Safety, Activity, and Immune Correlates of Anti–PD-1 Antibody in Cancer

[gdpawel]

At the ASCO trade show, there were separate presentations of the immune checkpoint inhibitor in renal cell carcinoma (RCC), melanoma and lung cancer. The data sets were amplified by simultaneous New England Journal publications. Approximately a quarter of patients with RCC were shown to have objective responses, ans as with high-dose IL-2, a small subet remain progression free a number of years out. To some clinicians, treatment is generally well tolerated, particularly in contrast to the checkpoint inhibitor of the CTLA-4 pathway (ipilimumab), which is currently approved in melanoma. There is a soon-to-be launched Phase III trial comparing this immune agent to everolimus for patients with disease progression on VEGF/TKIs.

N Engl J Med. 2012 Jun 28;366(26):2443-54. Epub 2012 Jun 2.

Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M.

Department of Surgery, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21287, USA. [email]stopali1@jhmi.edu

Abstract

BACKGROUND:

Blockade of programmed death 1 (PD-1), an inhibitory receptor expressed by T cells, can overcome immune resistance. We assessed the antitumor activity and safety of BMS-936558, an antibody that specifically blocks PD-1.

METHODS:

We enrolled patients with advanced melanoma, non-small-cell lung cancer, castration-resistant prostate cancer, or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks. Response was assessed after each 8-week treatment cycle. Patients received up to 12 cycles until disease progression or a complete response occurred.

RESULTS:

A total of 296 patients received treatment through February 24, 2012. Grade 3 or 4 drug-related adverse events occurred in 14% of patients; there were three deaths from pulmonary toxicity. No maximum tolerated dose was defined. Adverse events consistent with immune-related causes were observed. Among 236 patients in whom response could be evaluated, objective responses (complete or partial responses) were observed in those with non-small-cell lung cancer, melanoma, or renal-cell cancer. Cumulative response rates (all doses) were 18% among patients with non-small-cell lung cancer (14 of 76 patients), 28% among patients with melanoma (26 of 94 patients), and 27% among patients with renal-cell cancer (9 of 33 patients). Responses were durable; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up. To assess the role of intratumoral PD-1 ligand (PD-L1) expression in the modulation of the PD-1-PD-L1 pathway, immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients. Of 17 patients with PD-L1-negative tumors, none had an objective response; 9 of 25 patients (36%) with PD-L1-positive tumors had an objective response (P=0.006).

CONCLUSIONS:

Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer, melanoma, or renal-cell cancer; the adverse-event profile does not appear to preclude its use. Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00730639.).

Comment in

The future of cancer treatment: will it include immunotherapy? [Cancer Cell. 2012]

Tumor immunotherapy directed at PD-1. [N Engl J Med. 2012]

From ASCO-immunotherapy: programming cancer cell death. [Nat Rev Clin Oncol. 2012]

PMID: 22658127

[url]http://www.ncbi.nlm.nih.gov/pubmed/22658127

Immunological Research: A multi-faceted approach to curing disease

[url]http://cancerfocus.org/forum/showthread.php?t=3901

[gdpawel]

Jessica Yarber, M.D.

An experimental cancer drug successfully shrank tumors in patients with different kinds of cancer, including typically hard-to-treat lung cancers, according to a new study. Oncologists said the research was encouraging, but more study was needed to know whether the drug would prolong life for cancer patients.

The study, led by Dr. Suzanne Topalian, was presented at a meeting of the American Society of Clinical Oncology, and published in the New England Journal of Medicine.

In a small, early phase study, researchers used a drug targeting a portion of the body's immune system, a pathway called PD-1, which usually works to stop the body from fighting cancerous tumors. By shutting down the pathway, the drug stokes the body's immune system to fight tumor cells.

Researchers gave the drug to nearly 240 patients with advanced melanoma, colorectal, prostate, kidney and lung cancers. All the patients had tried up to five other treatments, which failed. After up to two years on the drug, tumors shrank in 26 of 94 patients with melanoma, nine of 33 patients with kidney cancer and 14 of 76 patients with lung cancer.

The drug was not without side effects. About 14 percent of patients in the trial reported conditions such as skin rashes, diarrhea or breathing problems.

Cancer specialists said the fact that the drug caused tumors to shrink, rather than simply to stop growing, is an important measure of success.

"Traditionally in cancer medicine, a tumor that shrinks is an indication that you're killing the cancer," said Dr. Jay Brooks, chairman of hematology and oncology at Ochsner Health System in Baton Rouge, La.

To see that kind of success against several different kinds of cancer, particularly against melanoma, kidney and lung cancers, which are notoriously unresponsive to many of the usual treatments doctors use to thwart them, was also unusual.

"To see this kind of response in cancers that are so difficult to treat is very encouraging," said Dr. Len Lichtenfeld, deputy chief medical officer of the American Cancer Society.

The study did not show whether patients lived longer after taking the drug, but experts said early phases of drug trials typically aren't designed to determine improvements in survival. As scientists study the drug in larger numbers of patients for longer periods of time, the drug's success in prolonging life for cancer patients will become clearer.

Lichtenfeld also noted that early trials of drugs are intended to show whether a drug is safe, and don't usually find impressive numbers of patients who respond to the drug. To see those numbers emerging early in drug trials is encouraging, he said.

The difference in the drug's early success may lie in the approach it takes in delivering targeted cancer therapy. Cancer researchers have been chasing more targeted ways to deliver cancer treatments for decades now, in search of a method more refined than the "slash, burn and poison" approaches available with traditional chemotherapy. Usually, targeted therapies home in on a particular part of the cancer itself – a particular kind of cell or a process vital to a tumor's survival.

The current drug is a different because it targets the body's own immune system, training it to recognize tumor cells as foreign, malicious agents.

"In spite of everything we've done so far with cancer drugs, chemotherapy and the rest, what could be more powerful than having the body's own immune system attack the cancer?" said Dr. Roy Herbst, chief of medical oncology at Yale Cancer Center.

Still, doctors remain cautiously optimistic about the drug's early promise.

"In all new studies, there's usually a lot of optimism and hope, but this should all be tempered with a dose of realism," Brooks said. "What's initially reported may not necessarily pan out with time."

[gdpawel]

An experimental drug that’s designed to unleash the body’s immune-system defenses against cancer sets the stage for an industry wide race to produce similar treatments.

The drug shrank tumors in people with advanced lung, kidney and skin cancer in 18 - 28 percent of patients, depending on the illness, who had failed on other therapies, according to data from a 296-patient trial reported at the American Society of Clinical Oncology (ASCO) meeting.

The findings hint that therapies that prompt killer T-cells to eliminate invaders, may work against many tumors, said James Allison, an immunologist at Memorial Sloan-Kettering Cancer Center in New York.

“There is no reason to think that all cancers might not be susceptible to immune therapy,” Allison told Bloomberg News, noting that the human immune system can wipe out whole organs when it rejects a transplant.

Drugmakers and scientists have been trying to find ways to boost the immune system against cancer for decades, with little successes until recently.

In 2010, Provenge, a prostate cancer treatment, was approved in the U.S. as the first therapy designed to train the body’s immune system to attack tumor cells as if they were a virus. Last year, the immune boosting antibody Yervoy was approved for advanced melanoma.

In the 1990s, Allison did pioneering work that led to Yervoy. Yervoy was the first drug proven to extend the survival of advanced melanoma patients. The therapy blocks a molecular off-switch on the immune cells that keeps them from attacking cancer. It has been shown in studies to shrink melanoma in 10 percent to 15 percent of patients.

The newest drug, BMS-936558, is an antibody that blocks a different immune system off-switch, called PD-1. Many types of tumors act to keep the off-switch in place to protect themselves from the immune system.

Results from a company-sponsored trial reported at the cancer meeting showed The anti-PD-1 drug shrank tumors in 18 percent of lung cancer patients, 27 percent of kidney cancer patients and 28 percent of melanoma patients.

A promising aspect of new immune-boosting therapies is that they may work for long periods of time, said Suzanne Topalian, a professor of surgery and oncology at Johns Hopkins University School of Medicine in Baltimore and a lead author on the study.

According to the results, 20 patients on the PD-1 drug had tumor responses that have lasted a year or more. This stands in contrast to existing drugs that hit mutated genes on cancer cells. These often stop working in a matter of months as the tumors become resistant.

Some patients who responded to BMS-936558 have now gone off therapy without their tumors regrowing, Topalian said. The immune system “has a memory component that continues to hold to the tumor in check” even after therapy is stopped.

A downside of boosting the immune system against cancer is that it may also attack normal tissue. Three patients in the trial died from lung inflammation linked to the drug, according to the results.

There haven’t been any deaths since they started a program to aggressively treat patients who showed signs of the lung inflammation.

In addition to lung, kidney and melanoma patients, the drug trial also included people with advanced colon cancer and prostate cancer. None of those patients experienced major tumor shrinkage, for reasons that aren’t clear.

Tumor-Cell Death, Autophagy, and Immunity

[url]http://cancerfocus.org/forum/showthread.php?t=3651

[gdpawel]

N Engl J Med. 2012 Jun 28;366(26):2455-65. Epub 2012 Jun 2.

Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.

Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM.

Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD 21231, USA.

Abstract

BACKGROUND:

Programmed death 1 (PD-1) protein, a T-cell coinhibitory receptor, and one of its ligands, PD-L1, play a pivotal role in the ability of tumor cells to evade the host's immune system. Blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models.

METHODS:

In this multicenter phase 1 trial, we administered intravenous anti-PD-L1 antibody (at escalating doses ranging from 0.3 to 10 mg per kilogram of body weight) to patients with selected advanced cancers. Anti-PD-L1 antibody was administered every 14 days in 6-week cycles for up to 16 cycles or until the patient had a complete response or confirmed disease progression.

RESULTS:

As of February 24, 2012, a total of 207 patients--75 with non-small-cell lung cancer, 55 with melanoma, 18 with colorectal cancer, 17 with renal-cell cancer, 17 with ovarian cancer, 14 with pancreatic cancer, 7 with gastric cancer, and 4 with breast cancer--had received anti-PD-L1 antibody. The median duration of therapy was 12 weeks (range, 2 to 111). Grade 3 or 4 toxic effects that investigators considered to be related to treatment occurred in 9% of patients. Among patients with a response that could be evaluated, an objective response (a complete or partial response) was observed in 9 of 52 patients with melanoma, 2 of 17 with renal-cell cancer, 5 of 49 with non-small-cell lung cancer, and 1 of 17 with ovarian cancer. Responses lasted for 1 year or more in 8 of 16 patients with at least 1 year of follow-up.

CONCLUSIONS:

Antibody-mediated blockade of PD-L1 induced durable tumor regression (objective response rate of 6 to 17%) and prolonged stabilization of disease (rates of 12 to 41% at 24 weeks) in patients with advanced cancers, including non-small-cell lung cancer, melanoma, and renal-cell cancer. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT00729664.).

Comment in

The future of cancer treatment: will it include immunotherapy? [Cancer Cell. 2012]

Tumor immunotherapy directed at PD-1. [N Engl J Med. 2012]

From ASCO-immunotherapy: programming cancer cell death. [Nat Rev Clin Oncol. 2012]

PMID: 22658128

[url]http://www.ncbi.nlm.nih.gov/pubmed/22658128

[gdpawel]

Adding the experimental immunotherapy AGS-003 (Argos Therapeutics) to standard targeted therapy with sunitinib (Sutent, Pfizer) prolonged expected survival time in patients with advanced kidney cancer.

This finding comes from a small single-group phase 2 study of patients with metastatic renal cell carcinoma. The results were presented by Asim Amin, MD, PhD, codirector of the Levine Cancer Institute in Charlotte, North Carolina, at the 2013 Genitourinary Cancers Symposium (GUCS) in Orlando, Florida.

All of the 21 patients had an unfavorable prognosis. For poor-risk patients, predicted overall survival was around 8 months; for intermediate-risk patients, it was 22 months. However, more half of the patients survived for more than 30 months, and one third are still alive after 4 years or more.

This "striking" prolongation of survival has prompted a larger phase 3 study, which has already started enrolling patients, according to Argos Therapeutics.

Fully Personalized Immunotherapy

AGS-003 is produced by extracting messenger RNA from a sample of a patient's tumor (obtained at the time of nephrectomy) and incorporating it into the patient's dendritic cells (obtained during a single leukapheresis procedure). This is a fully personalized immunotherapy, Dr. Amin told Medscape Medical News.

It is different from the prostate cancer vaccine, sipuleucel-T (Provenge, Dendreon), which is "personalized, but only in part," he noted. For the production of sipuleucel-T, dendritic cells are collected from patients, but these cells are then programmed with a 'generic' prostate cancer antigen; the same antigen is used in every patient, he explained. In AGS-003, the dendritic cells of each patient are programmed with antigens from their own tumor, he added.

"The issue with kidney cancer is that we have not identified any major antigens, unlike in melanoma and prostate cancer.... This is why we need to use the patient's own tumor," he said.

According to Argos Therapeutics, the tumor RNA is used to "program" the dendritic cells with the entire disease-antigen repertoire to trigger a response against the patient's specific tumor. In the phase 2 trial, blood samples indicate that patients have antitumor memory T cells. There is a correlation between overall survival and the number of these cells that are induced.

Prolongation of Survival

The prolongation of survival is not a complete surprise. "This has been seen before with immunomodulation," Dr. Amin noted. Some of kidney cancer patients treated with high-dose interleukin-2 are living for 10 to 15 years. However, because of the toxic events associated with this therapy, it is only applicable to about 10% of patients, he said.

Tyrosine-kinase inhibitors such as sunitinib have "revolutionized the treatment of kidney cancer; now everybody can get a drug treatment," he said. However, although they do prolong survival, the responses are not durable.

In this trial, Dr. Amin and colleagues have shown that adding immunotherapy to standard therapy increases the durability of the response, and AGS-003 is not associated with any toxic events, other than injection-site reactions and erythema, he said.

The researchers chose to combine AGS-003 with sunitinib because it also has some immunomodulatory properties; it suppresses T regulatory and myeloid suppressor cells. Other tyrosine-kinase inhibitors used in the treatment of kidney cancer might not be such a good match. For instance, sorafenib inhibits dendritic cell function, Dr. Amin noted, so could interfere with the mechanism of action of AGS-003.

In this trial, all patients were treated with standard 6-week cycles of sunitinib. AGS-003 was administered once every 3 weeks, for 5 doses, and then every 12 weeks until the disease progressed.

Median progression-free survival was 11.2 months and the final median overall survival was 30.2 months, Dr. Amin reported.

However, when the patients were subdivided according to baseline risk, the 11 intermediate-risk patients had a median progression-free survival of 19.4 months and a median overall survival of 39.5 months. The 10 poor-risk patients had a median progression-free survival of 5.8 months and a median overall survival of 9.1 months.

For comparison, Dr. Amin noted that a pivotal trial in which sunitinib was used alone showed that median overall survival was 5.3 months for poor-risk patients and 20.7 months for intermediate-risk patients.

The addition of immunotherapy to sunitinib led to a "near doubling of the expected progression-free and overall survival for unfavorable-risk subjects," he concluded.

Larger Trial Already Underway

The American Society of Clinical Oncology, which cosponsored GUCS, highlighted this abstract in its press materials. Leonard Gomella, MD, FACS, a member of the GUCS news planning team, noted that such prolonged survival is "very encouraging," but it will need to be confirmed in larger number of patients.

A larger trial is already underway. It is expected that the phase 3 ADAPT study, a randomized multicenter open-label trial, will enroll 450 patients, mainly in the United States. It will compare the immunotherapy plus sunitinib with sunitinib alone. The plan is to administer AGS-003 in 8 doses over the initial 12 months, followed by booster shots every 3 months for patients who are continuing to benefit.

Results from the phase 3 study will likely not be available until 2015, Dr. Amin said.

2013 Genitourinary Cancers Symposium (GUCS): Abstract 357. Presented February 16, 2013

Citation: Addition of Immunotherapy Prolongs Survival in Kidney Cancer. Medscape. Feb 20, 2013