Melanoma: less ipilimumab, more nivolumab improves safety


Takeaway

  • Results from the phase 3b/4 CheckMate 511 trial suggest that a dosing regimen of nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (NIVO3+IPI1) is associated with improved safety but similar efficacy compared with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg (NIVO1+IPI3) for patients with unresectable stage III/IV melanoma.

Why this matters

  • These results suggest a superior safety profile for NIVO3+IPI1.

Key results

  • Patients treated with NIVO3+IPI1 had lower incidence of grade 3-5 treatment-related adverse events (TRAEs) compared with patients treated with NIVO1+IPI3 (33.9% vs 48.3%; P=.006; primary endpoint).
  • NIVO3+IPI1 and NIVO1+IPI3 were associated with similar objective response rates (45.6% vs 50.6%, respectively; P=.35).
  • NIVO3+IPI1 and NIVO1+IPI3 were associated with similar median PFS (9.92 vs 8.94 months; HR, 1.06; 95% CI, 0.79-1.42) and OS (not reached for both; HR, 1.09; 95% CI, 0.73-1.62).

Study design

  • 360 patients with previously untreated, unresectable stage III/IV melanoma were randomly assigned 1:1 to NIVO3+IPI1 or NIVO1+IPI3 once every 3 weeks for 4 doses.
  • 6 weeks after the last combination dose, patients received NIVO 480 mg once every 4 weeks until progression or unacceptable toxicity.
  • Funding: Bristol-Myers Squibb and ONO Pharmaceutical Company.

Limitations

  • Study not designed to formally demonstrate noninferiority for efficacy endpoints.

PD-1 inhibitors surpass ipilimumab in advanced melanoma


Programmed cell death 1 (PD-1) inhibitors such as pembrolizumab and nivolumab, as monotherapy or in combination with ipilimumab, are better first-line therapies than ipilimumab alone in patients with advanced melanoma, data presented at the American Association for Cancer Research (AACR) 2015 Annual Meeting have shown.

In the phase III KEYNOTE-006 trial (n=834; 65.8 percent previously untreated), pembrolizumab significantly improved progression-free survival (PFS), overall survival (OS) and response rates (RRs) vs ipilimumab, an inhibitor of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) that is currently a standard first-line therapy for advanced melanoma. [N Engl J Med 2015, doi: 10.1056/NEJMoa1503093]

At 6 months, estimated PFS rates were 47.3 percent for pembrolizumab 10 mg/kg every 2 weeks and 46.4 percent for pembrolizumab 10 mg/kg every 3 weeks, compared with 26.5 percent for ipilimumab (3 mg/kg, 4 doses every 3 weeks) (hazard ratio [HR], 0.58; p<0.001).

“At 12 months, estimated OS rates were 74.1 percent for pembrolizumab every 2 weeks [HR, 0.63; p=0.0005] and 68.4 percent for pembrolizumab every 3 weeks [HR, 0.69; p=0.0036], vs 58.2 percent for ipilimumab,” reported lead author Dr. Antoni Ribas of the University of California, Los Angeles, CA, US.

RRs were also higher with pembrolizumab (33.7 percent for 2-weekly dosing, 32.9 percent for 3-weekly dosing) vs ipilimumab (11.9 percent; p<0.001).

Treatment-related grade 3-5 adverse events (AEs) were less common with pembrolizumab (13.3 and 10.1 percent for 2-weekly and 3-weekly dosing, respectively) than ipilimumab (19.9 percent).

“These results exceeded our expectations of the benefit of pembrolizumab over ipilimumab,” said Ribas. “The data will change the paradigm of treatment of advanced melanoma.”

Nivolumab, when used in combination with ipilimumab, also showed significant benefits over ipilimumab in patients with previously untreated advanced melanoma.

In a phase II trial of 142 patients, PFS and objective response rate (ORR) were significantly improved with the nivolumab/ipilimumab combination vs ipilimumab alone. [N Engl J Med 2015, doi: 10.1056/NEJMoa1414428]

“Among 109 patients with BRAF wild-type tumours, median PFS was not reached in the combination therapy arm vs 4.4 months with ipilimumab monotherapy [HR, 0.40; p<0.001],” reported lead investigator Dr. Stephen Hodi of the Dana-Farber Cancer Institute in Boston, MA, US.

ORR was 61 percent with combination therapy vs 11 percent with ipilimumab monotherapy (p<0.001). “Importantly, 22 percent of patients achieved complete response with the combination regimen,” said Hodi. “There were no complete responses with ipilimumab monotherapy.”

The investigators reported similar results for PFS and ORR in the 33 patients with BRAF V600 mutation-positive tumours. Again, 22 percent of patients achieved complete response with combination therapy.

However, the combination regimen was associated with higher rates of grade 3/4 drug-related AEs (54 percent vs 24 percent for ipilimumab monotherapy).

Pembrolizumab and nivolumab are currently approved by the US FDA for treatment of unresectable or metastatic melanoma that progressed after treatment with ipilimumab or a BRAF inhibitor.

Cancer Immunotherapy Named Science Magazine “Breakthrough of the Year”


Each year, Science magazine announces one pivotal scientific achievement as the “Breakthrough of the Year.” Memorial Sloan-Kettering researchers have played a leading role in pioneering this year’s winner: cancer immunotherapy.

Pictured: T cells

“Immunotherapy marks an entirely different way of treating cancer — by targeting the immune system, not the tumor itself,” Science said in choosing this burgeoning field. Based on the idea that the immune system can be trained to attack tumors in the same way that it targets infectious agents, cancer immunotherapy exploits the ability to harness different types of immune cells circulating in the body.

A Rich History at Memorial Sloan-Kettering

Although cancer immunotherapy is being touted as a recent breakthrough in cancer treatment, its origins at Memorial Sloan-Kettering go back more than a century. In the 1890s, William Coley, a surgeon at New York Cancer Hospital (the predecessor to Memorial Sloan-Kettering) discovered cancer patients who suffered from infections after surgery often fared better than those who did not. His finding led to the development of Coley’s toxins, a cocktail of inactive bacteria injected into tumors that occasionally resulted in complete remission. But eventually the use of this treatment fell out of favor.

In the 1960s, research by Memorial Sloan-Kettering investigator Lloyd Old led to the discovery of antibody receptors on the surface of cancer cells, which enabled the development of the first cancer vaccines and led to the understanding of how certain white blood cells, known as T cells or T lymphocytes, can be trained to recognize cancer.

Helping Patients Today

One of the pivotal milestones cited in the Science article is the work of immunologist James Allison in identifying a protein receptor on the surface of T cells called CTLA-4, which puts the brakes on T cells and prevents them carrying out immune attacks. He later identified an antibody that blocks CTLA-4 and showed that turning off those brakes allows T cells to destroy cancer in mice. (Dr. Allison, who spent nearly a decade of his career at Memorial Sloan-Kettering until last year, is now at MD Anderson Cancer Center in Houston.)

Anti-CTLA-4 eventually became ipilimumab (YervoyTM), a drug approved in 2011 for the treatment of metastatic melanoma, the most deadly form of skin cancer. Dr. Allison, together with Memorial Sloan-Kettering physician-scientist Jedd Wolchok, helped guide the development of ipilimumab from the first laboratory studies through the late-stage clinical trials that led to the drug’s approval.

Dr. Wolchok’s research on immune therapies for melanoma continues, including a study earlier this year that found that more than half of patients with advanced skin melanoma experienced tumor shrinkage of more than 80 percent when given the combination of ipilimumab and the antibody drug nivolumab, another promising immunotherapy drug under investigation, suggesting that these two drugs may work better together than on their own.

The other major area of research highlighted in the Science story is the development of chimeric antigen receptor (CAR) therapy, based on the idea that a patient’s own immune cell type, called T cells, can be collected from blood, engineered to recognize cancer cells and acquire stronger antitumor properties, and reinfused to circulate through the bloodstream and attack those cancerous cells. Memorial Sloan-Kettering has been a leading center in developing this technology.

The first successes in this field have come in the treatment of leukemia. In March, Memorial Sloan-Kettering investigators reported that genetically modified T cells had been successful in rapidly inducing complete remissions in patients with relapsed B cell acute lymphoblastic leukemia (ALL), an aggressive form of blood cancer.

“This is a very exciting finding for patients with B cell ALL, directly borne out of our basic research on CARs for over a decade, and a landmark proof of concept in the field of targeted immunotherapy,” says Michel Sadelain, Director of Memorial Sloan-Kettering’sCenter for Cell Engineering, who led the study, along with medical oncologist Renier Brentjens.

Memorial Sloan-Kettering continues to study this approach and now has clinical trials under way investigating it in other types of leukemia, lymphoma, and prostate cancer, with several more trials slated to begin soon.

Looking toward the Future

Today, investigators in Memorial Sloan-Kettering’s Immunology Program in the Sloan-Kettering Institute are conducting a diverse range of studies aimed at developing the next generation of immune-based cancer treatments.

For example, Immunology Program Chair Alexander Rudensky is focused on studying a subset of T lymphocytes called regulatory T cells, which are critical for keeping other white blood cells in check and therefore play an important role in controlling immune system reactions. Understanding how these cells function, and how to inhibit them will offer novel and effective ways to treat cancer.

The research also has implications for treating conditions characterized by an overactive immune system — including autoimmune disorders such as rheumatoid arthritis, psoriasis, and diabetes.

The PD-1 Immune Checkpoint Emerges as a Promising Therapeutic Target in NSCLC.


Several new studies presented at the American Society of Clinical Oncology (ASCO) 2013 annual meeting provide additional support for the growing interest in programmed cell death 1 (PD-1), a key immune-checkpoint receptor, as a therapeutic target in NSCLC and other tumor types.

“We now have a new pillar of treatment for cancer patients,” said Padmanee Sharma, MD, PhD, of the MD Anderson Cancer Center in Houston, Texas, a discussant in the session on developmental immunotherapy. “We have standard chemotherapy, targeted therapies, radiation therapy, surgery—and I propose now that immune-checkpoint therapy is really here.”

Under normal physiologic conditions, immune checkpoints such as PD-1 maintain self-tolerance and prevent autoimmunity by limiting T cell effector functions within tissues. Tumor cells can upregulate various ligands for PD-1, including PD-L1 and PD-L2, as a mechanism of evading antitumor immune responses in the tumor microenvironment. Therapeutic strategies for targeting the PD-1 pathway to restore tumor-specific T cell immunity include direct inhibition of the PD-1 receptor and PD-L1 blockade.

Nivolumab is an anti-PD-1 antibody with activity in advanced solid tumors, including melanoma, NSCLC, and renal cell carcinoma (RCC). In a phase I study, treatment with intravenous nivolumab induced an overall response rate of 16% in 122 patients with heavily pretreated, advanced NSCLC, and was associated with a median overall survival of 9.6 months (Topalian SL et al.). In the total study population of 304 patients with melanoma, NSCLC, and RCC, 10 patients (3%) developed drug-related pneumonitis, resulting in 3 deaths. Additional grade 3-4 adverse events were reported in 15% of patients.

Additional phase I trials demonstrated the utility of nivolumab in previously treated patients with advanced NSCLC (Brahmer JR et al.) and in combination with platinum-based doublet chemotherapy in chemotherapy-naïve patients with stage IIIB/IV NSCLC (Rizvi NA et al.). Based on these promising results, nivolumab is currently being evaluated in two phase III trials versus docetaxel for the second-line treatment of NSCLC, as well as a phase II trial of third-line therapy in patients with squamous cell histology.

MPDL32802 is a human monoclonal anti-PD-L1 antibody that contains an engineered Fc-domain designed to optimize efficacy and safety. Treatment with MPDL32802 yielded a 21% response rate in a phase I study of 171 patients with locally advanced or metastatic tumors, including NSCLC, melanoma, colorectal cancer, gastric cancer, and RCC (Herbst RS et al.). The highest response rates were in patients with NSCLC and melanoma. Intravenous treatment with MPDL32802 every 3 weeks was well tolerated, with no dose-limiting toxicities and no pneumonitis-related deaths.

Biomarker studies show that higher levels of PD-L1 tumor expression predict better response rates to PD-1 checkpoint inhibitors (Herbst RS et al.Powderly JD et al.). The investigational PD-1 checkpoint inhibitors are being developed with companion diagnostic assays to measure tumor PD-L1 expression by immunohistochemistry (IHC). Each agent, however, uses a different antibody to detect PD-L1 expression and a different IHC staining threshold to define PD-L1 positivity. Although some ongoing trials will include patients with any PD-L1 IHC status, others will require PD-L1 positivity for enrollment.

“Selection by PD-L1 expression may enhance response, but there is activity seen in PD-L1-negative tumors,” saidNatasha B. Leighl, MD, MMSc, of the University of Toronto, Canada, a discussant in the session on new agents for metastatic NSCLC. “I think it is far too early to close the door on this group.”

Several other agents targeting the PD-1 checkpoint are currently under development. Other direct inhibitors of PD-1 include the humanized monoclonal antibodies pidilizumab (CT-011) and lembrolizumab (MK-3475), and AMP-224, a recombinant fusion protein. Investigational monoclonal antibodies targeting PD-L1 include BMS-936559, Medl-4736, and MPDL-3280A 

Source: The oncologist

 

ght:1K�p;# 0 d:white’>Because of the very low doses of pollutants used in the mixture, these findings may have strong implications in terms of understanding the potential role of environmental contaminants in food in the development of metabolic diseases.”

 

Endocrine-Disrupting Chemicals Likely to Cause Harm Even at Low ‘Safe’ Doses

The chemical contaminants used in the study were chosen not only because they’re pervasive in the food supply, but also because they’re known endocrine disruptors. The glands of your endocrine system and the hormones they release influence almost every cell, organ, and function of your body. It is instrumental in regulating mood, growth and development, tissue function, metabolism, as well as sexual function and reproductive processes.

Endocrine disrupters are substances or mixtures that alter the functions of your endocrine system and consequently cause adverse health effects, either in your body or in your offspring. These types of chemicals can exert their effects by:

  • Mimicking the biological activity of your hormones by binding to a cellular receptor. This can initiate your cell’s normal response to the naturally-occurring hormone at the wrong time or to an excessive extent (agonistic effect).
  • Binding to the receptor but not activating it. Instead the presence of the chemical on the receptor prevents binding of the natural hormone (antagonistic effect).
  • Binding to transport proteins in your blood, thus altering the amounts of natural hormones that are present in your blood circulation.
  • Interfering with the metabolic processes in your body, affecting the synthesis or breakdown rates of your natural hormones.

The strongest evidence showing that exposure to these types of environmental chemicals can lead to disruption of endocrine function comes from the bizarre changes seen in a number of wildlife species, such as male fish transforming into females, frogs developing a variety of defects like multiple testes or ovaries, and hermaphrodite bears, just to name a few.  

Yet, it’s commonly stated that these chemicals are not dangerous to humans because they exist at such low levels, even as research suggests otherwise. For instance, of 115 published animal studies, 81 percent found significant effects from even low-level exposure to BPA.

And the latest study only adds to this undeniable knowledge:

“With this study, we have succeeded in providing proof-of-concept that low doses of contaminants, even at levels normally considered to be without health impacts in humans, do in fact affect humans when subjected to chronic exposure, and when the contaminants are combined with a high-calorie diet,” the researchers said.2

What Are the Long-Term Health Risks from Exposure to Common Food Contaminants?

A typical American comes in regular contact with some 6,000 chemicals and an untold number of potentially toxic substances on a less frequent basis. There are about 75,000 chemicals regularly manufactured and imported by US industries, so you could be exposed to any number of them. Disturbingly, many of them have never been fully tested for safety, and virtually none have been studied in combination with one another, which is how real-world exposure occurs and where their toxicities can be amplified exponentially.

Upwards of 20 environmental chemicals, most of them endocrine-disrupting chemicals, have been shown to cause weight gain when exposure occurs during fetal and infant development, although some are also linked to adult exposures. Others, including BPA, PCBs, phthalates and agricultural pesticides can lead to health problems including:

Non-descended testes in young males

Breast cancer in women

Prostate cancer in men

Developmental effects on the nervous system in children

Attention deficit hyperactivity in children

Thyroid cancer

 

According to a World Health Organization (WHO) and United Nations Environment Program (UNEP) report:3

“The diverse systems affected by endocrine-disrupting chemicals likely include all hormonal systems and range from those controlling development and function of reproductive organs to the tissues and organs regulating metabolism and satiety. Effects on these systems can lead to obesity, infertility or reduced fertility, learning and memory difficulties, adult-onset diabetes or cardiovascular disease, as well as a variety of other diseases.”

Specifically, health problems linked to some of the most common food contaminants include:

  • BPA: Plasticizing chemicals like BPA, found in plastics and canned food linings, disrupt embryonic development and are linked to heart disease and cancer. Beware that many manufacturers of ‘BPA-free’ products have simply replaced BPA with bisphenol-S (BPS), an equally toxic chemical. More recently, research has found that other bisphenols used in the production of consumer products, namely, bisphenols M, AP and P, are actually more toxic to DNA than BPA.4
  • Phthalates: Phthalates dysregulate gene expression and cause genital anomalies, especially in baby boys, that may pass down several generations. Phthalates are found in vinyl flooring, detergents, automotive plastics, soap, shampoo, deodorants, fragrances, hair spray, nail polish, plastic bags, food packaging, garden hoses, inflatable toys, blood-storage bags, and intravenous medical tubing.
  • Dioxins: Dioxins are a byproduct of industrial processes, such as chlorine bleaching of paper products and the manufacturing of some pesticides. Because they are persistent environmental pollutants, they accumulate in the food chain and more than 90 percent of human exposure is through foods like meat, dairy products and fish. According to WHO, “Dioxins are highly toxic and can cause reproductive and developmental problems, damage the immune system, interfere with hormones and also cause cancer.”5
  • PCBs: Like dioxins, PCBs are persistent organic pollutants (POPs) that persist in the environment and resist breaking down, accumulating in the food chain and posing serious risks to human health and the environment. For instance, even though PCBs have been banned in the US for decades, they are still present in your environment. PCBs and other POPs have caused birth defects and other abnormalities among wildlife, along with damage to virtually every human bodily system.

Tips for Finding the Purest Foods Possible

When it comes to staying healthy, avoiding processed foods and replacing them with fresh, whole foods is the “secret” you’ve been looking for. The more steps your food goes through before it reaches your plate, the greater your chances of contamination becomes. If you are able to get your food locally, you eliminate numerous routes that could expose your food to contamination with not only disease-causing pathogens but also with the chemical contaminants noted above, which often exist in food packaging.

It’s also important to choose your fresh foods wisely, as you’ll want to focus on those grown in non-polluted areas using organic farming methods. Whatever food you’re looking to eat, whether organic or locally grown, from either your local supermarket or a farmer’s market, the following are signs of a high-quality, healthy food. Most often, the best place to find these foods is from asustainable agricultural group in your area. You can also review my free nutrition plan to get started on a healthy eating program today:

It’s grown without pesticides and chemical fertilizers (organic foods fit this description, but so do some non-organic foods)

It’s not genetically engineered

It contains no added growth hormones, antibiotics, or other drugs

It does not contain artificial anything, nor any preservatives

It is fresh (if you have to choose between wilted organic produce or fresh conventional produce, the latter may still be the better option as freshness is important for optimal nutrient content)

It was not grown in a concentrated animal feeding operation (CAFO)

It is grown with the laws of nature in mind (meaning animals are fed their native diets, not a mix of grains and animal byproducts, and have free-range access to the outdoors)

It is grown in a sustainable way (using minimal amounts of water, protecting the soil from burnout, and turning animal wastes into natural fertilizers instead of environmental pollutants)

 

 

Source: mercola.com

Vemurafenib and Radiosensitization.


Importance  The BRAF inhibitor, vemurafenib, was recently approved for the treatment of patients with BRAFV600 metastatic melanoma. Wider use of this drug and longer follow-up periods of treatment are resulting in the emergence of a growing number of reports detailing new adverse effects. Cutaneous adverse effects are preeminent with UV-A–dependent phototoxicity, hyperkeratotic folliculitis, hand-foot skin reaction, hair changes, verrucous papillomas, keratoacanthomas, and squamous cell carcinomas.

Observations  We report 2 cases of dermatitis occurring on a previously irradiated skin area in patients treated with vemurafenib for a BRAFV600-mutated metastatic melanoma. The first case occurred 10 days after a low dose of radiation was delivered that usually does not induce any radiodermatitis, suggesting radiosensitization by vemurafenib. The second case occurred 30 days after radiotherapy and was diagnosed as radiation recall dermatitis.

Conclusions and Relevance  Vemurafenib should be considered a potential cutaneous radiosensitizer and an inducer of radiation recall dermatitis. However, these adverse effects are easily managed with topical corticosteroids. Dose reduction or interruption of vemurafenib is not required. Further studies and reports will enlighten us as to whether this pharmacodynamic interaction between x-rays and vemurafenib is also seen with other BRAF or MEK inhibitors on the same mitogen-activated protein kinase pathway currently under development.

Source: JAMA

 

Nivolumab plus Ipilimumab in Advanced Melanoma.


BACKGROUND

In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte–associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.

 

METHODS

We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.

 

RESULTS

A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.

 

CONCLUSIONS

Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.

 

Source: NEJM