		At the recent National Comprehensive Cancer Network (NCCN) 20th Annual Conference, experts discussed this year’s updates to the NCCN Clinical Practice Guidelines in Oncology. We asked NCCN panel members to highlight the latest recommendations for practicing oncologists.

				The updated ovarian cancer treatment guidelines recommend the use of two new treatment regimens: a comparatively well-tolerated chemotherapy mixture and a first-in-class targeted therapy.

				The first of those—18 weekly doses of paclitaxel at 60 mg/m2 infused over 1 hour followed by carboplatin (AUC = 2) infused over 30 minutes&mdash;now receives a category 1 recommendation as a primary chemotherapy regimen or a primary adjuvant therapy regimen for patients diagnosed with stage II to stage IV disease.

				It is one of several category-1 options for such patients, but it is a particularly good option for elderly patients.

				“Ovarian cancer tends to be a cancer that women develop in their 60s and 70s, and chemotherapy is not as well tolerated by patients in that age bracket as it is by the younger patients with other tumors,” said Robert J. Morgan, MD, co-director of the Gynecological Cancers Program at City of Hope and chairman of the NCCN’s ovarian cancer panel.

				“Recent research has shown that this paclitaxel/carboplatin regimen is about as effective as several other alternatives but consistently and significantly less toxic. It should thus make a real difference for older patients or those with poor performance status.”

				The other new treatment that appears in the updated guidelines is olaparib (Lynparza), the first poly ADP-ribose polymerase (PARP) inhibitor approved to treat any tumor. The drug is particularly active in tumors with

 gene mutations. The new NCCN guidelines list it as a preferred agent in the treatment of platinum-sensitive and platinum-resistant disease when FDA-approved tests show germline 

 mutations and patients have failed on 3 or more previous regimens.

				“There are few targeted therapies that have been shown to be effective in ovarian cancer,” said Morgan. He added that most other changes on this year’s guidelines are semantic improvements designed to clarify older recommendations. “It’s also rare for us to add two new regimens in 1 year, so this really constitutes a pretty exciting update.”

			The NCCN’s new prostate cancer guidelines feature significant changes to recommendations in two treatment areas and the use of molecular biomarkers.

			This year’s document rearranges the section on treating cancer that has recurred after androgen deprivation therapy and a second antiandrogen treatment. The FDA has approved several treatment options for such patients, and the guideline panel decided to bring some order to the chaos by listing treatments in preference order.

			“We by no means expect every physician to start at the top of the list with each patient,” said the panel’s chairman, James L. Mohler, MD, who also chairs the Urology Department at Roswell Park Cancer Institute.

			“We recognize that every patient is different, that every physician is different and that every insurer is different, but we think it’s helpful to provide one more tool for differentiating among the treatment options.”

			The new guidelines are also the first to feature a section on molecular biomarkers that have proven themselves as an early detection tool and are starting to be used, in conjunction with other factors, to decide between treatment and active surveillance. This new section makes few recommendations—the tests are too new and the data too limited to support confident assertions&mdash;but it summarizes existing data and highlights concerns such as the relative lack of regulatory oversight for assay makers.

			The last addition that Mohler highlighted was a discussion of the use of multiparameter magnetic resonance imaging to help with the staging and characterization of prostate cancer. Imaging can be used to stratify men who are considering active surveillance and to aid in the assessment of extracapsular extension in large or poorly differentiated prostate cancer.

			“The discussions of biomarkers and imaging are very preliminary,” Mohler said. “Looking forward, I’d guess that they are the two sections where you’ll find the biggest updates next year, because there are numerous trials right now in both areas.”

			David Ettinger, MD and Gregory Kalemkerian, MD

			Johns Hopkins Medicine and University of Michigan

			Of all the updates to the NCCN guidelines, the addition of nivolumab to some non—small cell lung cancer protocols ranks among the most exciting. The new document only recommends the drug as a subsequent therapy for a small subgroup of patients, those whose squamous cell carcinomas have progressed on or after platinum-based chemotherapy and been diagnosed as performance status 0 to 2.

			“The trial data we have so far only support its use in this group, but there’s obviously hope that it will prove effective in the very wide range of tumor types that express PD-L1,” said David Ettinger, MD, who is the Alex Grass Professor of Oncology at Johns Hopkins and the chair of the NCCN NSCLC Guidelines Panel.

			“The other big hope is for a biomarker test that predicts responders. The current response rate is only about 20%, but it’s still the most exciting thing in years because, for those who do respond, most of those responses last for years, which is utterly unprecedented in stage IV disease.”

			Ettinger highlighted one other update among the dozens to arrive over the past year, a strong recommendation that oncologists begin using next generation sequencing tests to identify a wide range of tumor mutations that can affect treatment decisions.

			The guidelines for small cell lung cancer saw far fewer updates.

			“Targeted therapy has not proven effective against small cell tumors in trials, so our treatment strategies often go years at a time without major changes,” said Gregory Kalemkerian, MD, the chair of the NCCN Small Cell Lung Cancer Guidelines Panel and a professor of medicine at the University of Michigan.

			“We did, however, add a recommendation to consider the addition of radiation to the chest, after standard chemotherapy, for patients with extensive-stage small cell. We’re also hopeful that ongoing immunotherapy trials will demonstrate benefit for our patients.”

			Kalemkerian noted that the added radiation was not curative, but 1 study had found that it was associated with a significant increase in 2-year survival.

			Robert H. Lurie Comprehensive Cancer Center

			“We are gaining a true appreciation that breast cancer is a complex disease. Not only are we dealing with a number of intrinsic subtypes, but we are learning that within those subtypes are smaller subsets that may require different therapies. In early-stage breast cancer, the trend is toward less invasive staging and treatment. In HER2-positive disease, duel targeting is impacting outcomes, but we are still facing the challenge of overcoming resistance to anti-HER2 agents. The fact that not all HER2-positive disease is HER2-enriched, and other subtypes can be HER2-positive, also complicates treatment selection. We think broadly about our treatments, but the reality is that intrinsic subtypes may be a little promiscuous. In advanced estrogen receptor (ER)-positive breast cancer, we still rely on multiple lines of endocrine agents alone, but we are developing agents that may combat endocrine resistance. For triple-negative disease, platinumbased therapy has proven active, but its efficacy appears to be influenced by 

 mutation status. We are hoping that germline biomarkers will emerge to help guide treatment selection in this challenging patient subset.”

					The NCCN now considers a surgical margin to be negative when there is “no ink on the tumor.”

					The NCCN endorses the use of short-course accelerated partial breast irradiation over standard (longer) courses of whole breast radiation.

					Axillary surgery is not recommended for clinically node-negative patients meeting the criteria of ACOSOG Z0011: T1/2 tumors, one or two positive sentinel nodes only, no neoadjuvant therapy, breast-conserving therapy, and whole breast radiation planned.

					For ER-negative, HER2-positive patients with very small (≤0.5 cm) tumors and no positive nodes, adjuvant chemotherapy with trastuzumab can now be considered.

					For postmenopausal patients with metastatic ER-positive disease, the Guidelines list CDK4/6 inhibitor palbociclib plus letrozole as a new therapeutic option.

					The improvement in survival in excess of 1 year, in CLEOPATRA, established trastuzumab/pertuzumab as the legitimate first-line treatment of metastatic HER2-positive breast cancer.

					The achievement of pathologic complete response (pCR) and the meaning of this varies according to tumor type, treatment, tumor genetics, and the microenvironment, eg, tumor infiltrating lymphocytes. The ALTTO trial demonstrated that pCR does not correlate with long-term outcomes.

					For premenopausal ER-negative patients, the Guidelines now recognize that ovarian suppression with GnRH agonists given during adjuvant chemotherapy may preserve ovarian function and diminish the likelihood of amenorrhea.

			“Long-term survival for patients with metastatic colorectal cancer is not based on choice of first-line therapy, but on the incremental benefits that accrue over time using available agents. With chemotherapy alone, median overall survival never exceeded 2 years. With current strategies, we have improved median overall survival to more than 30 months. It’s not one breakthrough drug but the art of oncology that keeps our patients alive. The emphasis should be on using all the available agents, and it is the clinician’s task to apply them optimally by using ‘tools’ that can help individualize treatment.”

					The goal in the palliative setting is to extend duration of life while maintaining quality of life. In this setting, FOLFOX, CapeOX and FOLFIRI are viewed as equivalent.

					The addition of biologics to chemotherapy has improved outcomes, but not as much as anticipated.

					Extended inhibition of the vascular endothelial growth factor (VEGF) enhances disease control. This means employing an anti-VEGF agent (bevacizumab) until progression, as maintenance therapy and beyond progression.

					The two monoclonal antibodies directed against the epidermal growth factor receptor (EGFR), cetuximab and panitumumab, are interchangeable.

Articles

Expert panel members highlight the latest NCCN guideline recommendations.  


2015 NCCN Guideline Updates: New Recommendations for Clinical Practice

It is fitting that Drs James P. Allison and Jedd D. Wolchok are featured this month (pages 11 and 36, respectively) in the same issue as our coverage of the 2015 AACR Annual Meeting (

). Both were pioneers in the development of the immune checkpoint blockade strategy that was a central focus of much of the key data presented at AACR.

Data shared at the meeting showed that the PD-1 checkpoint inhibitor pembrolizumab (Keytruda) produced response rates as high as 50% in some patients with non—small cell lung cancer. In a separate trial, pembrolizumab improved survival compared with another checkpoint agent, the CTLA-4 inhibitor ipilimumab (Yervoy), in treatment-naïve patients with advanced melanoma.

Also in the frontline setting for advanced melanoma, adding the PD-1 inhibitor nivolumab (Opdivo) to ipilimumab was shown to improve progression-free survival by 60% compared with ipilimumab alone. And in breast cancer, early stage data showed that the PD-L1 inhibitor MPDL3280A had promising activity in pretreated patients with metastatic triple-negative breast cancer.

The ongoing research success with these checkpoint agents continues to lead to regulatory approvals and their increased integration into standard practice guidelines. Indeed, this month we also highlight the guideline updates presented at the 2015 NCCN Annual Meeting, and one of the more noteworthy updates was the addition of nivolumab to the NCCN treatment algorithm for non-small cell lung cancer. 

And now with the AACR and NCCN annual meetings behind us, we arrive at the “main event” of oncology conferences, the 2015 ASCO Annual Meeting. In next month’s issue, we’ll have the latest on the checkpoint agents and all the other treatments and strategies that make waves at ASCO. As always, thank you for reading. 

Click here, to view all of the findings from AACR

Immune checkpoint blockade strategies were a central focus of much of the key data presented at AACR.

Checkpoint Inhibitors Shine Across Tumor Types at AACR

James P. Allison, PhD, who pioneered the checkpoint blockade strategy that led to the development of ipilimumab (Yervoy) and other immunotherapy agents, was recently honored with two prestigious awards: the Science of Oncology Award from ASCO and the Pezcoller Foundation—AACR International Award for Cancer Research.

The awards recognize not only his research accomplishments, but also the growing influence the field of immunotherapy has gained in the past few years, said Allison, a professor and chair in the Department of Immunology at the University of Texas MD Anderson Cancer Center, in an interview with 

“I am honored to be recognized by my peers for both of these prestigious awards,” said Allison, who also received a Giants of Cancer Care award from 

 in 2014. “But more importantly, the fact that two organizations recognized someone for an advancement in immunotherapy really acknowledges that the field is here to stay now, and skeptics should take notice. These awards are not just about me, they are about everyone over the past few decades that has been working to use the immune system to treat cancer.”

Allison himself has been dedicated to understanding the immune system, and the specific role T cells play in it, for most of his career. In 1982, while he was working at MD Anderson Cancer Center (then named University of Texas System Cancer Center), he became the first scientist to determine how T cells recognize alien proteins within the body.

While continuing his research into T-cell response mechanisms, Allison discovered that blocking signaling of the immune-checkpoint protein CTLA-4 improved antitumor immune responses. His lab went on to develop an antibody against CTLA-4, which inhibited tumor growth in mice. This discovery led to the development of ipilimumab, which blocks the inhibitor function of CTLA-4, allowing T cells to attack and eliminate cancer cells. In 2011, ipilimumab became the first immune checkpoint inhibitor approved by the FDA when it was authorized for use as a treatment for patients with advanced melanoma.

The discovery of the immune checkpoint blockade strategy and the subsequent approval of ipilimumab have changed the course of Allison’s career.

“Before, my work was almost always about understanding the mechanisms of T cells and not specifically focused on cancer,” said Allison. “But I was interested in using the immune system to fight cancer, and whenever we found something unique I would try to investigate how it could be applied to cancer. The CTLA-4 discovery was the one that really showed the most promise. Since then, 80% of my lab has been focused on doing experiments related to CTLA-4 blockade.”

Ipilimumab has shown significant promise in the treatment of melanoma. Also, it is being investigated in several other tumor types.

In the trial that led to the approval of ipilimumab for patients with unresectable or metastatic melanoma who had received at least one prior systemic treatment, overall survival (OS) was longer with ipilimumab alone compared with the experimental tumor vaccine gp100 (HR = 0.66; 

 = .0026). Patients treated with ipilimumab alone had a median OS of 10 months, while those treated with gp100 had a median OS of 6 months.

The trial also demonstrated a statistically significant improvement in OS for patients treated with the combination of ipilimumab plus gp100 compared with patients who received gp100 alone (HR = 0.68; 

Recently, the FDA accepted a supplemental biologics license application for ipilimumab as an adjuvant treatment of patients with stage III melanoma at high risk of recurrence following complete resection. The FDA is scheduled to make a decision on adjuvant ipilimumab by October 28, 2015.

Combination therapies with ipilimumab are also showing promise. The phase II CheckMate-069 trial, which was recently presented at the 2015 AACR Annual Meeting, showed that nivolumab (Opdivo) plus ipilimumab delayed disease progression by 60% compared with ipilimumab alone in patients with advanced melanoma. The checkpoint inhibitor combination had an overall response rate (ORR) of 61% in a subgroup of 

Multiple clinical trials have also been investigating ipilimumab with the oncolytic virus T-VEC, which was recently recommended for approval by the FDA’s Oncologic Drugs Advisory Committee (ODAC) and Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC).

One phase Ib study showed an ORR with the combination of T-VEC and ipilimumab was 56% in patients with advanced melanoma.

Allison believes ipilimumab has the most potential when used in combination with other agents, but additional research is required before this can truly be successful.

“I think it is even more important now to understand the mechanism of these drugs in patients as it becomes clear that we have to start combining them,” said Allison. “We really have to know how things work if we are going to combine. We don’t want to give two things together that do the exact same thing or oppose each other. It is amazing to me how little understanding there is on the mechanisms of some of the up-and-coming checkpoint inhibitors.”

Allison’s lab is aiming to combat this lack of understanding by investigating checkpoint inhibitor combinations by pairing them with each other, as well as with oncologic viruses, radiation, targeted therapies, and chemotherapy.

He is also interested in checkpoint inhibitor combinations that can be used to treat tumors with lower mutation loads, such as those seen in kidney and prostate cancer.

“Checkpoint inhibitors have been mostly used in cancers with high mutation loads such as melanoma and lung cancer,” said Allison. “But in those cancers with lower mutational loads, there are still responses. I think we need to understand how we can use ipilimumab, for example, to lower the threshold so you can get responses to antigens that aren’t seen by the immune system unless you can target CTLA-4. That is the next challenge.”

In addition to his recent awards, Allison’s other accolades include the inaugural AACR-Cancer Research Institute Lloyd J. Old Award in Cancer Immunology, the Canada Gairdner Foundation Award, the Breakthrough Prize in Life Sciences, the Lifetime Achievement Award of the American Association of Immunologists, the Centeon Award for Innovative Breakthroughs in Immunology, and the William B. Coley Award for Distinguished Research in Basic and Tumor Biology from the Cancer Research Institute.

Allison has been elected to numerous societies, including the National Academy of Sciences. He is also a fellow of the Institute of Medicine, the American Association for the Advancement of Sciences, and the American Academy of Microbiology.

Allison served as chair of the Immunology Program at Memorial Sloan Kettering Cancer Center in New York before joining MD Anderson Cancer Center in 2012.

James P. Allison, PhD, was recently honored with two prestigious awards: the Science of Oncology Award from ASCO and the Pezcoller Foundationâ€“AACR International Award for Cancer Research.

May 2015 | Oncology & Biotech News

2015 NCCN Guideline Updates: New Recommendations for Clinical Practice

Checkpoint Inhibitors Shine Across Tumor Types at AACR

ASCO, AACR Honor Immunotherapy Pioneer James Allison