Survival Bump in Bladder Cancer with Keytruda


But no outcome advantage for Tecentriq in metastatic urothelial cancer

Action Points

  • Note that these studies were published as abstracts and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Patients with recurrent urothelial cancer lived longer when they received pembrolizumab (Keytruda) instead of chemotherapy as second-line treatment, according to long-term follow of a randomized trial.

After a median follow-up of 28 months, patients treated with pembrolizumab had a median survival of 10.3 months versus 7.3 months for those who received chemotherapy. Both 12- and 24-month survival was significantly better in the group treated with the immunotherapeutic drug, according to Joaquim Bellmunt, MD, of Dana-Farber Cancer Institute in Boston, and colleagues.

 PD-L1 expression status did not influence response to treatment with pembrolizumab or the survival benefit, they reported here at the Genitourinary Cancers Symposium.

“Pembrolizumab is the first immunotherapy to demonstrate superior survival over chemotherapy in patients with advanced urothelial carcinoma after failure of platinum-based therapy,” Bellmunt said. “This study provides level 1 evidence that supports the use of pembrolizumab as a standard of care for this patient population.”

Data from the trial, known as KEYNOTE 045, provided the basis for approval of pembrolizumab for advanced urothelial carcinoma, irrespective of PD-L1 status, in the U.S., Europe, and Japan, he added. The 2-year follow-up data remained consistent with the data that supported the approval.

A different PD-1/PD-L1 inhibitor failed to demonstrate an advantage over chemotherapy for PD-L1-positive locally advanced/metastatic urothelial cancer that progressed or relapsed after initial platinum-based chemotherapy. As previously reported, patients treated with atezolizumab (Tecentriq) had a median overall survival (OS) of 11.1 months versus 10.6 months for investigator’s choice of chemotherapy. An intention-to-treat (ITT) analysis of all treated patients, irrespective of PD-L1 status, yielded a similar result, reported Thomas Powles, MD, of Barts Cancer Institute in London.

The pembrolizumab results should increase confidence in second-line use of the drug, said invited discussant Robert Jones, MD, PhD, of the University of Glasgow in Scotland.

“This helps our patients make an informed decision about whether or not to accept this treatment,” said Jones. “The results remain in keeping with the possibility of a long immunotherapy [survival] tail. None of these data support a role for second-line cytotoxics after failure of platinum in preference to a checkpoint inhibitor.”

The pembrolizumab data affirmed findings initially reported at the 2016 Society for Immunotherapy of Cancer, followed by publication in the New England Journal of Medicine. At that point, after a median follow-up of 14 months, the median OS was 10.3 versus 7.4 months for the pembrolizumab and chemotherapy arms, respectively.

KEYNOTE 045 involved 542 patients whose disease had progressed or relapsed after first-line platinum-based chemotherapy. Almost half the patients had two or more high-risk characteristics.

The patients were randomized to pembrolizumab or the investigators’ choice of three different chemotherapy options: paclitaxel, docetaxel, or vinflunine. The trial had coprimary endpoints of OS and progression-free survival (PFS), as assessed in the ITT population and according to PD-L1 status (using ≥10% PD-L1 expression in tumor cells, lymphocytes, and macrophages to define positivity).

The initial results in favor of pembrolizumab represented a 27% reduction in the survival hazard (P=0.0022). The updated data reflected a 30% reduction in the survival hazard (95% CI 0.57-0.85, P=0.00017). The 12-month survival was 44.4% with pembrolizumab and 29.8% with chemotherapy, and the 24-month survival was 27.0% versus 14.3% with pembrolizumab and chemotherapy, respectively.

“By 24 months, 60% of patients in the chemotherapy arm had received an immunotherapeutic agent, including those who received pembrolizumab at crossover,” said Bellmunt.

Subgroup analysis demonstrated a consistent survival advantage for patients treated with pembrolizumab.

Analysis by PD-L1 status showed a median OS of 8.0 months with pembrolizumab and 4.9 months with chemotherapy in the PD-L1-positive patients (n=124) and 10.8 versus 7.7 months in the PD-L1-negative group.

Median PFS did not differ significantly between treatment groups after 14 or 28 months of follow-up (2.1 vs 3.3 months) although the proportion of patients who remained progression free at 12 months (18.4% vs 9.5%) and 24 months (12.5% vs 2.5%) favored pembrolizumab.

Objective response rate was twice as high with the PD-1 inhibitor than with chemotherapy (21.1% vs 11.0%).

Pembrolizumab was associated with a more favorable adverse-event profile, as patients treated with chemotherapy had more fatigue, diarrhea, asthenia, anemia, constipation peripheral sensory neuropathy, peripheral neuropathy, decreased neutrophil count, neutropenia, and alopecia. Immune-related adverse events occurred more often with pembrolizumab: hypothyroidism, pneumonitis, hyperthyroidism, and colitis.

Investigators in the atezolizumab study, known as IMvigor211, performed extensive exploratory analyses to gain insight into the negative result. They found a correlation between DNA damage response (DDR) mutations tumor mutational burden (TMB). Additional analysis showed no association between DDR and efficacy. However, they identified a significant benefit of atezolizumab in the small subgroup of patients (about 100 of 931) who had high TMB and tested positive for PD-L1 expression (IC 2/3): median OS of 17.8 versus 10.6 months, representing a 50% reduction in the hazard ratio (95% CI 0.29-0.86).

In his review of the two trials, Jones concluded that neither provided compelling evidence of a biomarker to predict response to PD-1/PD-L1 inhibition.

Combo Therapy Highly Active in Untreated RCC


Objective responses with anti-VEGF/Anti-PD-1 pairing in three-fourths of patients

 Three-fourths of patients with newly diagnosed advanced renal cell carcinoma (RCC) had objective responses to the combination of axitinib (Inlyta) and pembrolizumab (Keytruda), a preliminary clinical trial showed.

Overall, 38 of 52 (73.1%) had tumor responses, including four complete responses. An additional eight patients had stable disease during treatment with the combination. Three patients had indeterminate status, and the remaining three had progressive disease as best response, according to Michael B. Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center in Washington, and colleagues.

The cohort had a median progression-free survival (PFS) exceeding 20 months, and overall survival (OS) had yet to be reached after a median follow-up of 17.6 months, they reported here at the Genitourinary Cancers Symposium and simultaneously in Lancet Oncology.

“The combination of axitinib and pembrolizumab is safe and tolerable in treatment-naïve patients with advanced renal cell carcinoma,” said Atkins. “The antitumor activity of the combination is superior to that expected from axitinib or PD-1/PD-L1 pathway inhibitor monotherapy.”

Combined treatment outperforms sequential treatment with a VEGF inhibitor followed by anti-PD-1 therapy; the ongoing phase III KN426 trial compares axitinib/pembrolizumab versus sunitinib (Sutent), he added.

The goal of this type of combination is to combine the “protracted progression-free survival with tyrosine kinase inhibitors with the plateau effect we see with immuno-oncology-based therapy, and achieve a higher plateau in terms of durable responses,” said invited discussant Sumanta Pal, MD, of City of Hope in Duarte, California.

“The real addition of this data set is the durability,” he added. “An 18.6-month median duration of response and a median PFS of 21 months — this is unprecedented.”

 Other anti-VEGF/anti-PD-1 combinations have yielded similar impressive results, and ongoing studies are evaluating various combination and determine the potential benefit that patients can derive, said Pal.

Previous studies of VEGF inhibitor/PD-1 inhibitor combination therapy demonstrated efficacy, but also excessive toxicity, that ruled out continued clinical development. Axitinib is a newer, highly selective VEGF receptor inhibitor, and investigators hypothesized the drug could be combined safely with pembrolizumab to achieve at least additive antitumor activity in patients with previously untreated advanced RCC.

Atkins reported findings from an open-label phase Ib multicenter trial separated into two stages: a dose-finding stage to estimate the maximum tolerated dose of the combination, followed by a dose-expansion stage. The primary endpoint of the dose-finding stage was dose-limiting toxicity (DLT), and the secondary endpoints of the dose-expansion stage were safety, objective response, PFS, OS, pharmacokinetics, and biomarkers.

Investigators enrolled 11 patients in the dose-finding part of the trial. Subsequently, three patients had DLTs: one transient ischemic attack and two patients who could not complete at least 75% of the planned axitinib dose because of treatment-related toxicity (including headache, fatigue, asthenia, and dehydration). The maximum tolerated dose was estimated to be axitinib 5 mg BID and pembrolizumab 2 mg/kg.

Treatment continued until disease progression or development of unacceptable toxicity. Investigators had the option to continue treating patients who had evidence of disease progression but who also continued to derive “clinical benefit” from the combination, said Atkins.

An additional 41 patients were enrolled in the dose-expansion phase, and all 52 patients were included in data analysis. The cohort had a median age of 63, and more than 90% of the patients had favorable or indeterminate risk characteristics.

At data cutoff 25 patients remained on treatment, including eight patients who had disease progression but continued treatment because of ongoing “clinical benefit.” Of the 27 patients who discontinued both study medications, 10 did so because of adverse events and nine because of disease progression.

The median treatment duration was 14.5 months. Atkins said 32 patients required axitinib dose reductions for at least two consecutive doses. The mean and median daily doses of axitinib were 8.2 and 8.8 mg, respectively, and corresponding daily doses of pembrolizumab were 1.9 and 2.0 mg/kg.

Two thirds of the patients had grade ≥3 adverse events, the most common being hypertension (23.1%, followed by fatigue and diarrhea at 9.6% each). About 20% of the patients had grade ≥3 immune-related adverse events, led by diarrhea (7.7%), liver enzyme elevation (ALT, AST 3.8% each), and fatigue (3.8%).

The combination resulted in an objective response rate of 73.1%, and 15.4% of patients had stable disease. The median time to response was 2.8 months and median duration of response was 18.6 months. Atkins said 10 patients discontinued both drugs and were censored at that point, despite no evidence of disease progression.

With regard to patients who continued treatment after evidence of progression, he said that “except in rare cases, continued treatment beyond disease progression was characterized more by stabilization or slow, continued progression, rather than regression.”

The estimated PFS was 20.9 months. Six patients died, four of RCC, one of cardiac causes, and one of unknown causes.

Pembrolizumab Promising in Advanced Esophageal Cancer


The checkpoint inhibitor pembrolizumab (Keytruda) was well tolerated and demonstrated results in patients with PD-L1–positive, advanced esophageal tumors in the Merck-sponsored phase IB KEYNOTE-028 trial.

As shown in the study, published online in the Journal of Clinical Oncologythere were partial responses in seven of 23 heavily pretreated patients, for an overall response rate (ORR) of 30%.

 This included five of 18 patients (28%) with squamous histology and two of five patients (40%) with adenocarcinoma, reported Toshihiko Doi, MD, PhD, of the National Cancer Center Hospital East in Japan, and colleagues..

The median duration of response was 15 months, and 12 patients (53%) showed a decrease in target lesion burden. Nine patients had treatment-related adverse effects — most commonly reduced appetite, decreased lymphocyte count, and rash.

“There is a high unmet need for effective and well-tolerated treatments for patients with advanced esophageal carcinoma,” the researchers wrote. “Pembrolizumab demonstrated manageable toxicity and durable antitumor activity in patients with heavily pretreated, PD-L1–positive advanced esophageal carcinoma.”

KEYNOTE-028 is an international trial of pembrolizumab in patients with 20 different types of PD-L1–positive advanced solid tumors. Patients in the esophageal carcinoma cohort were enrolled at nine sites in France, Japan, the Republic of Korea, Taiwan, the United Kingdom, and the United States.

Patients could participate if they were age 18 or older, had measurable disease at baseline, had an Eastern Cooperative Oncology Group performance status of 0 or 1, demonstrated adequate organ function, and had PD-L1–positive, squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction for which standard therapy did not exist or was ineffective.

Participants received 10 mg/kg of pembrolizumab intravenously once every 2 weeks for up to 2 years or until progression was confirmed, toxicity became intolerable, or the patient or investigator decided to stop. Patients had computed tomography (CT) or magnetic resonance imaging (MRI) scans every 8 weeks for the first 6 months and every 12 weeks thereafter. The researchers also profiled the gene expression of each patient’s tumor tissue.

Primary endpoints of the study were safety and overall response rate (ORR). Secondary endpoints were progression-free survival, overall survival, and duration of response.

Of the 23 patients enrolled in the study, 83% were men and 78% had squamous cell carcinoma histology; median age was 65. All but one patient had received previous therapy for advanced/metastatic disease; 87% had received at least two previous therapies for advanced/metastatic disease, and most (61%) had received previous radiation therapy.

The ORR was 30% (95% CI 13-53); all seven responses were confirmed partial responses. Of these seven patients, three (43%) had received prior radiation therapy. There was no discernible pattern in the previous chemotherapy regimen among these patients. For patients with squamous cell carcinoma, ORR was 28% (five of 18 patients); for those with adenocarcinoma, ORR was 40% (two of five patients).

Twelve patients (52%) experienced a decrease from baseline in target lesion burden; tumors shrank a median of -44.7% (range, -77.7 to -2.7).

Median progression-free survival was 1.8 months (95% CI 1.7-2.9); 6- and 12-month progression-free survival rates were 30% and 22%, respectively. Median overall survival was 7 months (95% CI 4.3-17.7); the overall survival rate was 60% at 6 months and 40% at 12 months.

All-grade treatment-related adverse events occurred in nine patients. Rash in three patients (13%), and reduced appetite and decreased lymphocyte count in two patients (9%) each, were most common.

Four patients had grade 3 treatment-related adverse events — two patients had decreased lymphocyte count, and one patient each had decreased appetite, liver disorder, and generalized rash. None had grade 4 adverse events.

Three patients had treatment-related serious adverse events: grade 2 pemphigoid, grade 3 decreased appetite, and grade 3 liver disorder in one patient each. No patients died because of a treatment-related adverse event.

The overall safety profile in the study was similar to that previously reported for pembrolizumab in patients with other advanced malignancies, the authors noted. Similar to the results from other studies of immune checkpoint inhibition in cancer, only a subset of patients with PDL1–positive esophageal cancer showed a clinical benefit from PD-1 blockade, suggesting that additional biomarkers could help predict clinical response.

Gene analysis showed delayed progression and increased response among pembrolizumab-treated patients with higher interferon-γ composite scores, consistent with findings in head and neck and gastric cancer, the researchers reported. However, they cautioned, there are limitations to this analysis, including the small sample size, variability in tissue biopsy storing, and potential sampling bias.

“These preliminary results regarding the potential predictive value of gene expression signature for pembrolizumab activity in esophageal carcinoma will therefore require additional exploration in a larger patient population.”

In addition, the team added, because all patients enrolled in KEYNOTE-028 had tumors with some degree of PD-L1 expression, the study cannot provide information about pembrolizumab in patients with advanced esophageal carcinoma and PD-L1–negative tumors.

Pembrolizumab Approved for Tumors with Specific Genetic Features. 


On May 23, the Food and Drug Administration (FDA) granted accelerated approval to the immunotherapy pembrolizumab (Keytruda®) for patients with solid tumors that have one of two specific genetic features known as mismatch repair deficiency and high microsatellite instability. The approval covers adult and pediatric patients whose cancer has progressed despite prior treatment and who have no alternative treatment options.

This is the first time that FDA has approved a cancer treatment based solely on the presence of a genetic feature in a tumor, rather than the patient’s cancer type.

“I think this is a step forward for precision medicine,” said James Gulley, M.D., Ph.D., head of the immunotherapy section of NCI’s Center for Cancer Research.

The approval provides another option for some patients who would not otherwise be candidates for treatment with pembrolizumab, such as those with pancreatic cancer, Dr. Gulley continued. But for some cancer types, he cautioned, only a small number of patients typically have these genetic features.

Mismatched DNA

The process of mismatch repair enables cells to correct mistakes in their DNA code that sometimes occur during DNA replication. It’s “like a spell-checker” for DNA, explained Dr. Gulley. Mismatch repair deficient (dMMR) cells, which lack this failsafe process, acquire multiple DNA mutations. Some dMMR cells acquire alterations in short, repetitive DNA sequences called microsatellites and are referred to as microsatellite instability-high (MSI-H).

Tumors that are dMMR and MSI-H are found in patients with Lynch syndrome, a genetic disorder caused by mutations in genes that control DNA mismatch repair. In addition, these genetic features can spontaneously occur in tumors and have been found in patients with several cancer types—most commonly colorectal, endometrial, and gastrointestinal cancers.

Compared with other tumors, dMMR and MSI-H tumors have a higher frequency of DNA mutations and, as a result, higher levels of abnormal antigens. Because immune cells attack cells that have abnormal antigens, researchers have hypothesized that immune cells may be more likely to recognize and attack dMMR and MSI-H tumor cells. Studies have suggested that this vulnerability, in turn, may make these tumors more susceptible to therapies like pembrolizumab that ramp up the immune response.

Regardless of Cancer Type

Patients with certain cancer types, like lung cancer and melanoma, typically have good responses to immune checkpoint inhibitors such as pembrolizumab. But not every patient with one of these cancer types responds well to the treatment. More recently, researchers have found that it’s the patients with tumors that have more DNA mutations, like dMMR and MSI-H tumors, that are most likely to respond.

So “why group tumors by cancer type,” when these genetic features are the more telling characteristic, remarked Dr. Gulley. What’s novel about the studies that led to the FDA approval, he explained, is that the investigators included any patient with a dMMR or MSI-H tumor, regardless of the cancer type.

The FDA approval is based on combined results from five single-arm clinical trials that evaluated the efficacy of pembrolizumab.

The investigators used standard lab tests to identify a total of 149 patients with 15 different types of cancer whose tumors were MSI-H or dMMR. All patients received one of two doses of pembrolizumab. Altogether, 40% of patients with MSI-H or dMMR tumors had measurable tumor shrinkage after treatment, and for 78% of these responders, their tumors shrank or stayed the same size for 6 or more months.

In an interim analysis of one of the five trials, the investigators reported that, among patients with colorectal cancer, 40% of those with dMMR tumors and 0% of those with mismatch repair-proficient tumors responded to the treatment. The FDA approval includes patients with colorectal cancer whose disease has progressed after treatment with certain chemotherapy drugs.

In a more recent analysis of the same study, the investigators evaluated 86 patients with dMMR tumors from 12 different cancer types. After several weeks of treatment with pembrolizumab, they found that 53% of the patients had measurable tumor shrinkage and 21% had no signs of cancer.

To estimate the fraction of patients whose tumors have these genetic features, the investigators then evaluated the mismatch repair status of more than 12,000 tumors from 32 different cancer types and found that about 5% were dMMR. This translates to approximately 60,000 cases of cancer in the United States each year, they noted.

Among the five clinical trials, common side effects included fatigue, itchy skin, diarrhea, and rash. Although not reported in the studies, pembrolizumab can also cause serious, sometimes life-threatening, inflammation in a number of organs.

With the FDA approval, dMMR and MSI-H are now definitively considered biomarkers for predicting a good response to treatment with pembrolizumab, Dr. Gulley said. Ongoing studies are examining whether they are also biomarkers for treatment with other immune checkpoint inhibitors, he added.

Having a biomarker to identify patients who are most likely to respond is “an area we have widely anticipated as being the next step in understanding how to better use immunotherapies,” said Dr. Gulley. “It’s a welcome first step, and there’s much more yet to be done.”

Under FDA’s accelerated approval, the drug manufacturer must verify and further describe the clinical benefit of the treatment. In one follow-up trial, called KEYNOTE-177, investigators will compare pembrolizumab with standard therapy for patients with dMMR or MSI-H colorectal tumors. The trial is currently recruiting participants.

Melanoma Tx Tied to Neurologic Disorder


Serious adverse effect of Keytruda in two patients.

Researchers reported two cases of demyelinating polyradiculoneuropathy after treatment with pembrolizumab (Keytruda) for advanced melanoma.

The report, in a letter published Wednesday in the New England Journal of Medicine, raises concerns about serious, perhaps irreversible, and previously unknown adverse effects from this class of drug, which targets the PD-1 immune checkpoint pathway. These immunotherapies, offering a whole new way of attacking cancer, have generated excitement across the oncology community in recent years.

The first patient was receiving treatment for recurrent nasal-cavity melanoma, and developed symptoms consistent with Guillain-Barré syndrome 8 weeks after beginning pembrolizumab therapy (2 mg/kg every 3 weeks), according to Philippe Saiag, MD, PhD, of Versailles Saint-Quentin-en-Yvelines University in Versailles, France, and colleagues.

The second patient was undergoing treatment for metastatic melanoma, and developed chronic inflammatory demyelinating polyradiculoneuropathy 20 weeks after beginning pembrolizumab therapy (2 mg/kg every 3 weeks). The patient also received ipilimumab (Yervoy) and binimetinib, they wrote.

The first patient presented with several symptoms including paresthesia and hypoesthesia of all limbs before the third infusion of pembrolizumab; the second patient also had multiple symptoms, including paresthesias of the arms and neck pain, between the sixth and seventh infusions.

In both cases, pembrolizumab was discontinued. The first patient responded to treatment in that her neurologic symptoms reached a peak within 3 weeks and decreased over the next 2 months. However, in the second patient, treatement did not lead to improvement in neurologic symptoms over 13 months of follow-up, the authors reported.

“We conclude that the two conditions may be associated with pembrolizumab, since neither patient had evidence of infectious causes or a documented paraneoplastic syndrome,” they wrote.

They explained that since, “demyelinating polyradiculoneuropathies are believed to be a result of autoimmunization, we speculate that PD-1–blocking antibodies may trigger one or more of the complex immune mechanisms involved in this disease.”

Pembrolizumab shows promise in brain metastases due to melanoma or non-small-cell lung cancer


Pembrolizumab, a PD-1 inhibitor, shows activity and an acceptable safety profile in patients with untreated brain metastases due to melanoma or non-small-cell lung cancer (NSCLC).

The non-randomized, open-label, phase II trial included patients aged 18 years or above who were diagnosed with melanoma (n=18) or NSCLC (n=18). All patients had untreated or progressive brain metastases measuring 5-20 mm in diameter without accompanying neurologic symptoms, and were not being given corticosteroids.

The patients received pembrolizumab 10 mg/kg every 2 weeks until disease progression.

Twenty-two percent of patients in the melanoma group and 33 percent in the NSCLC group achieved brain metastasis response. Overall, responses were durable, with all but one NSCLC patient who responded showing an ongoing response at the time of data analysis.

Adverse events reported by patients with NSCLC included grade 3 colitis (n=1), grade 3 pneumonitis (n=1), grade 3 fatigue (n=1), grade 4 hyperkalaemia (n=1), and grade 2 acute kidney injury (n=1).

In the melanoma group, one patient reported grade 3 elevated aminotransferases, while three patients experienced transient grade 3 cognitive dysfunction and grade 1 to 2 seizures.

Results suggested that systemic immunotherapy may have a role in melanoma or NSCLC patients with untreated or progressive brain metastases.

Melanoma Drug Boosting Survival for Many, Study Shows


A new drug for advancedmelanoma is dramatically shifting the odds in favor of patients, extending survival for many and even curing some.

Keytruda (pembrolizumab) helped keep four in 10 patients with advanced melanoma alive three years after starting treatment, according to the results of a new clinical trial.

The drug also caused complete remission in 15 percent of patients, and many remained cancer-free even after they quit taking Keytruda, said Dr. Caroline Robert, head of the dermatology unit at the Institut Gustave-Roussy in Paris, France.

Keytruda already has scored one very high-profile success — it’s one of the drugs taken by former President Jimmy Carter, 91, in his successful battle last year against melanoma that had spread to his brain.

However, the drug comes with a hefty price tag — an estimated $12,500 a month.

Prior to the advent of targeted therapies like Keytruda, advanced melanoma patients had an average survival prognosis of less than one year, Robert said.

“Pembrolizumab provides long-term survival benefit in patients with advanced melanoma, with 41 percent of patients alive at three years, which is so different from what we’ve come from,” Robert said. “We have durable responses in one-third of the patients, and we have complete responses that are durable even after stopping the treatment.”

The latest clinical trial findings, which are the first long-term follow-up results for Keytruda, are to be presented at the American Society of Clinical Oncology (ASCO) annual meeting in Chicago next month. Research presented at meetings is typically considered preliminary until published in a peer-reviewed journal.

Cancer expert Dr. Don Dizon called the results “incredibly exciting.”

“I think it’s incredibly encouraging that we could see a potential cure in melanoma as evidenced by the very prolonged response rate and the durability of this response,” said Dizon. He is an ASCO spokesman and clinical co-director of gynecologic oncology at Massachusetts General Hospital in Boston.

Keytruda helps the body’s immune system locate and destroy tumor cells by thwarting a genetic cloaking mechanism that cancer has developed to avoid immune detection.

“It teaches the body’s own immune system how to fight and control melanoma,” said Dr. Michael Postow, an oncologist specializing in immunotherapy with Memorial Sloan Kettering Cancer Center in New York City.

Robert’s clinical trial involved 655 patients diagnosed with advanced melanoma. Three-fourths of the patients had received other treatments for their cancer prior to the study.

Participants received Keytruda either every two or three weeks. The drug is administered via IV.

Long-term follow-up showed that four out of 10 patients were alive three years after starting Keytruda, whether or not they had been previously treated.

Further, 95 patients went into complete remission after taking Keytruda, Robert said.

Of those patients, 61 stopped taking Keytruda after they were judged cancer-free, Robert said. Only two wound up relapsing.

About 8 percent of the patients dropped out of the study due to drug side effects, Robert said. The most common were fatigue (40 percent), itchiness (28 percent) and rash (23 percent).

But, Postow said, “Most patients get through the drug without any serious side effects.”

The main downside is the cost of the drug. The drug’s maker, Merck, has set the price at about $12,500 a month, or about $150,000 a year, according to The New York Times.

“It is pretty expensive, unfortunately,” Postow said.

Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab


Importance  Vitiligo is an autoimmune skin disorder that reacts against melanocytes. The association of vitiligo with tumor response in patients with melanoma who undergo immunotherapy has been reported but is still controversial.

Objective  To prospectively evaluate the appearance of vitiligo in patients receiving pembrolizumab, a monoclonal antibody directed against the programmed death cell receptor.

Design, Setting, and Participants  This prospective observational study was conducted from January 1, 2012, through September 24, 2013, in a single tertiary care hospital with a unit dedicated to patients with melanoma. Sixty-seven patients with metastatic melanoma who received pembrolizumab treatment in the context of a phase 1 study were included and screened for the emergence of vitiligo. Data were collected from January 1, 2012, to February 28, 2014, and analyzed from February through December 2014.

Main Outcomes and Measures  Objective tumor response with regard to the occurrence of vitiligo in patients receiving pembrolizumab therapy. Correlation between vitiligo occurrence and overall survival was also estimated using the Kaplan-Meier product-limit method and compared with a log-rank test. To prevent guarantee- or lead-time bias, a landmark analysis approach after 12, 16, and 20 weeks of treatment was retained.

Results  Of the 67 patients included in the study, 17 (25%) developed vitiligo during pembrolizumab treatment and 50 (75%) did not. An objective (complete or partial) response to treatment was associated with a higher occurrence of vitiligo (12 of 17 [71%] vs 14 of 50 [28%]; P = .002). The time to onset of vitiligo ranged from 52 to 453 (median, 126) days from the start of treatment. Of the 17 patients with vitiligo, 3 (18%) had a complete response, 9 (53%) had a partial response, 3 (18%) had stable disease, and 2 (12%) had progressive disease at the final follow-up. All the patients treated with pembrolizumab who developed vitiligo were alive at the time of analysis, with a median follow-up of 441 days.

Conclusions and Relevance  Vitiligo, a clinically visible immune-related adverse event could be associated with clinical benefit in the context of pembrolizumab treatment.

Groundbreaking Cancer Immunotherapeutic Approved by FDA


The U.S. Food and Drug Administration (FDA) announced the highly anticipated approval of the cancer immunotherapeutic pembrolizumab (Keytruda) for the treatment of certain patients with metastatic melanoma, the most deadly form of skin cancer.

3D structure of a melanoma cell
3D structure of a melanoma cell 

Pembrolizumab is the first in a new class of cancer immunotherapeutics called PD-1 inhibitors to be approved by the FDA. While the FDA decision came earlier than initially expected, the excitement surrounding it has been palpable for a while because pembrolizumab, as well as other PD-1 inhibitors, has been yielding dramatic and durable responses for patients with metastatic melanoma. In fact, many patients are continuing to benefit from pembrolizumab more than one year after starting treatment.

As I discussed in an earlier blog post, “Cancer Immunotherapy: Breaking Through to the Standard of Care,” PD-1 inhibitors work by releasing the PD-1 brake on cancer-fighting immune cells called T cells. Once the PD-1 brake is released, the T cells are able to carry out their natural function and can destroy cancer cells.

Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center and a spokesman for the American Association for Cancer Research, told the New York Times: “This is really opening up a whole new avenue of effective therapies previously not available. It allows us to see a time when we can treat many dreaded cancers without resorting to cytotoxic chemotherapy.”

The patients who will benefit from yesterday’s FDA approval are those with metastatic melanoma that does not respond, or has stopped responding, to another cancer immunotherapeutic, ipilimumab (Yervoy). Ipilimumab targets another T-cell brake, CTLA4. A substantial number of patients with metastatic melanoma are still benefiting from ipilimumab more than five years after starting treatment, and it is hoped that pembrolizumab and other PD-1 inhibitors will have a similar impact so that significant inroads can be made against metastatic melanoma – a disease that has an overall five-year survival rate of only 16 percent.

Metastatic melanoma is a cancer diagnosis projected to be received by more than 3,000 U.S. residents in 2014 alone. With PD-1 inhibitors also showing tremendous promise in clinical trials as a potential treatment for other types of cancer, in particular non-small cell lung cancer – a disease that more than 180,000 individuals in the United States are expected to be diagnosed with in 2014 – it is hoped that additional FDA approvals for this groundbreaking class of drugs lie in the near future.

FDA Approves First Immunotherapy-Companion Diagnostic Combo for Lung Cancer


On the heels of the U.S. Food and Drug Administration’s approval of acombination of immune checkpoint inhibitors for unresectable and metastatic melanoma comes yet another immunotherapy approval. This time it is pembrolizumab (Keytruda), an immune checkpoint inhibitor, being approved for patients with metastatic non-small cell lung cancer (NSCLC) that has progressed after other treatments, and whose tumors express the protein PD-L1.

Lung cancer cell
Illustration of lung cancer cell during cell division.

This is the first immunotherapeutic to be approved in conjunction with a companion diagnostic test, the PD-L1 IHC 22C3 pharmDx test, which can detect the presence of the protein PD-L1 in non-small cell lung tumors.

Pembrolizumab is the second drug in the class of immune checkpoint inhibitors to be approved for NSCLC, the first being nivolumab, which was approved for treating squamous NSCLC in March this year. Pembrolizumab works by blocking the PD-1/PD-L1 pathway that cancer cells sometimes engage in order to apply “brakes” on cancer-fighting T cells, preventing the T cells from doing their job. Blocking the PD-1/PD-L1 pathway releases the brakes on T cells and enables them to fight cancer cells.

The FDA’s approval is based on the results of a randomized clinical trial of 550 patients with advanced NSCLC. In a subgroup of patients who received pembrolizumab after their lung cancer progressed following chemotherapy or targeted therapy and whose tumors had PD-L1, the overall response rate was 41 percent, and the treatment effect lasted between 2.1 and 9.1 months.

Early results from this trial were presented in April at the AACR Annual Meeting 2015. At that time, describing the promising data from the study, Edward B. Garon, MD, associate professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles, said in a press release, “Neither the drug nor the biomarker test is approved for use in this setting at this time, but if I had a patient whose tumor had PD-L1 expression on at least half of the cells and if pembrolizumab was available, I think that I would find the data compelling to look at the drug as the treatment option for that patient.” The results of this study were published in the New England Journal of Medicine.

The Diagnostic Tests Dilemma

While immune checkpoint inhibitors are one of the most promising classes of drugs to be tested and approved in recent years, their use is not without challenges.

As individual pharmaceutical companies continue to develop diagnostic tests to identify patients most likely to benefit from the immune checkpoint inhibitor they are each developing, and as more and more therapeutics from this class of drugs are approved by the FDA for a range of cancer types, identifying the right drug in a reasonable timeframe and making it a cost-effective endeavor poses challenges for both the patient and his or her physician.

Recognizing the challenges and in an effort to develop some solutions, the FDA, the AACR, and the American Society of Clinical Oncology (ASCO) held a one-dayworkshop in March this year in Washington, D.C., titled “Complexities in Personalized Medicine: Harmonizing Companion Diagnostics across a Class of Targeted Therapies.”

A significant development to emerge from the workshop was a commitment from six companies to work together in the pre-competitive space and analytically characterize the performance of their individual PD-1/PD-L1 companion diagnostic test systems. The project is continuing to make strides, and results are expected to help build an evidence base for post-approval studies that will help inform patients, physicians, pathologists, and others on how best to use the tests to determine treatment decisions.

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