Immune Checkpoint Blockade: The New Rage

December 13, 2018 0 By S Harachand

NSCLC tumours overexpress the immunosuppressive checkpoint protein programmed death ligand 1 (PD-L1) to evade detection and attack by immune cells. Inhibiting the PD-1/PD-L1 axis with monoclonal antibodies has significantly changed the treatment approach in lung cancer during the last 5 years.
Immune checkpoint inhibitors that block the PD-1/PD-L1 pathway, such as nivolumab, pembrolizumab and atezolizumab, have become a standard treatment option for patients with advanced non-small-cell lung cancer (NSCLC).

Nivolumab is a fully human monoclonal immunoglobulin G4 antibody targetting PD-1. The treatment won US FDA approval in March 2015 for the treatment of squamous cell lung cancer. Marketed by Bristol-Myers Squibb under the brand name Opdivo, its efficacy to treat squamous NSCLC was established in a randomized trial of 272 participants of whom 135 received nivolumab and 137 received docetaxel.
In October 2015, FDA expanded nivolumab’s approval to advanced (metastatic) nonsquamous non-small cell lung cancer in cases where the disease progressed during or after platinum-based chemotherapy.
Patients who received nivolumab lived longer than those who received docetaxel in the study. However, it was found that the level of PD-L1 expression in NSCLC tumours may help identify the patients who are more likely to live longer with the help of nivolumab treatment. Therefore, the FDA also approved the PD-L1 IHC 28-8 pharmDx test to detect PD-L1 protein expression levels and help physicians determine which patients may benefit most from treatment with nivolumab.
Currently, several studies are underway to determine whether nivolumab, in combination with other therapies, is effective in patients with advanced NSCLC. Among them are Biomarker-Targeted Second-Line Therapy in Treating Patients with Recurrent Stage IV Squamous Cell Lung Cancer (The Lung-MAP Screening Trial) and Alchemist treatment trial. Studies using nivolumab in NSCLC patients are ongoing in India as well, according to
“We are continuing to explore the potential of Opdivo through our broad development programme in thoracic malignancies, including early- and late-stage NSCLC, SCLC and malignant pleural mesothelioma,” says Sabine Maier, M D, Development Lead, Thoracic Cancers, Bristol-Myers Squibb.
In October, BMS announced topline results from the Phase 3 CheckMate-331 study evaluating nivolumab versus the current standard of care, topotecan or amrubicin, in patients with SCLC who relapsed following platinum-based chemotherapy did not meet its primary endpoint of overall survival.
Earlier, in 2016, BMS said nivolumab failed to achieve its endpoint in a study and was no better than traditional chemotherapy at treating newly diagnosed lung cancer.
Nivolumab has been approved for second-line NSCLC in more than 65 countries, including the US, Europe, Japan and China.

Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against PD-1 receptor.
Pembrolizumab was approved by the US FDA on October 2015 for the treatment of metastatic NSCLC in patients whose tumours express PD-L1 and who have failed treatment with other chemotherapeutic agents.
Merck sells the drug under the brand name Keytruda.
Following the results of Keynote 024 trial, the initial approval of pembrolizumab as a second-line treatment was extended to first-line treatment in NSCLC patients with high PD-L1-expressing tumours (PD-L1 >50%) with no EGFR or ALK mutations.
The study found treatment with pembrolizumab prolonged progression-free survival (PFS) and overall survival (OS) and improved objective response rates (45% vs 28%, respectively) compared with chemotherapy in a first-line setting.
The drug was granted accelerated approval by the US regulator in May 2017 as a first-line combination therapy for metastatic non-squamous NSCLC regardless of PD-L1 status, based on the results of the Keynote-021 Phase 1/2 clinical trial.
“With Keynote-407 and Keynote-042, there are now five Phase 3 studies in patients with advanced NSCLC across common histologies where pembrolizumab, in combination or as a monotherapy, has demonstrated an improved OS benefit over chemotherapy,” said a Merck spokesperson.
In a first-line setting, pembrolizumab has shown an OS benefit in around 80% of all NSCLC patients. In Keynote-189, pembrolizumab in combination with pemetrexed and platinum chemotherapy reduced the risk of death by half compared to chemotherapy alone as a first-line treatment for metastatic nonsquamous NSCLC, regardless of PD-L1 expression.
In Keynote-407, pembrolizumab, in combination with carboplatin-paclitaxel or nab-paclitaxel, significantly improved OS and PFS as a first-line treatment in patients with metastatic squamous NSCLC, regardless of PD-L1 expression.
As a monotherapy, in Keynote-024, pembrolizumab more than doubled median OS compared to chemotherapy in first-line treatment of patients with metastatic NSCLC whose tumours expressed PD-L1 with a TPS =50%.
Keynote-042 showed that pembrolizumab monotherapy significantly improved OS as the first-line treatment in patients with locally advanced or metastatic nonsquamous or squamous NSCLC whose tumors expressed PD-L1 (TPS =1%).
In a second-line setting, in Keynote-010, pembrolizumab significantly improved OS compared to chemotherapy in patients whose tumours express PD-L1 (TPS of one percent or more).
According to the Merck spokesperson, the company has an extensive clinical development programme in lung cancer and is advancing multiple registration-enabling studies with pembrolizumab in combination with other treatments, as well as in the form of a monotherapy. The programme, which comprises nearly 9,000 patients across 15 clinical studies, is evaluating pembrolizumab across multiple settings and stages of the disease. Some of the subsets include: Pembrolizumab in patients
with EGFR mutations (Keynote-789) or ALK translocations; and pembrolizumab for the treatment of SCLC as monotherapy (Keynote-158) and in combination with chemotherapy (Keynote-604).
“Merck has more than 20 early phase molecules that we are exploring as monotherapy or for potential combination activity with pembrolizumab, including STING, LAG-3, TIGIT, RIG-I and an oncolytic virus CAVATAK. All these agents have the potential to add significantly to the effectiveness of pembrolizumab,” she added.

Atezolizumab, marketed as Tecentriq by F Hoffmann-La Roche/Genentech is approved in Europe and the USA for second-line treatment of NSCLC following platinum-based chemotherapy. A Phase 3 study compared atezolizumab with docetaxel in unselected patients who had received up to two previous chemotherapy regimens, including at least one platinum-based therapy. The data showed that the regimen significantly improved OS in the atezolizumab treatment group compared with the docetaxel group. This benefit was independent of the level of PD-L1 expression, with the patients with low or undetectable PD-L1 expression also demonstrating a prolonged OS with atezolizumab versus docetaxel (12.6 vs 8.9 months).
In March 2018, Phase III IMpower150 study showed that atezolizumab and bevacizumab plus carboplatin and paclitaxel helped people with advanced lung cancer live longer compared to bevacizumab plus carboplatin and paclitaxel.
Currently, Roche has eight Phase III lung cancer studies underway, evaluating atezolizumab alone or in combination with other medicines.

Durvalumab, avelumab
Other PD-L1 inhibitors in late-stage development for NSCLC include durvalumab (Imfinzi, AstraZeneca) and avelumab (Bavencio, EMD Serona and Pfizer). Data for both have recently been reported.
Data from Pacific Phase 3 trial involving durvalumab showed that
the drug reduced the risk of death by 32% for patients with unresectable, stage III NSCLC following chemoradiation therapy.
Avelumab failed to outdo docetaxel in second-line NSCLC patients with PD-L1-positive tumours that cannot be removed surgically.