666 | CANCER DISCOVERY June 2018 www.aacrjournals.org

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Although many of the grants awardedin the next year may go to research powerhouses, institutions of all sizes are expected to benefi t. For example, funding has increased for the NIH’s Institutional Development Award (IDeA) program, Rasouli points out. This program aims to build biomedi-cal research capacity by supporting cancer research and other scientifi c ventures in states that have historically received lower levels of NIH funding.

Researchers and public policy expertsemphasize that the budget increase conveys an important message to budding cancer researchers. “When Congress invests substantially and consistently in the NIH, it sends a strong signal to the next generation of scientists about the prospects for a career in medical research,” says Rasouli.

Although the forecast for cancer research looks bright for FY 2018, researchers are already looking ahead to FY 2019 and wondering whether the NIH will be as lucky. “Most people mean to do well, and Congress values cancer research tremendously. But the budget process is remarkably anxiety-provoking,” refl ects Gerson. –Kristin Harper n

Adjuvant Therapy for Melanoma Prolongs RFs

The PD-1 inhibitor pembrolizumab (Keytruda; Merck) may be an effective adjuvant therapy for patients with advanced melanoma: The drug signifi -cantly reduces the risk of recurrence for patients with stage III melanoma, according to clinical trial data pre-sented on April 15 at the American Association for Cancer Research 2018 Annual Meeting in Chicago, IL, and concurrently published in The New Eng-land Journal of Medicine (N Engl J Med 2018 Apr 15 [Epub ahead of print]).

Pembrolizumab received FDA approval in 2014 for metastatic mela-noma, and it has since been greenlighted for certain forms of lung, head and neck, and gastric cancers, as well as urothelial carcinoma and Hodgkin lymphoma.

In the phase III KEYNOTE-054/EORTC1325-MG trial, researchers enrolled 1,019 patients with stage IIIa, IIIb, and IIIc melanoma at high risk of recurrence

Congress Gives nIh $3 Billion Increase

In March, President Donald Trump signed into law a budget bill for fi scal year (FY) 2018 that increased NIH funding by $3 billion—a 5% boost over last year—and NCI funding by $275 million—a 9% jump. Researchers expect this money to translate into more cancer research grants and a greater willingness to fund risky projects.

Roy Jensen, MD, director of The University of Kansas Cancer Center inKansas City, had hoped that the NIHwould see more funding than in FY 2017, and rumors had led most researchers to expect a $2 billion hike. “It came as a real surprise that Congress was going to increase it by $3 billion,” he says. “It is a testament to the fact that a bipartisan majority believes in the power of biomedical research and is willing to prioritize it.”

One benefi t of the funding boost is that the NCI will be able to fund more research grants. Tannaz Rasouli, senior director of Public Policy & Strategic Outreach at the Association of Ameri-can Medical Colleges in Washington, DC, notes that six out of every seven proposals submitted to the NCI cur-rently go unfunded.

More grant funding will particularly benefi t two groups of investigators, says Stan Gerson, MD, director of the Case Comprehensive Cancer Center in Cleve-land, OH: young researchers establish-ing their labs, and researchers at risk of shuttering their labs because one of their proposals has scored what would currently be just below the pay line. For these individuals, “the increased fund-ing will have a huge effect.”

Higher levels of funding will also encourage researchers to submit more high-risk, high-reward proposals, says George Demetri, MD, director of the Center for Sarcoma and Bone Oncol-ogy at Dana-Farber Cancer Institute in Boston, MA. “If our usual success rates continue to apply, we could bring in nearly 10% more money to do our research. The increased federal fund-ing should allow for more fl exibility for our best investigators to pursue riskier but potentially high-impact scientifi c projects.”

Monica M. Berta-gnolli, MD, began a 1-year term as presi-dent of the American Society of Clinical Oncology (ASCO) on June 4 at the organi-zation’s 2018 Annual

Meeting in Chicago, IL, succeeding Bruce Johnson, MD . Bertagnolli is chief of the division of surgical oncology at Dana-Farber/Brigham and Women’s Cancer Center and a professor of surgery at Harvard Medical School, both in Boston, MA . Bertagnolli has previously served on the ASCO Board of Directors and the ASCO Cancer Prevention Committee . Her laboratory studies the adenomatous pol-yposis coli gene, which is involved in colorectal carcinogenesis .

Ralph R. weichsel-baum, MD, profes-sor and chairman of the Department of Radiation and Cellular Oncology and co-director of the Ludwig Center for Metastasis

Research at the University of Chicago in Illinois, received the David A . Karnofsky Memorial Award at the ASCO annual meeting for his outstanding contributions to cancer research . Weichsel baum’s dis-coveries in basic mechanisms of signal transduction and gene expression after radiation exposure led to research on radio-inducible gene therapy and the inte-gration of chemotherapy and radiotherapy .

Also at the ASCO an nual meeting, Douglas Lowy, MD,deputy director of the NCI and the chief of the Labora tory of Cellular Oncology in its Center for Cancer

Research, received the Science of Oncology Award for his contributions to basic and translational research . Lowy studies the biology of papilloma viruses and the regulation of normal and neo-plastic cell growth . His research on human papillomavirus (HPV) led to the development of three FDA-approved HPV vaccines .

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“promising” because MPR is consid-ered predictive of long-term survival.

More detailed analyses showed that PD-L1 expression levels had lit-tle impact on response rates, but the tumor mutation burden (TMB), as measured by exome sequencing on pretreatment biopsies, was highly pre-dictive of MPR. This dovetails with the findings of other NSCLC immunother-apy trials—including a phase III study of nivolumab given in combination with the CTLA4 inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) as first-line therapy for stage IV NSCLC, the results of which were also concurrently published and presented at the AACR meeting (N Engl J Med 2018 Apr 16 [Epub ahead of print]).

“TMB is basically dominating as the most clinically important biomarker of response to these therapies,” said Naiyer Rizvi, MD, of Columbia Univer-sity Medical Center in New York, NY, who was not involved in either study.

The trial investigators also found that blood levels of tumor-associated, neo-antigen-specific T cells jumped in the weeks following drug administration and then declined again post-surgery, indicating that “there’s the potential for a long-lived immune response,” Forde said. The finding also suggests that neoadjuvant anti–PD-1 administra-tion could help generate a more robust immune response than adjuvant use, as is typically done with chemotherapy.

“Some of the patients in this study would probably have gone straight to the OR” with standard care, noted Aaron Mansfield, MD, of the Mayo Clinic in Rochester, MN. These results suggest there’s another “window of opportu-nity” to treat early for long-term benefit, he added. “We do now need to ask the

after surgery—defined as having meta-static disease in one or more regional lymph nodes. Researchers randomly assigned patients to receive pembroli-zumab or a placebo every 3 weeks for up to a year. Patients treated with the drug had a 12-month recurrence-free survival (RFS) rate of 75.4%, compared with 61% for patients who received a placebo, and RFS was consistently prolonged across subgroups. For example, PD-L1–positive and –negative patients were 46% and 53% less likely, respectively, to experience recurrence or death than patients in the placebo group.  

“The significance of these results is that what works in advanced melanoma also works in the adjuvant setting,” explained Alexander Eggermont, MD, PhD, of the Institut Gustave Roussy in Villejuif, France. He noted that pem-brolizumab is generally associated with less severe immune-related adverse effects than the CTLA4 inhibitor ipili-mumab (Yervoy; Bristol-Myers Squibb), another adjuvant therapy for melanoma.

However, Eggermont said the trial’s crossover design, in which patients in the placebo group who relapse can access the drug, will eventually allow it to ans-wer an even bigger question: “Do we need to provide adjuvant therapy to the whole patient population, or would it be just as effective to follow patients very closely and treat those who relapse immediately . . . with that medication?”

For Evan Lipson, MD, of Johns Hopkins University in Baltimore, MD, the results are exciting, although not surprising. He pointed out that the FDA approved the PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) as an adjuvant therapy for melanoma in December 2017 based on similar study results (N Engl J Med 2017;377:1824–35).

“There doesn’t seem to be a huge dif-ference between what was reported with nivolumab and what’s been reported with pembrolizumab,” he said. “I think this further solidifies the place of anti–PD-1 generally as the new adjuvant therapy standard of care for patients with high-risk resected melanoma.”

Michael Postow, MD, of Memo-rial Sloan Kettering Cancer Center in New York, NY, agreed, adding that the pembrolizumab trial builds on the nivolumab results by including patients with stage IIIa disease. However, both trials have yet to answer what he views

as the major clinical question: “Is there overall survival benefit to giving adju-vant PD-1 therapy versus PD-1 therapy in the metastatic setting?”

“I think the most impact this trial can have in our field is yet to be seen, when the overall survival results come in,” he said. “It’s a nice study, but we really need more time.” –Catherine Caruso n

neoadjuvant nivolumab Checks Lung Cancer

The PD-1 inhibitor nivolumab (Opdivo; Bristol-Myers Squibb) given prior to surgical removal of non–small cell lung cancer (NSCLC) is safe and leaves only trace amounts of residual tumor cells behind in nearly half of all patients, according to the first neoadjuvant immunotherapy trial for patients with early-stage lung cancer.

The results—presented on April 16 at the American Association for Cancer Research (AACR) 2018 Annual Meeting in Chicago, IL, and published concur-rently—also indicate that neoadjuvant immunotherapy leads to sustained anti-tumor immune responses that could help fight micrometastatic disease and prevent relapse and recurrence after surgery (N Engl J Med 2018 Apr 16 [Epub ahead of print]).

“We’ve opened up a new huge interest in investigating these agents preopera-tively with the goal of finally increasing cure rates in lung cancer,” said Jamie Chaft, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who co-led the trial. Senior author Drew Pardoll, MD, PhD, of Johns Hopkins Bloomberg–Kimmel Institute for Cancer Immunotherapy in Baltimore, MD, pre-sented the findings at the meeting.

Researchers enrolled 22 patients with stage I, II, or IIIa NSCLC, 20 of whom received two doses of nivolumab in the month leading up to surgery and then had their tumors completely removed. Of these 20 individuals, nine exhibited major pathologic response (MPR), defined as having 10% or fewer viable cancer cells in the resected tumor tissue; no viable cancer cells were found in two patients.

Although the sample size was small, the MPR rate of 45% is more than double what’s typically seen with neo-adjuvant chemotherapy—a result that trial co-leader Patrick Forde, MB, BCh, also of Johns Hopkins, described as

Drew Pardoll, MD, PhD, reported that 45% of resected lung tumors demonstrated a major pathologic response to neoadjuvant therapy with nivolumab (shown with Alice Shaw, MD, PhD) .

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