarcinoma, squamous carcinoma, and large cell carcinoma ) and 15–20% small cell lung carcinoma.
In the majority of cases, patients present with unresectable and/or non-curable disease.
Locally advanced, good performance status NSCLC patients may be offered concurrent chemotherapy, radical radiotherapy, and/or surgery, with a resultant 8-month progression-free survival rate and less than 15% 5-year survival.
Patients diagnosed with metastatic disease newer cytotoxic chemotherapies such as Pemetrexed [ 17-month median overall survival ] and treatment with molecularly targeted therapeutics for adenocarcinomas, such as next generation small molecules targeting the EGFR ( 24 months median overall survival ) and ALK inhibitors ( 20 months median overall survival ), the survival rate for advanced disease has improved only marginally.
In the last decade, there has been a better understanding on how cancer interacts with the immune cells and the ways that the cancer have developed to evade the immune system, resulting in a new era of cancer immunotherapy protocols, which may aid in overcoming the limitations of conventional therapeutic strategies.
Two such immunotherapeutic strategies in NSCLC are currently in clinical trials that involve increasing tumor immunogenicity by using cancer vaccines to augment tumor-immune recognition and overcoming tumor immunosuppression by using immune checkpoint inhibitors.
Immune checkpoint regulators
Initiation of adaptive immunity is a complex multifaceted mechanism that takes place between APCs and T-cells. A homeostatic balance between stimulatory and inhibitory signals is required to prevent over/under stimulation of T-cells, which may result in autoimmunity or immunosuppression sequelae, respectively.
APCs take up foreign antigen, process it, and express the antigen on its surface in the context of class II HLA, which then engages the T-cell receptor on the surface of T-cells.
A second signal through the costimulatory molecules facilitated by binding of CD28 on T-cell surface by CD86 ( B7-2 ) on APCs.
As a result of these specific interactions, T-cells are activated and secrete cytokines ( third signal ) such as IL-2 stimulating T-cell clonal proliferation.
In order to prevent autoimmunity, T-cell proliferation is negatively regulated by cytotoxic T-lymphocyte antigen 4 ( CTLA-4 ), which is expressed on the surface of activated T-cells.
CTLA-4 is a member of immunoglobulin superfamily and binds to B7-2 with much higher affinity than CD28 and therefore when expressed the T-cell response is down regulated.
Furthermore, CTLA-4 is expressed by the Tregs thereby enabling them to suppress the effector T-cells.
CTLA-4 regulation takes place in the early activation phase of immune induction occurring in the regional lymph nodes at the level of the APC and unprimed T-cell interaction.
Another significant immune check point regulator molecule that has been extensively studied is the programed death-1 ( PD-1 ) molecule.
PD-1 is expressed on the surface of activated T-cells and its active ligand [ PD-L ( B7-H1 ) ] is expressed on macrophages and can be also actively induced in endothelial, epithelial, and tumor cells.
PD-1 can also binds to PDL-2, which is expressed mainly on APC and some tumor cells.
Unlike CTLA-4 negative regulation PD-1/PDL-1 takes place in the peripheral tissue/tumor during the effector phase of T-cell activation.
Both CTLA-4 and PD-1 have been targeted by inhibitory antibodies as an adjuvant therapy in cancer in attempt to enhance T-cell activation and tumor immunity.
Ipilimumab also known as MDX-010 and MDX-101 ( Yervoy ) is a human monoclonal antibody directed against CTLA-4 molecule. Ipilimumab blocks the interaction of CTLA-4 with its ligand B7-2, resulting in T-cell activation, proliferation, induction of cytotoxic cytokines, and tumor suppression.
Phase I/II trials have identified the safety and tolerability of CTLA-4 inhibition in several cancers that include the significant risk of colitis and, hepatotoxicity, skin rash, and hypophysitis / hypopituitarism. Moreover, they significantly improved overall survival in patients with malignant melanoma in phase III trials.
Two concurrent randomized phase II trials used Ipilimumab in combination with chemotherapy ( Carboplatin / Paclitaxel ) for extensive stage small cell lung cancer ( n=130 ) and advanced stage NSCLC ( n=204 ).
The primary endpoint of these studies was immune-related progression-free survival ( irPFS ). Secondary endpoints included progression-free survival, best overall response rate ( BORR ), immune-related BORR ( irBORR ), overall survival, and safety.
Patients were randomized to three groups ( 1:1:1 ), placebo / chemotherapy alone for up to six cycles, concurrent Ipilimumab plus chemotherapy ( four doses of Ipilimumab / chemotherapy followed by two doses of placebo/chemotherapy ) or phased Ipilimumab ( two doses of placebo / chemotherapy followed by four cycles of Ipilimumab / chemotherapy ).
Phased Ipilimumab, but not concurrent Ipilimumab group, significantly improved irPFS in both the SCLC and NSCLC studies ( hazard ratio, HR=0.64 p=0.03; HR=0.72, p=0.05, respectively ) and progression-free survival in the NSCLC study ( HR=0.69, p=0.02 ) compared to patients who received placebo / chemotherapy alone.
This finding was felt to be explained by chemotherapy induced tumor antigen release by chemotherapy trigger T-cell activation thus augmenting the effects of the immune checkpoint blockade.
Of note, the improved irPFS in the phased Ipilimumab NSCLC study was mainly confined to patients who had squamous cell histology. This is consistent with an increase T-cell infiltration found in squamous NSCLC.
Further, an interesting case report of a patient with metastatic systemic treatment refractory NSCLC who was treated with palliative concurrent radiotherapy and Ipilimumab that was associated with both a local and distant tumor complete response.
A post-treatment increase in tumor-infiltrating cytotoxic lymphocytes, tumor regression, and normalization of tumor markers was observed. One year after treatment the patient was without evidence of disease based on PET/CT imaging.
Two phase III trials NCT01450761 ( ED-SCLC, Etoposide / Platinum, n=1125 ) and NCT01285609 ( advanced NSCLC, carboplatin/paclitaxel, n=920 ) are still recruiting participants comparing Ipilimumab plus chemotherapy versus chemotherapy alone in patients recently diagnosed ED-SCLC and squamous NSCLC, respectively.
Nivolumab and Pembrolizumab
Nivolumab ( Opdivo ) and Pembrolizumab ( Keytruda; MK-3475 ) are fully human antibodies that inhibit PD-1 receptors expressed on activated T-cells.
Both block the binding of PDL-1/2 with PD-1 on surface of activated T-cells, and consequently increases T-cell activation by removing the inhibitory signaling of PD-1.
As PDL-1 is only expressed on selected tumor cells, the adverse effect of the drug is expected to be less than Ipilimumab.
A Phase I trial ( n=129 ) for Nivolumab at three different doses ( 1, 5, and 10 mg/kg every 2 week ) in NSCLC treatment refractory patients reported an overall 2 years survival rate 24% with median overall survival of 9.9 months with minimal toxicity. Interestingly, the 3 mg/kg group did the best with a BORR of 24.3% and a duration of response of 74 weeks and a median overall survival of 14.9 months.
A Phase III trial involving Nivolumab compared to Docetaxel in second line and beyond is ongoing ( NCT01673867 ) and will recruit 582 patients with metastatic / recurrent non-squamous NSCLC with a primary objective of overall surival in PD-1 inhibitor versus chemotherapy groups.
The secondary objectives will determine progression-free survival and disease related symptom progression, and evaluation of clinical benefit of PD-1 blocker.
A second phase III trial has just started accrual in advanced stage NSCLC PD-1 positive patients in first-line setting randomized to 3 mg/kg Nivolumab every 2 week versus investigator choice chemotherapy.
It is anticipated that 330 patients will be accrued to the study with a reporting date in 2017.
Merck also announced the result of phase Ib trial with a 24% immune-related response ( IRRC ), median overall survival was under a year and with minimal toxicity.
Interestingly, 6/9 patients who met the IRRC had high levels of PDL-1, suggesting that this could be a predictor of response and survival. ( Xagena )
Mostafa AA, Morris DG, Front Oncol 2014 | doi: 10.3389/fonc.2014.00288