One of the most exciting features of immune checkpoint inhibitors ( ICIs ) is that they provide impressive tumour responses in metastatic cancers of different histologies.
The antitumour activity of ICIs appears to cross the traditional boundary of immune-driven malignancies, namely melanoma and renal cell cancer.
The strategy to harness the host’s immune system to fight cancer has been a cornerstone of immunotherapy in oncology and has gained substantial momentum with the emergence of ICIs. These agents block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 ( CTLA-4 ), programmed death-1 ( PD-1 ) and its ligand PD-L1, and thus liberate tumour-specific T cells to exert their effector function against tumour cells.
Ipilimumab ( Yervoy ) and Pembrolizumab ( Keytruda ) are the only two FDA-approved ICIs for the treatment of metastatic malignant melanoma. It is expected that other anti-PD-1/PD-L1 antibodies will achieve regulatory approval in the near future, likely first in melanoma.
For anti-CTLA4 blockade, Ipilimumab is the only antibody approved for clinical use and Tremelimumab is presently undergoing phase II to III development.
There are at least eight anti-PD-1/PD-L1 antibodies in clinical development, spanning phases I to III. These include Nivolumab ( Opdivo ), Pembrolizumab / MK-3475, Pidilizumab and AMP-224 targeting PD-1; and BMS-935559, MEDI4736, MPDL3280A and MSB0010718C targeting PD-L1.
In addition, the preclinical and early clinical development of inhibitors against other immune checkpoints, such as TIM3, LAG3 and VISTA, and against costimulatory molecules, such as OX40 and CD137, are underway.
The clinical development of ICIs is most advanced in malignant melanoma. Besides the approval of Ipilimumab, in September 2014, the FDA has granted Pembrolizumab Accelerated Approval status for patients with advanced melanoma previously treated with Ipilimumab.
When tested as a single agent in 411 patients with advanced melanoma, Pembrolizumab demonstrated an overall response rate of 34% by RECIST v1.1 in all patients, and a 28% response rate among those refractory to Ipilimumab.
The phase III CheckMate-066 trial comparing Nivolumab versus Dacarbazine in 418 patients with previously untreated BRAF wild-type advanced melanoma was stopped early because of an improvement in overall survival favouring the Nivolumab arm.
An expanded phase I study of the ICI doublet Ipilimumab and Nivolumab in 53 patients gave overall response rates of 42% and an impressive two-year overall survival rate of 79% across concurrent schedules tested.
The efficacy results of ICIs in renal cell carcinomas are highly promising. The phase II CheckMate-010 study of Nivolumab as monotherapy in 168 patients with advanced renal cell carcinoma previously treated with anti-angiogenic therapy reported an overall response rate of 20% to 22%.
CheckMate-016, a multi-arm phase Ib study evaluating Nivolumab in combination with targeted agents and with Ipilimumab found overall response rates of 43% to 48% in the ICI doublet arms ( n=44 ) and progression-free survival rates at 24 weeks of about 65%.
A phase I/II study to assess the safety and efficacy of Pembrolizumab and Pazopanib in patients with advanced renal cell carcinoma is ongoing ( NCT02014636 ).
The clinical development of ICIs in tumour types beyond melanoma and renal cell carcinoma is ongoing. These include non-small cell lung cancer, head and neck cancer and bladder cancer.
In non-small cell lung cancer, ICIs, especially anti-PD-1/PD-L1 antibodies, have garnered extensive interest. Overall response rates of these agents given as monotherapy have ranged from 10% to 24%.
Many clinical trials are going to evaluate ICIs as first-line or in the relapsed setting of non-small cell lung cancer.
In recurrent or metastatic squamous cell cancer of the head and neck, Pembrolizumab produced an overall response rate of 20%, with subgroup analysis showing a higher response rate ( 45.5% ) in those with tumours expressing PD-L1 above a cut point ( 1% of staining in tumour cells or stroma ) versus 11.4% in those below the cut point.
Similarly, preliminary data from MEDI4736 across different tumour types revealed an overall response rate of 14% in 22 patients with recurrent or metastatic squamous cell cancer of the head and neck, with a response rate of 50% in those whose tumours are PD-L1 positive versus 6% in those whose tumours are PD-L1 negative.
These data must be interpreted with caution as they are derived from single arm studies with limited numbers of patients. Regardless, these results have sparked the development of several planned or ongoing phase II and III trials in recurrent or metastatic squamous cell cancer of the head and neck, a disease where the only non-cytotoxic agent with FDA approval is the anti-epidermal growth factor receptor inhibitor, Cetuximab ( Erbitux ).
Results from an expanded phase I study of the anti-PD-L1 antibody MPDL3280A in 175 patients with melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial bladder cancer and other tumour types showed an overall response rate of 21%.
In the cohort of 30 patients with PD-L1 positive ( 2+ or 3+ by immunohistochemistry ) urothelial bladder cancer, an overall response rate of 42% was achieved.
Among the 35 patients with PD-L1 negative tumours ( 0 or 1+ by immunohistochemistry ), an overall response rate of 11% was reported.
At the present time, there are no validated markers to enable patient selection for ICIs, although different pharmaceutical companies have focused their efforts on companion diagnostic tests such as PD-L1 testing ( for anti-PD-1/PD-L1 antibodies ).
It appears that a proportion of PD-L1 negative patients may benefit from such agents, thus further complicating the selection strategy and trial designs.
Combination studies of ICIs with cytotoxic chemotherapy, or with molecularly targeted agents such as inhibitors of the epidermal growth factor receptor or angiogenesis, are actively being conducted with acceptable safety profiles in most cases. ( Xagena )
Source: ESMO Congress, 2014
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