Data presented at the 2013 European Cancer Congress (ECC2013) being held in Amsterdam, The Netherlands from September 27 to October 1, 2013 shows results from a trial of an antibody that helps the immune system to recognise and attack cancer cells, showing particularly encouraging responses in patients who are currently smoking or who are former smokers. The experimental drug, MPDL3280A (RG7446, also known as anti-PDL1), was generally well tolerated and yielded often rapid, durable responses.[1]

Presenting the most up-to-date data from 85 patients with non-small cell lung cancer in a large, phase I clinical trial of MPDL3280A, Professor Jean-Charles Soria MD, Ph.D, said ?This is the first study to suggest a potential relationship between smoking history and response to inhibiting the PD-L1/PD-1 pathway ? a pathway that is instrumental in enabling cancer cells to escape detection by the immune system. In this study, 26% of smokers responded to treatment, whereas only 10% of never-smokers responded. The fact that smokers seemed to respond better is great news for lung cancer patients, because the majority of them are former or current smokers. Most advances in lung cancer over the last five years have mainly focused in never or light smokers. While the data are preliminary, the trend is potentially promising.?

Immune response
Lung cancer, which is usually caused by smoking, is extremely difficult to treat successfully and once it metastasizes it is incurable. The programmed death 1 protein or PD-1 and its signalling molecule (or ligand) called PD-L1 act as a ‘stop sign,’ preventing the body?s immune system from attacking and killing cancer cells. This allows the cancer to spread. However, the anti-PD-L1 monoclonal antibody, MPDL3280A, which is being developed by Roche/Genentech, works by blocking the interaction between PD-L1 and the immune system, thereby boosting a patient?s anti-cancer immune response.

Soria, Director of the Site de Recherche Int?gr?e sur le Cancer (SIRIC) Socrate project at the Institut Gustave Roussy, Paris, France, and his colleagues are enrolling patients with metastatic non-small cell lung cancer (NSCLC) who have failed to respond to chemotherapy into the international trial. They are treating them with an intravenous infusion of MPDL3280A once every three weeks. At the ECC2013 congress, they presented efficacy data for 53 NSCLC patients and safety data for 85 NSCLC patients ? the largest group of patients to be treated with anti-PD-L1 blockade to date.


This compound is capable of producing striking and durable responses in non-small cell lung cancer patients with metastatic disease who have failed to respond to previous chemotherapy.

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Partial response to therapy
?We hypothesised that smoking was associated with tumors that harbor more genetic mutations and, therefore, the immune systems of these patients might be more likely to respond and attack the tumors once PD-L1 had been blocked,? explained Soria. ?Our results show that this is likely to be the case because more smokers than non-smokers had a partial response to the therapy.?

A sustained and rapidresponse
Although the best results were seen in smokers or former smokers, Soria said that the anti-PD-L1 antibody was also an important strategy for non-smokers. ?Some of them benefited from this compound as well.? Among the responding patients, treatment duration ranged from 170 to 534 days. ?We observed sustained and rapid responses,? Soria further noted. ?Some patients responded to the drug within six weeks, and we can now report for the first time that the median average time to first response is 11.9 weeks.?

In addition, the researchers also discovered that there was an increase in response rates in patients who had tumors that had high numbers of cells expressing PD-L1. Patients with higher levels of PD-L1 expression were more likely to respond to anti-PD-L1 blockade than patients with lower levels of PD-L1 expression. Using an immunohistochemistry (IHC) scoring system — a process of detecting particular proteins (or antigens) in cells in tissue samples in the laboratory — for PD-L1 with a scale for IHC expression ranging from 0 to 3, patients with IHC 3 had a response rate of 83% and patients with IHC 2/3 had a response rate of 46% (See table 1).

?The higher the percentage of PD-L1 staining in a tumour, the better the probability a patient will have an objective response with the PD-L1 antibody,? explained Soria. ?Our results so far demonstrate that the compound is capable of producing striking and durable responses in non-small cell lung cancer patients with metastatic disease who have failed to respond to previous chemotherapy. The study defines a novel approach to identifying the patients most likely to respond to treatment and identifies potential association between smoking and responses to MPDL3280A. A new therapy, with few serious adverse side-effects, that is easy to use ? one intravenous infusion every three weeks ? and a robust clinical activity as a single agent should soon be available,? he concluded.

The large phase I expansion trial is continuing, and based on the data, large-stage phase II/III clinical trials of the drug have already started. These studies also include a Roche companion diagnostic to potentially identify patients who are more likely to respond to treatment. In addition, a Phase I melanoma study is assessing the potential utility of the combination of vemurafenib (Zelboraf?; Genentech) and MPDL3280A in patients with previously untreated, BRAFV600-mutation positive metastatic disease. The potential of MPDL3280A is also being explored in combination with bevacizumab (Avastin?; Genentech) in a Phase I study enrolling patients with advanced solid tumours. Further studies in other tumor types are planned. [A- G]

MPDL3280A Phase Ia: Best Response by PD-L1 immunohistochemistry (IHC Status) ? NSCLC

Diagnostic Population(n = 53) [1]

ORR [2]% (n/n)

PD Rate% (n/n)

IHC 3

83%(5/6)

17%(1/6)

IHC 2 and 3

46%(6/13)

23%(3/13)

IHC 1/2/3

31%(8/26)

38%(10/26)

All Patients[3]

23%(12/53)

40%(21/53)

[1] IHC 3: ? 10% tumor immune cells positive for PD-L1 (IC+); IHC 2 and 3: ? 5% tumor immune cells positive for PD-L1 (IC+); IHC 1/2/3: ? 1% tumor immune cells positive for PD-L1 (IC+); IHC 0/1/2/3: all patients with evaluable PD-L1 tumor IC status.
[2] ORR (overall response rate) includes investigator-assessed unconfirmed and confirmed partial response.
PD=progressive disease
[3] All patients includes patients with IHC 0/1/2/3 and 7 patients have an unknown diagnostic status.
Patients first dosed at 1-20 mg/kg by Oct 1, 2012; data cutoff Apr 30, 2013.

Table 1

?This is an extremely important study for patients with non-small cell lung cancer for whom there are few treatment options that make much impact on their disease. Hundreds of millions of Euros have been spent chasing the dream of immunotherapy for lung cancer patients, but with zero results. These early findings on the effect of the anti-PD-L1 monoclonal antibody, MPDL3280A, suggest that it has the potential to open new therapeutic approaches, particularly for smokers and former smokers,”ECCO President, Professor Cornelis van de Velde, MD, Ph.D commented.

For more information:
[1] Abstract no: 3408: 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). Lung cancer ? metastatic and localised/systemic proffered papers session, 08.50 a.m. CEST, Sunday 29 September, 2013 Elicium 2, (presenting at 09.14 a.m. CEST).

Clinical trials
[A] NCT01984242 – A Study of MPDL3280A as Monotherapy or in Combination With Avastin (Bevacizumab) Versus Sunitinib in Patients With Untreated Advanced Renal Cell Carcinoma [Study Record Detail]
[B] NCT01633970 – A Study of MPDL3280A in Combination With Avastin (Bevacizumab) and/or With Chemotherapy in Patients With Advanced Solid Tumors [Study Record Detail]
[C] NCT01656642 – A Study of The Safety and Pharmacology of MPDL3280A Administered in Combination With Vemurafenib (Zelboraf?) in Patients With Previously Untreated BRAFV600-Mutation Positive Metastatic Melanoma [Study Record Detail]
[D] NCT01846416 – A Study Of MPDL3280A in Patients With PD-L1-Positive Locally Advanced or Metastatic Non-Small Cell Lung Cancer [Study Record Detail]
[E] NCT01988896 – A Study of the Safety and Pharmacology of MPDL3280A Given With Cobimetinib in Patients With Locally Advanced or Metastatic Cancer [Study Record Detail]
[F] NCT01903993 – A Study of MPDL3280A Compared With Docetaxel in Patients With Non-Small Cell Lung Cancer After Platinum Failure [Study Record Detail]
[G] NCT01375842 – Study of the Safety and Pharmacokinetics of MPDL3280A Administered Intravenously As a Single Agent to Patients With Locally Advanced or Metastatic Solid Tumors or Hematologic Malignancies [Study Record Detail]

Educational Book
The Educational Book from ECC 2013 is published as a supplement to the European Journal of Cancer. [Download]

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