July 2015, Special ASCO Edition

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Immunotherapies Steal the Show at ASCO


Oncologists looking to learn about immunotherapy didn’t have to go very far at the American Society of Clinical Oncology Annual Meeting. Many of the highest-impact presentations this year, including a plenary session abstract, the Karnofsky Award, and the Science of Oncology Award, focused on cancer therapy’s most exciting field.

Checkpoint blockades and their immunologic cousins have come a long way, lately extending beyond melanoma and lung and renal cell carcinoma. Immunotherapy in oncology now infiltrates the likes of head and neck, bladder, gastric, breast, and ovarian cancers, to name a few.

Although checkpoint inhibitors remain the star of the show, other immuno-oncology approaches are emerging, including oncolytic viruses, vaccines, and chimeric antigen receptor T cells.

Approach Extends to Multiple Tumor Types

The phase 3 CheckMate 067 trial made national headlines by demonstrating an almost doubling in median progression-free survival (PFS) when 2 checkpoint inhibitors were paired in advanced melanoma. Patients who received nivolumab plus ipilimumab had a median PFS of 11.5 months versus 6.9 months for nivolumab alone and 2.9 months for ipi­limumab alone. In patients with programmed death-1 (PD-1) ligand 1 (PD-L1) expression ?5%, median PFS was 14 months with the combination.

Michael B. Atkins, MD, Deputy Director, Lombardi Comprehensive Cancer Center of Georgetown University, Washington, DC, discussed CheckMate 067 at the plenary session, concluding, “In my opinion, ipilimumab can no longer be considered a standard first-line immunotherapy for patients with advanced melanoma. This clearly has important implications for the field and for our patients.”

A randomized, phase 3 trial comparing nivolumab with docetaxel set a new standard of care for the treatment of previously treated nonsquamous non–small cell lung cancer, as nivolumab-treated patients gained 2 months in overall survival time. Another study showed promise for pembrolizumab in head and neck cancer, demonstrating a clinically significant 24.8% overall response rate in patients with recurrent or metastatic carcinoma.

“This is twice as good as our best targeted therapy in this early preliminary report,” said study author Tanguy Sei­wert, MD, University of Chicago, IL.

There were even promising data for hepatocellular cancer. A phase 1/2 study showed a potential new role for nivolu­mab in advanced liver cancer, a disease for which just 1 approved treatment exists. Approximately 1 in 5 patients responded to the anti–PD-1 drug.

Karnofsky Lecture

Accepting the 2015 David A. Karnofsky Memorial Award, Suzanne L. Topalian, MD, Professor, Oncology and Surgery at Johns Hopkins University School of Medicine and Director of the Melanoma Program at the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, spoke about discovering a common denominator for cancer therapy—anti–PD-1.

“The immune system is in many ways the ‘ideal’ anticancer weapon,” she said. “There are diverse modes of attack through different cells and antibodies, which can recognize cancer cells. This system is very precisely targeted, and it has recall. So, if we can educate or prime the immune system the right way to recognize cancer, this immunity should last for a lifetime.”

According to a slide presented by Topalian, drugs blocking PD-1 or its ligand, PD-L1, have shown durable, objective tumor responses in clinical trials for melanoma (17%-40%), lung cancer (10%-30%), kidney cancer (12%-29%), bladder cancer (25%), ovarian cancer (6%-23%), head and neck cancer (14%-20%), and Hodgkin lymphoma (87%).

“We have found a single molecular pathway that, if we target it,” said Topalian, “these drugs can have an unprecedented activity spectrum and provide a common denominator for cancer therapy.”

Immune checkpoints are molecules that are expressed on the surface of activated immune cells. Their role is to terminate immune responses at the right time to avoid normal tissue damage, but as Topalian pointed out, they are susceptible to cancers’ manipulation.

“Our job as cancer immunotherapists is to block these checkpoints and therefore turn on immune responses in the right way,” she explained.

The use of blocking antibodies to obstruct either the PD-1 receptor on T cells or the PD-L1 ligand on tumor cells has shown success so far in interrupting this interaction and activating the T cells.

The PD-1 inhibitors nivolumab and pembrolizumab have performed extraordinarily well, both as monotherapies and in combination, compared with ipilimumab, which was the previous benchmark and targets the cytotoxic T-lymphocyte antigen-4 pathway. Combination therapies, in particular, appear to enhance the effects of these drugs and render resistant tumors sensitive to treatment.

According to Topalian, however, these drugs will not be alone in the marketplace for long. Six different drug companies are currently testing a total of 8 unique PD-1 pathway-blocking agents in the clinic, with more on the way.

New Challenges

Along with promise, immunotherapy brings with it new challenges for the healthcare industry, including physical and financial toxicities. Questions also remain regarding proper sequencing of these drugs with targeted agents and the use of biomarkers to identify appropriate patients. None of these issues, however, seemed to dampen the enthusiasm surrounding this new weapon in the fight against cancer. Immunotherapy is here to stay.

“Immunotherapy has now earned its place as one of the pillars of oncology, alongside more traditional modes of treatment,” Topalian concluded.

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T-DM1 Not Superior to Standard of Care in First-Line Metastatic Breast Cancer

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