Pembrolizumab Improves Progression-Free Survival in Patients with Ipilimumab-Resistant Melanoma

Interim formula from a randomized tranquil proviso II hearing uncover that pembrolizumab (Keytruda®) improves progression-free presence in patients with cancer that has gotten worse during diagnosis with ipilimumab (Yervoy®), and with a BRAF or MEK inhibitor (if a growth carried a BRAF V600 mutation), compared with chemotherapy. The findings were published online in The Lancet … Continue reading “Pembrolizumab Improves Progression-Free Survival in Patients with Ipilimumab-Resistant Melanoma”

Interim formula from a randomized tranquil proviso II hearing uncover that pembrolizumab (Keytruda®) improves progression-free presence in patients with cancer that has gotten worse during diagnosis with ipilimumab (Yervoy®), and with a BRAF or MEK inhibitor (if a growth carried a BRAF V600 mutation), compared with chemotherapy.

The findings were published online in The Lancet Oncology on Jun 24. Antoni Ribas, M.D., Ph.D., of a University of California, Los Angeles, was a initial author of a study, that was sponsored by Merck Sharp Dohme, a builder of pembrolizumab.

Pembrolizumab is a targeted therapy famous as an defence checkpoint inhibitor. The drug, a monoclonal antibody, binds to a protein on T cells called PD-1. When PD-1 is activated by contracting to a protein that is constructed by many growth cells, a defence response is suppressed. Binding of pembrolizumab to PD-1 blocks activation of a PD-1 pathway, permitting a defence response to proceed.

In Sep 2014, a Food and Drug Administration (FDA) postulated accelerated capitulation to pembrolizumab as a second-line therapy for modernized cancer that has progressed (gotten worse) during diagnosis with ipilimumab or BRAF inhibitors. The capitulation was formed on formula from a randomized proviso IB trial, called KEYNOTE-001. As a condition of this accelerated approval, Merck was compulsory to control a multicenter randomized hearing to settle a supremacy of pembrolizumab over customary therapy and to report a clinical benefit.

In a stream trial, called KEYNOTE-002, 540 patients with modernized cancer were incidentally reserved to accept one of 3 diagnosis regimens: pembrolizumab during a sip of 2 milligrams per kilogram of physique weight each 3 weeks, pembrolizumab during a sip of 10 milligrams per kilogram of physique weight each 3 weeks, or chemotherapy comparison by a patient’s physician. Neither a patients nor a investigators knew that sip of pembrolizumab particular patients received, nonetheless they knew possibly a diagnosis was pembrolizumab or chemotherapy.

Overall presence will be a primary endpoint during a final analysis. At this halt analysis, a primary endpoint was progression-free survival, and a delegate endpoints enclosed safety.

The 6-month progression-free presence rates were 34 percent for patients who perceived a reduce sip of pembrolizumab, 38 percent for patients who perceived a aloft sip of pembrolizumab, and 16 percent for patients who perceived chemotherapy.

Patients in a pembrolizumab groups had reduce incidences of treatment-related class 3-4 inauspicious events than patients in a chemotherapy group. Such side effects were seen in 20 patients who perceived a reduce sip of pembrolizumab (11 percent), 25 patients who perceived a aloft sip of pembrolizumab (14 percent), and 45 patients who perceived chemotherapy (26 percent).

The many common treatment-related class 3-4 inauspicious events in a lower-dose pembrolizumab organisation were fatigue, edema, and myalgia. In a higher-dose pembrolizumab group, a many common treatment-related class 3-4 inauspicious events enclosed colitis, decreased appetite, and diarrhea. And for a chemotherapy group, a many common class 3-4 treatment-related inauspicious events enclosed anemia, fatigue, and neutropenia.

Study participants were surveyed about their health-related peculiarity of life (HRQoL). Overall, patients in a pembrolizumab groups scored improved on HRQoL measures than patients in a chemotherapy group. “The inclusion of HRQoL information is a genuine strength and reflects a auspicious tolerability of pembrolizumab, quite in a organisation of patients with bad augury and who have been heavily pretreated,” wrote a authors of an concomitant editorial.

Although some-more information are indispensable to consider altogether survival, a stream formula advise that a dual doses of pembrolizumab are compared with identical outcomes, a investigate authors noted.

“These commentary uphold published formula as good as a FDA’s preference to extend accelerated capitulation to pembrolizumab,” pronounced Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program, who was not concerned in a trial. “The investigate clearly demonstrates a alleviation of progression-free presence during possibly sip of pembrolizumab opposite each organisation in a investigate but courtesy to age or a series of before treatments.”

Based on a published studies to date, Dr. Streicher added, a rising customary of caring for a initial diagnosis of metastatic cancer will engage giving sequences and combinations of a BRAF/MEK inhibitors and PD1/PDL1/CTLA4 monoclonal antibodies, such as ipilimumab, pembrolizumab, and nivolumab (Opdivo®).

Nivolumab-Based Treatments Delay Progression of Advanced Melanoma

Summary

Results from an international, double-blind, randomized proviso III hearing uncover that patients with modernized cancer who perceived nivolumab (Opdivo®) and ipilimumab (Yervoy®) had longer progression-free presence than patients who perceived ipilimumab alone. Progression-free presence was also longer among patients who perceived nivolumab alone than among those who perceived ipilimumab alone.

Source

New England Journal of Medicine, May 31, 2015 (See a abstract.)

Background

Nivolumab and ipilimumab retard a activity of certain proteins, called defence checkpoint proteins, that extent a strength of defence responses. When activated, these checkpoint proteins offer as a stop on a defence system, preventing overly clever defence responses that could mistreat normal cells as good as aberrant cells. Treatments that retard a activity of checkpoint proteins might mislay this brake, enabling a defence complement to destroy cancer cells.

Nivolumab inhibits a activity of a protein receptor called PD-1 on defence cells called T cells. When PD-1 on T cells binds to another protein called PD-L1, that is benefaction on a aspect of some cancer cells, a T cells turn inactive. Nivolumab blocks PD-1 contracting to PD-L1 and prevents T dungeon inactivation, permitting a defence complement to conflict a growth cells.

Some prior studies have suggested that patients whose tumors exam certain for a PD-L1 protein tend to have improved responses to anti-PD-1 therapy than patients whose tumors exam negative. Nivolumab has been authorized by a Food and Drug Administration (FDA) for a diagnosis of certain patients with cancer and lung cancer.

Ipilimumab binds to a checkpoint protein on a aspect of T cells called CTLA-4. Ipilimumab was a initial defence checkpoint inhibitor to be authorized by a FDA (in 2011) to provide modernized melanoma. Both nivolumab and ipilimumab are monoclonal antibodies that are given as intravenous infusions  by a alloy or helper in a sanatorium or medical facility.

An early-phase study demonstrated that a multiple of nivolumab and ipilimumab was protected and led to growth retrogression in some patients with modernized melanoma. More recently, a proviso III investigate showed that nivolumab improves altogether presence compared with a chemotherapy dacarbazine in certain patients with a disease. The stream investigate is a initial proviso III hearing to review a multiple of defence checkpoint inhibitors with ipilimumab alone.

The Study

In a CheckMate 067 trial, 945 patients with formerly untreated modernized cancer were incidentally reserved to accept nivolumab and ipilimumab, nivolumab alone, or ipilimumab alone. The 3 regimens were given as follows:

The primary endpoints of a investigate were progression-free presence and altogether survival. The stream news includes usually progression-free presence data, as a formula on altogether presence were not accessible during a time of publication. Secondary endpoints enclosed a design response rate, safety, and growth countenance of a protein PD-L1 as a predictive biological pen of diagnosis efficacy.

James Larkin, M.D., Ph.D., of a Royal Marsden Hospital in London was a initial author of a study, that was sponsored by Bristol-Myers Squibb, a builder of ipilimumab and nivolumab.

Results

After a median follow-up of approximately 12 months, patients treated with a multiple therapy and with nivolumab alone had longer progression-free presence than patients treated with ipilimumab alone. The median progression-free presence was 11.5 months in a multiple therapy group, 6.9 months in a nivolumab-alone group, and 2.9 months in a ipilimumab-alone group.

Among patients with PD-L1-negative tumors, median progression-free presence was longer for patients in a nivolumab-plus-ipilimumab organisation than for those in possibly of a singular diagnosis groups. Among patients with PD-L1-positive tumors, those receiving a multiple therapy and nivolumab alone had likewise aloft median progression-free presence compared with those receiving ipilimumab alone.

The design response rates—the percentages of patients whose cancers shrank or left after treatment—were aloft in a combination-therapy organisation and a nivolumab-alone organisation than in a ipilimumab-alone group. Patients with PD-L1-positive tumors had aloft design response rates than patients with PD-L1-negative tumors.

The commission of patients with a finish response was also aloft in a combination-therapy organisation than in possibly a nivolumab-alone organisation or a ipilimumab-alone group.

Treatment-related side effects of class 3 or 4 occurred in 55 percent of patients in a combination-therapy group, 16.3 percent of patients in a nivolumab group, and 27.3 percent of patients in a ipilimumab group. There was one genocide in any of a dual single-agent groups due to poisonous effects of a investigate drug, though nothing in a combination-therapy group. In a combination-therapy group, 36.4 percent of a patients stopped diagnosis since of side effects of any grade.

The many common side effects among patients in a combination-therapy organisation enclosed diarrhea, rash, and fatigue. “Adverse events were docile with determined diagnosis guidelines, and many name inauspicious events were resolved with a use of immune-modulatory agents,” a investigate authors wrote. 

Limitations

The generation of response for patients receiving a multiple therapy is not nonetheless known. More information are indispensable to establish if a alleviation in progression-free presence seen for a multiple therapy in this hearing will interpret into an altogether presence advantage for patients.

As a investigate authors noted, there is no accord about a many effective process for measuring PD-L1 countenance and defining “positive” PD-L1 expression, and a clinical utility of this protein as a biomarker has not been established. 

Comment

“This investigate is a vital allege for a margin of immunotherapy and for a diagnosis of cancer in general,” pronounced Dr. James C. Yang, M.D., of NCI’s Center for Cancer Research, who studies immunotherapy and cancer though was not concerned in this trial. “These commentary endorse several other studies display that nivolumab does means a thespian retrogression of cancer in a poignant apportionment of patients.”

The new investigate also helps to strengthen a thought that many melanomas are “primed to be deserted by a defence system,” explained Dr. Yang. “But a vital approach that tumors are avoiding that rejecting is by a PD-1 pathway. Until recently, we didn’t comprehend that this pathway was so widespread in this disease.”

Dr. Yang forked out that adding ipilimumab to nivolumab increases a poisonous side effects for some patients considerably, nonetheless a continuance of a multiple therapy is not known. In a future, he noted, “the preference to use a multiple therapy rather than nivolumab alone might count on either a long-term advantage from adding ipilimumab is value a cost of a additional side effects for particular patients.”

The take-home summary of this investigate “is that ipilimumab can no longer be deliberate a customary first-line immunotherapy for patients with modernized melanoma,” pronounced Michael B. Atkins, M.D., of Georgetown University Medical Center, who was a discussant when a CheckPoint 067 investigate commentary were presented during a 2015 American Society of Clinical Oncology annual meeting.

Based on a new formula and prior studies, Dr. Atkin pronounced that nivolumab alone and in multiple with ipilimumab—along with pembrolizumab (Keytruda®)—should be deliberate a new standards of caring for patients with modernized melanoma.

Noting that tests for assessing PD-L1 countenance are technically formidable to do and imperfect, Dr. Atkins also cautioned that some-more investigate is indispensable on PD-L1 before it should be used as a biomarker to beam a preference of treatments for patients.

Combining Two Types of Targeted Therapy Improves Survival in Some Patients with Advanced Melanoma (Updated)

In dual proviso III trials, patients with metastatic cancer whose tumors have specific mutations in a BRAF gene lived longer following diagnosis with dabrafenib (Tafinlar®), a BRAF inhibitor, and trametinib (Mekinist®), a MEK inhibitor, than following diagnosis with a BRAF inhibitor alone. The formula of both trials were published in Nov 2014 in a New England Journal of Medicine (NEJM).

In prior clinical trials, both dabrafenib and another BRAF inhibitor, vemurafenib (Zelboraf®), softened progression-free presence when used alone to provide patients with modernized cancer whose tumors bear specific mutations in a BRAF gene. These mutations, that impact an amino poison in a BRAF protein (V600), means clever growth-promoting signals and are mostly found in modernized melanomas.

Unfortunately, tumors frequently rise insurgency to BRAF inhibitors within 6 to7 months. Studies have shown that insurgency develops, during slightest in part, given tumors are means to activate a mitogen-activated protein kinase (MAP kinase/MEK) signaling pathway, that allows a tumors to resume growing. By mixing dabrafenib with trametinib, a drug that inhibits a activity of MEK proteins, researchers wish to forestall tumors from regulating this shun mechanism.

In a larger of a dual trials, led by Caroline Robert, M.D., Ph.D., of a Institut Gustave Roussy, 704 patients with metastatic cancer temperament a BRAF V600 turn were  incidentally reserved to accept possibly a multiple of dabrafenib and trametinib or vemurafenib alone. Patients in a combination-therapy organisation had a 12-month presence rate of 72 percent, compared with 65 percent in a vemurafenib group. The dabrafenib-trametinib organisation also had a improved median progression-free presence than a vemurafenib group: 11.4 months contra 7.3 months, respectively.

Five patients (1 percent) who perceived dabrafenib and trametinib grown cutaneous squamous-cell carcinoma—a critical and common snarl in patients treated with BRAF inhibitors—compared with 63 of a patients (18 percent) who perceived vemurafenib alone. The many common inauspicious events in this hearing were pyrexia (fever), fatigue, nausea, headaches, and chills. The suit of patients in a multiple organisation discontinuing diagnosis due to inauspicious events was identical to that of a vemurafenib organisation (13 percent contra 12 percent).

In a apart trial, led by Georgina V. Long, M.D., Ph.D., of a Melanoma Institute Australia, 423 formerly untreated patients with modernized cancer were incidentally reserved to accept possibly a multiple of dabrafenib and trametinib daily or dabrafenib and placebo. Patients in a combination-therapy organisation had an altogether response rate of 67 percent and a 6-month presence rate of 93 percent, given patients in a dabrafenib and remedy organisation had a 51 percent response rate and 6-month presence rate of 85 percent. Median progression-free presence was longer in a multiple organisation than a dabrafenib group: 9.3 months contra 8.8 months, respectively. [See a refurbish next for formula on altogether survival.]

Five patients in a hearing who perceived dabrafenib and trametinib (2 percent) grown cutaneous squamous-cell carcinoma, compared with 20 of a patients who perceived dabrafenib alone (9 percent). The many common inauspicious events were identical to those celebrated in a incomparable hearing and contributed to a discontinuation of diagnosis by 9 percent of patients in a multiple organisation contra 5 percent in a dabrafenib and remedy group.

Both trials were saved by GlaxoSmithKline, a manufacturer of dabrafenib and trametinib. The Food and Drug Administration (FDA) authorized both drugs in 2013 for use as singular agents in patients with BRAF mutation-positive melanomas, and a FDA authorized a dabrafenib-trametinib multiple in 2014.

Data from clinical trials that have tested a BRAF and MEK inhibitor in multiple have convincingly shown that “the multiple of a BRAF and MEK inhibitor is improved than possibly drug alone, and safer with courtesy to a risk of cutaneous squamous carcinoma,” pronounced Howard Streicher, M.D., of NCI’s Cancer Therapy Evaluation Program.

The impact of these trials on studious outcomes could be important, suggested Brendan Curti, M.D., of a Providence Cancer Center, in an concomitant editorial in NEJM.

“The good news is that we now have agents with a most aloft intensity to satisfy clinically suggestive cancer regression, as compared with therapies used before,” Dr. Curti wrote. However, given cancer adapts and develops drug insurgency really quickly, Dr. Curti cautioned that some-more work stays to be finished to rise healing strategies that are improved means to residence diagnosis resistance.

Update: In a follow-up report, Dr. Long and her colleagues published results on altogether survival, that was a delegate endpoint of their study. The median altogether presence for patients in a dabrafenib-plus-trametinib organisation was 25.1 months, contra 18.7 months for patients in a dabrafenib-only group, a researchers reported May 29, 2015, in The Lancet. The alleviation in progression-free presence and altogether presence with a multiple treatment, and a fact that it was seen in all subgroups of patients analyzed, “support a choice of total dabrafenib and trametinib as a customary targeted treatment, rather than singular drug BRAF inhibition, for a patients with BRAF Val600 mutation-positive metastatic melanoma,” a authors concluded.