Clinical Updates, July 2018

Link Found Between Mammographies, Other Screenings in Medicare Enrollees

Women who undergo mammography screenings are more inclined to follow up with other preventive measures, according to new study results. US Medicare claims data gathered between 2010 and 2014 have found that women enrolled in Medicare were more likely to follow preventive guidelines and use those services following a mammography screening. The additional preventive screenings that were evaluated include bone mass measurement, Papanicolaou testing, and influenza vaccination.

For their study, published in Radiology,¹ investigators at New York University (NYU) School of Medicine used a sample of women aged 65 years or older. The 555,705 women were sorted into 2 groups: 185,675 (33.4%) patients who received mammogram screenings and 370,080 (66.6%) who did not. The screened group was further divided between false and positive results and then subdivided among false-positive and true-positive patients.

The data were collected via multivariate logistic regression models and inverse probability of treatment weighting to evaluate the relationship between screening status and other preventive tests. Standards from the American College of Radiology were used to categorize results, because these factors play a critical role in the patient experience and willingness to participate in other preventive tests, according to the investigators.

The group of women who initially underwent mammography screenings, having either positive or negative results, had a greater chance of participating in a bone mass measurement (odds ratio [OR], 1.70; 95% CI, 1.63-1.78), Papanicolaou test (OR, 1.49; 95% CI, 1.40-1.58), and influenza vaccination (OR, 1.45; 95% CI, 1.37-1.53) compared with the control group. The study found that women with false-positive screenings showed no difference in their likelihood of undergoing further preventive testing. Also, at screening, false-positive and true-positive findings were found to be the same.

“Screening has the potential to identify early disease that can be curable,” said Stella Kang, MD, MSc, assistant professor in the departments of Radiology and Population Health at NYU School of Medicine, in a statement. “It’s encouraging to see that women undergoing mammography may have increased awareness to other preventive screening measures.”² The current study sheds light on the idea of bundling preventive services for women.

The lack of data on the link between mammography screenings and other preventive tests motivated them to do this study, the investigators said. Further research must be done to reveal the association’s impact on policy and clinical practices.

References

1. S Kang, M Jiang, R Duszak, Heller SL, Hughes DR, Moy L. Use of breast cancer screening and its association with later use of preventative services among Medicare beneficiaries [published online June 5, 2018]. Radiology. doi: 0.1148/radiol.2018172326.
2. Study finds older patients who undergo mammography also are more likely to pursue other preven- tive tests [press release]. New York, NY: NYU Langone Health; June 4, 2018. newswise.com/articles/ view/695536/?sc=sphn. Accessed June 18, 2018.

MS Drug Could Reduce Adverse Events Associated With Cancer Treatment

Fingolimod (Gilenya), an FDA-approved orally administered drug to treat multiple sclerosis, could reduce painful adverse effects (AEs) of multiple myeloma treatments, according to findings recently published in the Journal of Experimental Medicine.¹

Chemotherapy-induced peripheral neuropathy (CIPN), a common and painful AE of many anticancer drugs, can persist for years, reducing quality of life for cancer survivors. Bortezomib (Velcade), which is used to treat multiple myeloma and mantle cell lymphoma, causes CIPN in over 40% of patients, but why this occurs was not previously known.

Investigators from Saint Louis University School of Medicine in Missouri have discovered that bortezomib causes the dysregulation of sphingolipid metabo- lism in the spinal cord and increases the levels of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate. Higher levels of these molecules can activate S1PR1, a cell surface receptor protein, on specialized nervous system support cells called astrocytes. This results in neuroinflammation and enhanced release of the excitatory neurotransmitter glutamate.

In a preclinical model, rats treated with bortezomib had higher accumulations of sphingosine 1-phosphate and dihydrosphingosine 1-phosphate at the time they started to show signs of neuropathic pain. By blocking the production of these molecules with the fingolimod inhibitor, researchers prevented the animals from developing CIPN and even reversed its effects.

Notably, fingolimod did not inhibit bortezomib’s ability to kill myeloma cells. In fact, fingolimod was previously reported to inhibit tumor growth and enhance the effects of bortezomib in vitro and in tumor-bearing animals.²

“Our studies provide a compelling case for the consideration of repurposing [fingolimod] as an adjuvant to bortezomib for the prevention and treatment of chemotherapy-related neurotoxicity to address an immense unmet medical need,” concluded the study authors. “As [fingolimod] also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated.”

References

1. Stockstill K, Doyle T, Yan X, et al. Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. J Exp Med. 2018;215(5):1301-1313. doi: 10.1084/jem.20170584.
2. Yasui H, Hideshima T, Raje N, et al. FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. Cancer Res. 2005;65(16):7478-7484. doi: 10.1158/0008-5472.CAN-05-0850.

New Immunotherapy Increases Survival Time for Patients With Brain Cancer

Tocagen, a cancer-selective gene therapy company, is developing vocimagene amiretrorepvec (Toca 511) and extended-release 5-fluorocytosine (Toca FC), an immunotherapy for patients with recurrent brain cancer. Known as the Toca regimen, the investigational products are being evaluated in a phase 2/3 randomized, multicenter, open-label trial.¹

The trial is being conducted at 68 sites across the United States, Canada, Israel, and South Korea in patients undergoing planned resection for recurrent glioblastoma or anaplastic astrocytoma. Enrollment is scheduled to be completed by the end of 2018.

After completion of the successful phase 1 study, the Toca regimen showed a favorable safety profile, extended patient survival compared with other therapies, and provided complete tumor shrinkage.²

In phase 2/3, patients will be randomized 1:1 to receive either the Toca regimen or standard of care treatment of single-agent chemotherapy (lomus- tine or temozolomide) or bevacizumab. The Toca regimen will involve 2 parts. In the first step, patients will receive Toca 511, a replicating virus that selec- tively infects cancer cells during surgery. The second step requires patients to receive cycles of Toca FC, a potent anticancer pill that kills cancerous cells and activates immune cells selectively to fight off cancerous ones, leaving healthy cells unharmed.³

“Toca 5 uses a virus to stimulate a patient’s own immune system and attack recurring high-grade gliomas—glioblastoma and anaplastic astrocytoma,” said Yaron Moshel, MD, PhD, a neurosurgeon with Atlantic NeuroSurgical Specialists and codirector of the Gerald J. Glasser Brain Tumor Center, the principal investigator for the local arm of the study in a statement.⁴

With the current standard of care treatment, newly diagnosed patients have a median survival 14 to 16 months. After recurrence, this falls to 7 to 9 months, on average.¹ Conversely, phase 1 results of the Toca regimen showed a median longevity of 14.4 months for patients with a recurrence.

“Patients with complete tumor shrinkage are still alive almost 3 years after starting the Toca regimen. These results are encouraging—for patients, their loved ones, and the medical community—and we look forward to sharing further findings from phase 3 within the next 18 months,” Moshel said in statement.²

References:

1. Immunotherapy clinical trial reveals brain tumor shrinkage, continues with phase 3 study [press release]. Summit, NJ: Atlantic Health System; May 29, 2018. newswise.com/articles/view/695219/?sc=mwhr&xy=10022175. Accessed June 19, 2018.
2. Walbert T, Bota D, Vogelbaum MA, et al. Intravenous delivery of Toca 511 in patients with high grade glioma results in quantifiable expression of cytosine deaminase in tumor tissue. Neuro-oncology. 2017;19(suppl 6):30- 31. doi:10.1093/neuonc/nox168.116.
3. The Toca 5 Trial: Toca 511 & Toca FC versus standard of care in patients with recurrent high grade glioma (Toca5). clinicaltrials.gov/ct2/show/NCT02414165. Updated May 16, 2018. Accessed June 19, 2018.
4. Immnunotherapy clinical trial reveals brain tumor shrinkage continues with phase 3 study [press release]. Summit, NJ: Atlantic NeuroSurgical Specialists; April 25, 2018. prnewswire.com/news-releases/immunotherapy-clinical-trial-reveals-brain-tumor-shrinkage-continues-with-phase-3-study-300635663.html. Accessed June 19, 2018.

Pembrolizumab Indications Expand to Include Cervical Cancer

The indications of pembrolizumab (Keytruda) now include recurrent or metastatic cervical cancer with disease progression on or after chemotherapy for patients whose tumors express PD-L1, the FDA announced on June 12.¹

The agency approved this expanded indication following a priority review based on tumor response rate and durability of response. Pembrolizumab’s indications include an earlier approval as a first-line treatment in patients with metastatic non—small cell lung cancer, as well as unresectable or metastatic melanoma.

“Keytruda is now the first anti-PD-1 therapy approved for the treatment of advanced cervical cancer, providing an important new second-line option for certain patients with this disease,” Roy Baynes, MD, senior vice president, head of global clinical development, and chief medical officer at Merck Research Laboratories, said in a prepared statement.¹ “This approval also marks the first indication for Keytruda in a gynecologic cancer and reflects our ongoing commitment to bring forward innovative treatment options across a broad range of cancers, including cancers that disproportionately affect women.”

The approval was based on results from the KEYNOTE-158 trial, in which 98 patients with recurrent or metastatic cervical cancer were enrolled in a multicenter, nonrandomized, open-label, multicohort trial. Participants were treated with 200 mg of pembrolizumab delivered intravenously every 3 weeks until they showed either unsafe levels of toxicity or documented disease progression. Patients without disease progression could be treated for up to 24 months, and a tumor status assessment was completed every 9 weeks for the first 12 months and every 12 weeks thereafter.

Within the trial, 77 patients had tumors that expressed PD-L1, with a combined positive score of 1 or greater. The objective response rate was 14.3% (95% CI, 7.4%-24.1%), with a complete response rate of 2.6% and partial response rate of 11.7%. Among 11 patients who responded, median diagnostic odds ratio was not yet reached (range, 4.1-18.6+ months), and 91% of patients had a response duration of 6 months or longer.

Overall, the most common adverse events (AEs) reported, occurring in at least 20% of patients, were fatigue, musculoskeletal pain, diarrhea, pain and abdominal pain, and decreased appetite. In addition, 8% of patients discontinued treatment due to AEs. Serious AEs occurred in 39% of patients, the most serious of which were anemia, fistula, hemorrhage, and infections.²

“Even with the many advances observed across gynecologic cancers, new treatment options have been lacking for previously treated patients with advanced cervical cancer. The approval of Keytruda in this indication is important news—and as an oncologist, [I am excited] to see a much-needed option made available to these patients,” Bradley Monk, MD, an oncologist at Arizona Oncology and medical director of US Oncology Research’s gynecology program, said in a statement.¹

The FDA also announced on June 13 that it had granted pembrolizumab accelerated approval for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL) or patients who have relapsed after 2 or more lines of prior therapy. The approval was based on data from 53 patients with relapsed or refractory PMBCL who participated in KEYNOTE-170, a multicenter, open-label, single-arm trial. Pembrolizumab also received orphan product and breakthrough therapy designations for this indication; however, “continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to a statement from the FDA.³

References:

1. FDA approves Merck’s Keytruda (pembrolizumab) for previously treated patients with recurrent or metastatic cervical cancer whose tumors express PD-L1 (CPS greater than or equal to 1). Kenilworth, NJ: Merck; June 12, 2018. investors.merck.com/news/press-release-details/2018/FDA-Approves-Mercks-KEYTRUDA-pembrolizumab-for-Previously-Treated-Patients-with-Recurrent-or-Metastatic-Cervical-Cancer-Whose-Tumors-Ex- press-PD-L1-CPS-Greater-Than-or-Equal-to-1/default.aspx. Accessed June 19, 2018.
2. Schellens JHM, Marabelle A, Zeigenfuss S, Ding J, Pruitt SK, Chung HC. Pembrolizumab for previously treated advanced cervical squamous cell cancer: preliminary results from the phase 2 KEYNOTE-158 study. J Clin Oncol 2017;35(suppl 15):5514.
3. FDA approves pembrolizumab for treatment of relapsed or refractory PMBCL [press release]. Silver Spring, MD: FDA Newsroom; June 13, 2018. fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm610670. htm. Accessed June 19, 2018.

RA Drug May Reduce Toxicity Caused By CAR T Treatment

Although the development of chimeric antigen receptor (CAR) T-cell therapy changed the landscape of cancer treatment and was named Advance of the Year by the American Society of Clinical Oncology for 2018,¹ the treatment can cause challenging, difficult-to-treat adverse effects, such as cytokine release syndrome (CRS).

Symptoms caused by CRS vary, including rash, fever, and neurotoxicity. Last year, the FDA expanded the treatment indications of tocilizumab (Actemra) from its original designation for rheumatoid arthritis (RA) to include CRS in patients undergoing CAR T treatment. Tocilizumab works by blocking inter- leukin 6 (IL-6), an inflammatory cytokine. Though oncologists have used this inhibitor with some success in patients receiving CAR T treatment, it doesn’t always provide relief from symptoms.²

Recently, 2 studies published in Nature Medicine reported on another rheumatoid arthritis drug that could help treat CRS.

The first study³ investigated the effect of anakinra (Kineret) on patients if administered prior to CAR T therapy. Unlike tocilizumab, anakinra targets interleukin 1 (IL-1) and is able to cross the blood-brain barrier, potentially limiting the toxic adverse effects of CRS. During the study, investigators noticed that IL-1 cytokines were present well before IL-6, and IL-1 actually induced IL-6 production. When the mice being studied were given anakinra, they had significantly improved overall survival, and investigators discovered that targeted intervention against IL-1 may help successfully treat toxicity caused by CAR T-cell treatment.

The second study⁴ also investigated the role of IL-1 in connection with CRS. The investigators found that IL-1, IL-6, and nitric oxide produced by recipient macrophages can counteract CRS. The mouse models used also included treatment with anakinra, which was found to be more effective than simply targeting IL-6.

The next step in determining the safety and efficacy of this approach in treating CRS is to study it in human clinical trials. Investigators hypothesized that these results could lead to a CAR T treatment that has an IL-1 inhibitor built into the genetically modified immune cells.

References:

1. American Society of Clinical Oncology. Advance of the year. ASCO website. asco.org/research-progress/reports-studies/clinical-cancer-advances-2018/advance-year. Accessed June 19, 2018.
2. FDA approves Genentech’s Actemra (tocilizumab) for the treatment of CAR T cell-induced cytokine release syndrome [press release]. South San Francisco, CA: Genentch; August 30, 2017. businesswire.com/news/ home/20170830005803/en/FDA-Approves-Genentech%E2%80%99s-Actemra-Tocilizumab-Treatment-CAR. Accessed June 19, 2018.
3. Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739-748. doi: 10.1038/ s41591-018-0036-4.
4. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine released syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731-738. doi: 10.1038/s41591-018-0041-7.

Genetic Analysis of Thyroid Cancer Suggests Personalized Treatment Possible

University of Colorado Cancer Center investigators have completed the largest study of thyroid cancer genetics to date, the results of which were published in Clinical Cancer Research.¹

The study included data from 583 patient samples of advanced differen- tiated and 196 anaplastic thyroid cancers (ATC) generated from targeted next-generation sequencing (NGS) cancer-associated gene panels MSK-IMPACT and FoundationOne CDx. Investigators aimed to identify genetic alterations with potential diagnostic, prognostic, and therapeutic significance.¹

FoundationOne CDx, the first comprehensive companion diagnostic test for solid tumors, made history in December 2017, when it was under parallel review and subsequent approval by both the FDA and CMS. The test helps identify which patients may benefit from on-label targeted therapies. Both Foundation- One CDx and MSK-IMPACT are commonly used for cancer genotyping in clinical practice. By combining data generated by both panels, investigators compiled the largest collection of genetic alterations in advanced thyroid cancer to date.

In their analysis of data from the NGS tests, the study authors found that in several samples of advanced differentiated thyroid cancer and ATC, DNA repair mechanisms were broken and led to a subset of thyroid cancers with a high mutational burden.

The investigators also found specific genetic mutations associated with anaplastic cancers, including amplifications of the KDR, KIT, and PDGFRA genes. These receptor tyrosine kinases enable cancer cells to reproduce faster and are targeted by lenvatinib, which is FDA approved to treat kidney cancer. Investigators administered this drug to a cohort of participants within the study and found that the cell line that amplified KDR, KIT, and PDGFRA responded well, suggesting that treatment with lenvatinib could show promising results.

Finally, the study identified several genetic alterations that may be vital for developing personalized therapies for thyroid cancer. The amplifications of CD274, PDCD1LG2, JAK2, and DNA mismatch repair (MMR) deficiencies have been associated with a positive response to immune checkpoint inhibitors such as pembrolizumab and nivolumab.

“As a clinician, I learn from this study that every patient with advanced thyroid cancer that we consider for systemic therapy should be genotyped— knowledge of genetic background may affect how we treat that patient,” the lead study author, Nikita Pozdeyev, MD, PhD, an assistant professor of medicine in the Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado School of Medicine, said in a statement. “There are many drugs targeting many genetic changes that are approved for other cancers, which we would not usually think to use in thyroid cancer. Some of the findings in this paper will potentially change that.”²

References:

1. Pozdeyev N, Gay LM, Sokol ES, et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers [published online April 3, 2018]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-0373.
2. Sundem G. Largest ever study of thyroid cancer genetics finds new mutations, suggests immunotherapy. Colorado Cancer Blogs website. coloradocancerblogs.org/largest-ever-study-of-thyroid-cancer-genetics-finds-new-mutations-suggests-immunotherapy/. Published April 26, 2018. Accessed June 19, 2018.

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