Keytruda

FDA approves Keytruda-based combination for advanced cervical cancer

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The FDA approved pembrolizumab in combination with chemoradiotherapy for the treatment of certain women with stage III to stage IVA cervical cancer.

This is the third approved cervical cancer indication for pembrolizumab (Keytruda, Merck), an anti-PD-1 therapy. The FDA previously approved the agent in combination with chemotherapy, with or without bevacizumab, for the treatment of women with PD-L1-expressing persistent, recurrent, or metastatic cervical cancer and as monotherapy for women with recurrent or metastatic cervical cancer who experienced disease progression while receiving or after chemotherapy.

Generic FDA News infographic
The approved combination resulted in a 41% reduction in risk for disease progression or death. 

The agency based the new indication on data from the double-blind phase 3 KEYNOTE-A18 trial, which assessed pembrolizumab plus chemoradiotherapy compared with placebo in patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 stage III to stage IVA disease.

The study enrolled 1,060 women with cervical cancer who had not previously received any definitive surgery, radiation or systemic therapy.

Researchers randomly assigned patients in a 1:1 ratio to receive 200 mg IV pembrolizumab every 3 weeks for five cycles concurrent with 40 mg/m2 IV cisplatin for five cycles with radiotherapy, followed by 400 mg IV pembrolizumab every 6 weeks for 15 cycles, or the same regimen with placebo instead of pembrolizumab.

PFS and OS served as the study’s major efficacy outcomes measurements.

Researchers observed a statistically significant improvement in PFS in the overall population; patients in the investigative cohort had a 41% reduction in risk for disease progression or death (HR = 0.59; 95% CI, 0.43-0.82) compared with those in the placebo group.

Researchers noted that the study did not reach a median PFS in either group and determined OS data to be not mature at time of PFS analysis.

“Today’s approval of Keytruda plus chemoradiotherapy is welcome news and gives patients with newly diagnosed FIGO 2014 stage III-IVA cervical cancer, for the first time ever, the option of an anti-PD-1–based regimen to treat their cancer,” Bradley Monk, MD, oncologist and professor of obstetrics and gynecology at University of Arizona’s College of Medicine and Creighton University School of Medicine, said in a Merck press release. “This Keytruda-based regimen offers a new treatment option for these patients, so today’s approval has important implications for the way we treat them moving forward.”

Researchers observed serious adverse reactions in 30% of patients who received pembrolizumab plus chemoradiotherapy; serious adverse reactions included urinary tract infections (2.7%), urosepsis (1.4%) and sepsis (1%).

Researchers discontinued pembrolizumab for adverse reactions in 7% of patients during the study.

Survival Bump in Bladder Cancer with Keytruda

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But no outcome advantage for Tecentriq in metastatic urothelial cancer

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  • 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.

Melanoma Tx Tied to Neurologic Disorder

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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.”

Merck Says FDA Accepts Its SBLA For Keytruda For Treatment Of Head & Neck Cancer

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Merck & Co. Inc. (MRK), known as MSD outside the United States and Canada, Wednesday announced that the U.S. Food and Drug Administration has accepted its supplemental Biologics License Application for Keytruda. It will be reviewed under the FDA’s Accelerated Approval program. The compound is intended for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy.

The company noted that the application envisages Keytruda as single agent at a dose of 200 mg administered intravenously every three weeks.

Keytruda is a humanized monoclonal antibody that can increase the ability of the body’s immune system to help detect and fight tumor cells. Keytruda blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Groundbreaking Cancer Immunotherapeutic Approved by FDA

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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.

Pembrolizumab Approved by FDA .

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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 (Source: Sriram Subramaniam, National Cancer Institute)

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.