Immunotherapy of thoracic cancers

The concept of using the immune system to tackle cancer was first mooted by Virchow in 1863 and has its nascent history has been littered with multiple compounds and studies that have not quite paralleled its promise (Fig 1.) till the current era.

Understanding the processes that tumors have evolved to evade and suppress the immune system by downregulating tumor antigen presentation, increasing immunosuppressive or anergic T-cells  in the tumor microenvironment, dysregulating T-cell antigen recognition and presentation, and secretion of immunosuppressive factors, has now allowed the development of methods  to  target  and  regulate these processes. (Fig 2)

For lung cancer and  specifically  lung adenocarcinoma, lung cancer care has been transformed through the use of targeted agents that give up to 60% response rates in advanced disease for specific oncogene driven  and  “druggable” subtypes e.g. EGFR and ALK.  These tyrosine kinase inhibitors are responsible for improving median overall survival in stage 4 lung cancer for a large proportion of patients in our part of the world from 1 year to 3 years. Nevertheless, unmet needs have remained for other subtypes of thoracic cancer where there are no known drivers. These include squamous lung cancer, mesothelioma, and small cell lung cancer.

The PD1 and PDl-1 inhibitors are among the first  of many immune targets that have proved successful in addressing these unmet needs in lung cancer.  This class of agents are specific engineered monoclonal antibodies directed at regulating the T-cell  response (Fig 3), and we will summarize the advances in immunotherapy over the last 2 years for these agents.

Non-small cell lung cancers (NSCLC) with no ‘druggable’ oncogene This still represents a significant proportion of patients in Asia. Platinum-based chemotherapy has remained the backbone of care for the last 30 years for this subtype. Most recently this has been superseded in no small way by pembrolizumab, an anti-PD1 inhibitor. Reck M, et al. demonstrated in a phase 3 clinical trial involving treatment-naïve, EGFR/ALK negative non-small cell lung cancer, who highly express PDL-1 protein (>50% of tumor cells by immunohistochemistry), that treatment with pembrolizumab was superior to standard of care (SOC) chemotherapy platinum-based chemotherapy. This benefit was seen in terms of objective responses, superior progression-free survival and an emerging trend to better overall survival.  Crucially this benefit extended to patients with squamous lung cancer and smokers. In addition, benefit extended across all ages including the elderly > 65 years of age.

While this positive study marks a paradigm shift in how we manage patients in who are treatment naïve, there remain patients who have previously been treated with SOC chemotherapy and now need a 2nd line treatment. SOC chemotherapy, docetaxel, performs poorly in this group of patients with low response rates (<10%) and short median duration of responses. At least 4 randomized controlled trials involving patients in 2nd line and beyond have been published and show reproducibly the benefit of anti-PD1 or anti-PDL1 therapy in these patients (Table 1).

Emerging indications for immunotherapy - Small cell lung cancer (SCLC) and mesothelioma

Small cell lung cancer in the metastatic state is highly aggressive and prognosis after 1st line chemotherapy is poor. Preliminary data emerging from early studies in small cell lung cancer suggests that the use of nivolumab monotherapy or nivolumab/ipilimumab combination immunotherapy in this aggressive disease is promising. Confirmatory phase 3 studies are being conducted. Mesothelioma while rare in the local setting is difficult to treat and there are no effective treatment options available after 1st line treatment with chemotherapy and VEGFR monoclonal antibody. In a phase Ib study of pembrolizumab in PDL-1 expressing mesothelioma, 5 of 25 patients achieved a partial response, and 52% had stabilization of disease. This result requires further validation in a larger study.

The era of immunotherapy has well and truly dawned on us. Patient selection in NSCLC is critical and patients who do not carry a “druggable” oncogenic driver, and who over express PDL-1 are most likely to benefit.

Target-specific tyrosine kinase inhibitors remain the SOC for oncogenically driven cancers like EGFR and ALK, and immunotherapy play no role in the initial therapy for such cancers. There remain unmet needs likemesothelioma

and SCLC that will likely undergo a paradigm shift in treatment soon.

 

 

 

 

 

 

Immunotherapy of thoracic cancers

The concept of using the immune system to tackle cancer was first mooted by Virchow in 1863 and has its nascent history has been littered with multiple compounds and studies that have not quite paralleled its promise (Fig 1.) till the current era. Understanding the processes that tumors have evolved to evade and suppress the immune system by downregulating tumor antigen presentation, increasing immunosuppressive or anergic T-cells in the tumor microenvironment, dysregulating T-cell antigen recognition and presentation, and secretion of immunosuppressive factors, has now allowed the development of methods to target and regulate these processes. (Fig 2) For lung cancer and specifically lung adenocarcinoma, lung cancer care has been transformed through the use of targeted agents that give up to 60% response rates in advanced disease for specific oncogene driven and druggable subtypes e.g. EGFR and ALK. These tyrosine kinase inhibitors are responsible for improving median overall survival in stage 4 lung cancer for a large proportion of patients in our part of the world from 1 year to 3 years. Nevertheless, unmet needs have remained for other subtypes of thoracic cancer where there are no known drivers. These include squamous lung cancer, mesothelioma, and small cell lung cancer. The PD1 and PDl-1 inhibitors are among the first of many immune targets that have proved successful in addressing these unmet needs in lung cancer. This class of agents are specific engineered monoclonal antibodies directed at regulating the T-cell response (Fig 3), and we will summarize the advances in immunotherapy over the last 2 years for these agents. Non-small cell lung cancers (NSCLC) with no druggable oncogene This still represents a significant proportion of patients in Asia. Platinum-based chemotherapy has remained the backbone of care for the last 30 years for this subtype. Most recently this has been superseded in no small way by pembrolizumab, an anti-PD1 inhibitor. Reck M, et al. demonstrated in a phase 3 clinical trial involving treatment-nave, EGFR/ALK negative non-small cell lung cancer, who highly express PDL-1 protein (50% of tumor cells by immunohistochemistry), that treatment with pembrolizumab was superior to standard of care (SOC) chemotherapy platinum-based chemotherapy. This benefit was seen in terms of objective responses, superior progression-free survival and an emerging trend to better overall survival. Crucially this benefit extended to patients with squamous lung cancer and smokers. In addition, benefit extended across all ages including the elderly 65 years of age. While this positive study marks a paradigm shift in how we manage patients in who are treatment nave, there remain patients who have previously been treated with SOC chemotherapy and now need a 2nd line treatment. SOC chemotherapy, docetaxel, performs poorly in this group of patients with low response rates (10%) and short median duration of responses. At least 4 randomized controlled trials involving patients in 2nd line and beyond have been published and show reproducibly the benefit of anti-PD1 or anti-PDL1 therapy in these patients (Table 1). Emerging indications for immunotherapy - Small cell lung cancer (SCLC) and mesothelioma Small cell lung cancer in the metastatic state is highly aggressive and prognosis after 1st line chemotherapy is poor. Preliminary data emerging from early studies in small cell lung cancer suggests that the use of nivolumab monotherapy or nivolumab/ipilimumab combination immunotherapy in this aggressive disease is promising. Confirmatory phase 3 studies are being conducted. Mesothelioma while rare in the local setting is difficult to treat and there are no effective treatment options available after 1st line treatment with chemotherapy and VEGFR monoclonal antibody. In a phase Ib study of pembrolizumab in PDL-1 expressing mesothelioma, 5 of 25 patients achieved a partial response, and 52% had stabilization of disease. This result requires further validation in a larger study. The era of immunotherapy has well and truly dawned on us. Patient selection in NSCLC is critical and patients who do not carry a druggable oncogenic driver, and who over express PDL-1 are most likely to benefit. Target-specific tyrosine kinase inhibitors remain the SOC for oncogenically driven cancers like EGFR and ALK, and immunotherapy play no role in the initial therapy for such cancers. There remain unmet needs likemesothelioma and SCLC that will likely undergo a paradigm shift in treatment soon.