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He was once laughed at for pouring his talent into the “reviled” field of oncology, but Larry Norton, MD, said he was driven by his passion to learn about cancer. In fact, even now, seldom do his thoughts or actions stray far from the problem of how to cure this disease. “There’s a constant churn of activity toward making a difference— my own research, teaching, taking care of patients,” said Norton, who is deputy physician in chief for breast cancer at Memorial Sloan Kettering (MSK) Cancer Center, New York, New York, where he also serves as medical director of the Evelyn H. Lauder Breast Center.

His dedication moves full speed ahead almost all of the time, and when Norton is not engaged in fighting the battle against cancer, he is a husband and father who unwinds by hiking in Vermont, skiing with his wife, and going to the theater. He is also very passionate about music.

Norton, who is conservatory trained, was initially interested in becoming a professional musician. He can play multiple instuments, from the keyboard to the guitar to woodwinds. In 2010, he even hit the stage for a duet with Sir Elton John at a breast cancer charity event. Elton played the piano, Norton the harmonica—a performance the celebrated oncologist and musical talent says he will never forget.

As a youth, Norton knew the extremes of environment that New York has to offer. He lived in the Bronx, the poorest borough of New York City, and Valley Stream, a suburb of wealthy Nassau County in Long Island. His father was a journalist and his mother a secretary. Somehow, the bug for medicine flourished in the younger generation. His sister became a pediatric radiologist and is now retired. But before medicine even crossed his mind, Norton earned a living as a truck driver by delivering fishing tackle.

When the 1960s arrived, Norton was a struggling musician. He grew his hair long and could be found playing the bongos and saxophone in Greenwich Village. The Vietnam War was raging in the background. It was then that the study of medicine attracted Norton, and he nourished that interest by going to college. He did not serve in Vietnam, but during the war he did serve in the US Public Health Service after finishing medical school.

It was during a summer rotation at Roswell Park Memorial Institute in Buffalo, New York, when he was taken under the wing of William Regelson, MD, that something happened that made Norton decide that oncology was the right choice for him. “I was just a college student at the time and [Regelson] said to me, ‘I want to show you something,’ and he brought me to see a patient who had a pelvic tumor that had erupted through the pelvis up to the skin. It was this big, ugly, horrible-looking cancer. Bleeding, smelly—really the kind of nightmare that cancer can be,” Norton recalled.

Over that summer, Norton watched the tumor melt away under Regelson’s care. The patient’s skin closed and healed. She was able to be discharged and treated at an outpatient facility.

“I thought it was the most magical thing I had ever seen in my life,” Norton said. “It was like I saw this monster that was devouring this patient and a medicine—carefully chosen to work in this setting&mdash;was making this obviously fatal process just go away. Everything about that experience was something that I knew I had to do, and that convinced me that I belonged in medicine and not in music. The fact is that it was the great science, the great clinical thinking, and Regelson’s intuition&mdash;I mean everything good about the world was in that one case. And that was my revelation.”

When Norton entered the field of oncology, it was overshadowed by pessimism. Few believed that oncology would become a promising branch of medicine unto itself. In medical school, Norton’s mentor once said to him, “Larry, you’re so good with your hands. You belong in surgery. It’s surgery that really helps people. You don’t want to get involved in drug treatment of cancer. It’s never going to go anywhere. We can’t kill cancer with drugs.”

But Norton said he was encouraged by the pioneering spirit of some of the founding doctors of the field, such as Emil “Tom” Frei III, James Holland, Vincent DeVita Jr, and Paul Carbone, who trained him and made the field of oncology more and more attractive to him. “Oncologists are very special people. You’re dealing with very severe illness and it’s not always a success, but you’re always dedicated to making things better,” said Norton. “We are making progress faster and faster.”

Norton received his bachelor’s degree with highest distinction from the University of Rochester and his medical degree from the College of Physicians and Surgeons of Columbia University. He trained in medicine and medical research at Albert Einstein College of Medicine and the National Cancer Institute (NCI).

Besides his work at MSK, he is a founder and scientific director of the Breast Cancer Research Foundation. Although Norton is known across the country as a top investigator in breast cancer, he said he is interested in all cancers. He studied lymphoma before breast cancer, and most recently, he conducted trials in pancreatic cancer.

Based on mathematical work that he had done with Richard Simon, DSc, chief of the Biometric Research Branch at the NCI, Norton developed the concept of “dose density,” the successful application of which has proven that schedule, not just the right drug, is important in the treatment of cancer. He has also worked on genetic testing for breast cancer and the development of several effective agents, including paclitaxel (Taxol) and trastuzumab (Herceptin).

Norton has held national level titles in oncology, including chair of the Breast Committee of the NCI’s Cancer and Leukemia Group B and president of ASCO from 2001 to 2002. He also was appointed by former President Bill Clinton to serve on the National Cancer Advisory Board.

A man of many achievements, Norton refuses to name what he feels is his greatest contribution to the field of oncology—he said that’s for other people to decide. “I’ve been involved in a lot of things that have turned out to help people,” he said. “Every single one of them was a collaborative effort. The thing that I am happiest about in my career is my contact with people my junior, who have not only worked together with me to accomplish the things that needed to be accomplished, but who have grown into substantial investigators and wonderful physicians on their own. It’s my opportunity to train that excites me the most.”

There is always a new, exciting development in the oncology world, but Norton warns that neither he nor anyone else knows it all.

Two areas where oncologists are excited currently are precision medicine and immuno-oncology. Norton reminds fellow oncologists that it’s important to develop an accurate understanding of the mechanisms of these approaches. “Find the germ of the truth that’s within it,” explained Norton. “It’s how to use the drugs better with precision medicine and immuno-oncology and how to use the power of the immune system, in combination with other ways of affecting the cancer cell, by making it more amendable.”

He describes 2 natural responses to the excitement: either jumping on the bandwagon or rejecting it. Both, he said, are your enemies. One of Norton’s favorite sayings goes as follows: “It’s not the things you don’t know that get you in trouble. It’s the things you know for sure that turn out to be wrong.”

“My whole career in oncology has been dealing with the issue where everybody knows something is true that turns out not to be,” he said. “That’s what slows us down. I think people have to keep an open mind and accept new data, but be open to changes.” One of those changes is bringing the power of mathematics and chemistry into cancer, something he hopes former Vice President Joe Biden’s Cancer Moonshot program will do. Norton, who attended the summit in Washington, DC, in June 2016, said mathematicians should be engaged in the process.

“We have good engineering for airplanes, good engineering for automobiles, and good engineering for TV sets,” he said. “We don’t have good engineering for biology. We have to understand biology better from an engineering point of view, which means a mathematical point of view. I’m hoping this will be part of the Moonshot’s progress.”

The Moonshot is intended to achieve 10 years’ worth of progress in just 5 years, something Norton feels can be accomplished as long as people are willing to push forward, generate new ideas with hard work, and support creativity.

After decades of pushing for that progress himself, Norton said it isn’t credit that he’s seeking, but rather victory over cancer. “It’s seriously of less consequence to me to be the one that does it than to be there when it happens. My whole career has been focused on doing everything that I possibly can to accomplish that goal. So, it’s not just research, and it’s not just patient care; it’s not just teaching, it’s not just administration, it’s not just political activity. But it is everything that I can contribute in the time that I have on this earth to do it.”

Articles

He was once laughed at for pouring his talent into the “reviled” field of oncology, but Larry Norton, MD, said he was driven by his passion to learn about cancer.

How Elbow Grease and Inspiration Forged a Winning Career

Investigators are looking into a combination of immunotherapy agents for patients with unresectable hepatocellular carcinoma (HCC), for whom there are limited treatment options in the first line. Researchers think the combination of durvalumab (Imfinzi), a PD-L1 inhibitor, and tremelimumab, a CTLA-4 inhibitor, may be the answer to this clinical need.

According to the National Comprehensive Cancer Network guidelines, the recommended first-line treatments for patients with untreated HCC who are not candidates for transpant include locoregional therapy with ablation, arterially directed therapies, or external beam radiation therapy, or chemotherapy.

 Sorafenib (Nexavar) is the only systemic therapy currentaly approved for patients with unresectable HCC in the first line.

 In 2017, the FDA approved regorafenib (Stivarga) and nivolumab (Opdivo) as second-line treatment options for patients who had previously received sorafenib.

The randomized, multicenter, phase III HIMALAYA trial (NCT03298451) will have 4 arms for patients with previously untreated, unresectable HCC: 2 regimens of durvalumab plus tremelimumab combination therapy, durvalumab monotherapy, and sorafenib monotherapy (FIGURE). The investigators are using overall survival (OS) as the primary endpoint, with time to progression, progression-free survival (PFS), and objective response rate (ORR) as secondary endpoints.

Figure. Durvalumab Plus Tremelimumab in First-Line Unresectable HCC

Prior studies have demonstrated that durvalumab and tremelimumab are active in HCC. Patients who are eligible for the HIMALAYA phase III trial must have had no prior systemic therapy for HCC and have an ECOG performance status of 0 or 1. “This is a population that you care for by using systemic therapy, because there are no other eligible things they can do. They are not eligible for surgeries or local therapy, and as such, they need something that will take care of their disease,” said Ghassan K. Abou-Alfa, MD, medical oncologist and principal investigator for the trial at Memorial Sloan Kettering Cancer Center in New York, New York.

Durvalumab is a human IgG monoclonal antibody and PD-L1 inhibitor that binds to PD-1 and CD80, allowing T cells to recognize and kill tumor cells without the need for cytotoxic activity that is antibody-dependent and cell-mediated.

 Tremelimumab has a similar mechanism, inhibiting CTLA-4, a cell surface receptor that is expressed primarily on activated T cells.

 According to Abou-Alfa, the combination of durvalumab and tremelimumab has a lot of promise in this patient population. The hypothesis is that, due to the way the immune system functions, inhibiting CTLA-4 will increase the activity of the PD-L1 inhibitor.

“The combination has shown a clear synergy. The anti-CTLA-4 drug will work actively on some of the immune molecules in the lymph nodes and further promote activity of the anti-PD-1 drug, which will affect the tumor itself,” Abou-Alfa explained. “There is a very pure science that tells us that this is, by definition, a more efficient way of getting the response that we are looking for.”

In a prior, phase I/II study, 40 patients with HCC were evaluable to assess the safety and tolerability of the drug combination. The confirmed ORR was 17.5%, with 7 patients having a partial response. The ORR on the basis of confirmed and unconfirmed response was 25% (10/40 patients). The median time to response was 8 weeks (range, 7.6-24.0 weeks).

The combination was also generally well tolerated and exhibited no unexpected safety signals in patients with unresectable HCC. The most common treatment-related adverse events (trAEs) included fatigue (27.5%),  increased alanine aminotransferase (ALT; 20%), pruritus (22.5%), and increased aspartate aminotransferase (AST; 17.5%). The most common grade ≥3 trAE was asymptomatic increased AST (10%). At the time the results were presented, 24 patients had discontinued treatment: 3 due to trAEs (grade 3 pneumonitis, grade 3 colitis/diarrhea, and asymptomatic grade 4 elevated AST and ALT); 16 due to progressive disease; and 4 due to death unrelated to treatment (cardiac arrest, variceal bleed, progressive disease, and probable HCC rupture). One patient entered hospice care.

The 2 drugs are being developed by AstraZeneca, based in Wilmington, Delaware.

Hepatobiliary cancers version 4.2017. NCCN clinical practice guidelines in oncology. National Comprehensive Cancer Network. nccn.org/ professionals/physician_gls/pdf/hepatobiliary.pdf. Published October 9, 2017. Accessed January 17, 2018.

FDA expands use of Stivarga to treat liver cancer [press release]. Silver Spring, MD: US Food and Drug Administration; April 27, 2017. fda. gov/NewsEvents/Newsroom/PressAnnouncements/ucm555608. htm. Accessed January 17, 2018.

FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib [press release]. Silver Spring, MD: US Food and Drug Administration; September 22, 2017. fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm577166.htm. Accessed January 17, 2018.

Durvalumab (MEDI4736, IMFINZI). NIH Division of Cancer Treatment and Diagnosis website. https://nciformulary.cancer.gov/available_ agents/Durvalumab.htm/. Updated June 30, 2017. Accessed January 17, 2018.

Tremelimumab (CP-675,206). NIH Division of Cancer Treatment and Diagnosis website. https://nciformulary.cancer.gov/available_agents/ Tremelimumab.htm. Updated June 30, 2017. Accessed January 17, 2018.

Kelley RK, Abou-Alfa GK, Bendell JC, et al. Phase I/II study of durvalumab and tremelimumab in patients with unresectable hepatocellular carcinoma (HCC): phase I safety and efficacy analyses. Presented at: 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract 4073. https://meetinglibrary.asco.org/record/147423/abstract.

Investigators are looking into a combination of immunotherapy agents for patients with unresectable hepatocellular carcinoma, for whom there are limited treatment options in the first line.

Immunotherapy Combination Explored in Unresectable HCC

Investigators looking for a superior means of testing for response to therapy in metastatic castration-resistant prostate cancer (mCRPC) said they found the solution in a study of circulating tumor cells (CTCs). These markers proved to be better, earlier predictors of response than prostate-specific antigen (PSA) tests.

The findings come from an analysis of results from 5 phase III trials that enrolled a total of 6081 patients: COU-AA-301, AFFIRM, ELM-PC 5, ELM-PC 4, and COMET-1.1 Investigators evaluated CTC activity at baseline and after 13 weeks, theorizing that because various tumors release CTCs into the bloodstream and have been associated with tumor metastasis, CTC declines would reliably indicate response and overall survival (OS).

Historically, clinicians have depended on PSA levels, such as maximal percent or percent at a fixed point in time, to determine treatment efficacy in mCRPC, but this has not been a strong indicator of OS, the investigators wrote in their report. Radiographic measures and changes in measurable disease by RECIST also have been insufficient as prognostic indicators that could aid clinicians and accelerate the pace of clinical trials.

Investigators examined 8 endpoints across the 5 prospective randomized phase III trials. The evaluable cohorts from each trial were patients who survived at least 13 weeks and had a recorded baseline CTC or PSA value. The response measures were CTC0 (patients with CTC count ≥1 at baseline and 0 at week 13), CTC conversion (patients with CTC count ≥5 at baseline and ≤4 at week 13), percent change in CTC (patients with CTC count ≥5 at baseline and a 30%, 50%, or 70% decline from baseline to week 13), and percent change in PSA (PSA level ≥5 ng/mL at baseline and a 30%, 50%, or 70% decline from baseline to week 13). Patients who achieved these biomarker thresholds were recorded as responders.

At 13 weeks, the ability to differentiate the survival outcomes for week 13 responders and nonresponders was greatest using the CTC0 and CTC conversion endpoints. An absence of CTCs after treatment or finding that CTC values had dropped from above to below the threshold of 5 CTCs “provided greater discrimination for patient survival than the percent change in CTC or PSA response endpoints,” investigators wrote.

They used a weighted C-index to estimate the probability of longer survival for responders. A value closer to 1 signified higher discriminatory power, and a C-index score closer to 0.5 would indicate little discriminatory power—that responders and nonresponders would have nearly identical survival curves. The average weighted C-index for the CTC0 and CTC conversion response endpoints was 0.81 and 0.79, respectively (FIGURE). The average weighted C-indices for the percent change CTC and PSA endpoints ranged from 0.71 to 0.74.

Figure. CTC Measures Prove Better Determinants of Response

“To develop new therapeutic agents requires the ability to determine whether a systemic therapy has clinical benefit (eg, improving how a patient feels and functions and how long the patient survives),” corresponding author Howard I. Scher, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, and coauthors wrote.

“The CTC0 endpoint is an indicator that cancer cells that were circulating in the blood are no longer detectable, an easily recognized outcome that is clinically meaningful to patients. It is an outcome that occurs shortly after treatment initiation, providing researchers and practitioners with objective and reliable evidence that the therapy being administered has altered the patient’s prognosis in a favorable way. Taken together, the results of this study support the use of CTC0 as a response endpoint in earlyphase clinical trials,” the authors wrote.

The highest median baseline CTC and PSA values were seen in COMET-1, which enrolled patients who received at least 2 therapies—a taxanebased chemotherapy and either abiraterone (Zytiga) or enzalutamide (Xtandi)&mdash;and whose disease had progressed. The lowest baseline CTC and PSA values occurred in ELM-PC 4, which enrolled patients who had not received any prior proven therapy for mCRPC. The other 3 trials enrolled patients who had previously received only 1 therapy&mdash;docetaxel&mdash;and their baseline values fell in the middle region.

In addition to allowing greater discrimination, the CTC0 and CTC conversion response endpoints were more robust across the 5 trials, investigators found. Importantly, investigators found that CTC0 was applicable to a significantly higher percentage of patients than CTC conversion. Overall, 75% of eligible patients were evaluable for the CTC0 endpoint compared with 51% for the CTC conversion endpoint.

Another reason investigators expressed greater conviction in the predictive power of CTC values is that PSA levels can be influenced by therapy. Investigators said 4 of the trials studied included hormonal agents that can “modulate PSA levels independent of an effect on cell kill,” which they said compromises PSA testing as an indicator of therapy efficacy.

Use of the CTC0 endpoint improved the ability to evaluate response from 29% to 71% across the 5 trials, the investigators said. “This increase in the percent of evaluable patients, 71% in the first-line, 46% in the second-line, and 29% in the third-line setting, significantly enlarges the patient population, enabling more rapid trial accrual and shorter drug evaluation times in trials while providing greater reliability in studies of treatment efficacy,” the authors wrote.

Heller G, McCormack R, Kheoh T, et al. Circulating tumor cell number as a response measure of prolonged survival for metastatic castration-resistant prostate cancer: a comparison with prostate-specific antigen across five randomized phase III clinical trials [published online December 22, 2017].

Investigators looking for a superior means of testing for response to therapy in metastatic castration-resistant prostate cancer said they found the solution in a study of circulating tumor cells.

CTCs Demonstrate Predictive Power in Prostate Cancer

The past decade of drug discovery has brought a dramatic expansion in the number of new therapies to treat patients with advanced or metastatic melanoma in 2 modalities: checkpoint blockade immunotherapies and molecularly targeted drugs. In both areas, these therapeutic categories have grown from single-agent regimens into combination strategies.

Now, investigators are seeking to determine whether triplet regimens that combine an immunotherapy that targets the PD-1/PD-L1 pathway with small molecules that inhibit BRAF and MEK signaling would be more effective than single- or dual-agent approaches.

The rationale for the multipronged strategy has been building for several years, according to Antoni Ribas, MD, PhD, a leading melanoma investigator who discussed clinical trial findings at recent conferences. Ribas, a 2015 Giants of Cancer Care

 award winner, is a professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles.

Overall, approximately 65% of melanomas harbor mutations that activate signaling in the RAS/RAF/ MEK/ERK pathway, Ribas has observed.1 These mutations cause aberrations within the melanoma cell that in turn spark interactions with T lymphocytes whose activity is controlled by immune checkpoints such as PD-1 (FIGURE).

Figure. Merging Strategies in Melanoma Therapy

The triplet strategies combine a monoclonal antibody targeting either PD-1 or PD-L1 with drugs that inhibit BRAF and MEK kinases, which are key components of the protein signaling pathway within the melanoma cell.

The safety and efficacy of such combinations have been explored in phase I studies, Ribas noted during a presentation at the Ninth World Congress of Melanoma, held in Brisbane, Australia, in October 2017. The regimens proved to be safe, and most patients had either stable disease or a response, a level of efficacy that Ribas called “surprising.” In these studies, very few patients did not demonstrate some level of clinical benefit, he said. These early results led to several ongoing later-stage studies, which are now enrolling participants, representing a potential new standard of care on the horizon (TABLE).

Table. Selected Melanoma Trials Exploring 3-Drug Combinations

“Three phase I trials attest to the overall safety of combined full-dose therapy with a BRAF and a MEK inhibitor with anti—PD-1/PD-L1 and provide early encouraging evidence of combined efficacy,” Ribas said. “There are toxicities, but they are usually responsive to stopping the targeted therapies for a little bit of time and then restarting.”

In preclinical models, the triplet combination of dabrafenib (Tafinlar), trametinib (Mekinist), and pembrolizumab (Keytruda) demonstrated superior antitumor activity in mouse models of 

 Dabrafenib is a BRAF inhibitor, trametinib is a MEK inhibitor, and pembrolizumab targets PD-1.

Mechanistically, treatment with BRAF plus MEK inhibition was found to increase T-cell accumulation at the site of the tumor. “The triple therapy, but also the doublet of the BRAF and MEK inhibitor, had the highest accumulation and expansion of the T-cell intratumor,” Ribas noted.

In RNA sequencing data, the BRAF/MEK combination was found to increase CD8, interferon gamma, granzyme B, and the PD-1:PD-L1 ratio, resulting in a more immunogenic microenvironment. Additionally, BRAF inhibition was found to increase PD-L1 expression.

“Those who received the doublet of dabrafenib and trametinib had increased immune signaling in the tumor,” Ribas said. “Another thing that was important was an upregulation of PD-L1 with dabrafenib inside of the tumor and not in the spleen. It was localized to where the targeted therapy has activity.”

These triplet regimens are among the emerging melanoma combinations that are generating excitement throughout the field, noted Michael A. Postow, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, in an interview with 

. “The world is moving to 2- and 3-drug combinations and, if those show benefit in randomized studies, we will all be happy about that,” he said. “We need to keep in mind that we should be conservative with our thinking until we have the data to support what could be more expensive and toxic regimens.”

In the KEYNOTE-022 study, which was updated at the ESMO 2017 Congress,

 the combination of pembrolizumab, dabrafenib, and trametinib was assessed in 15 patients with metastatic 

-mutated melanoma. The confirmed response rate was 67%, and the confirmed plus unconfirmed response rate was 73%. This included a complete response (CR) rate of 13%.

The median duration of response was not yet reached at the time of assessment (95% CI, 1.6-26.5 months). After a median follow-up of approximately 20 months, 7 of the 11 (64%) responding patients had not yet progressed, including the 2 patients with a CR. Of those with a CR, 1 continued to receive the triplet, and the other had discontinued dabrafenib and trametinib at 18 months and continued pembrolizumab monotherapy.

There were no late or unexpected toxicities with the triplet therapy during the follow-up period. Grade 3/4 treatment-related adverse events (AEs) were experienced by 73% of patients, with the most common being alanine aminotransferase increase (20%), aspartate aminotransferase increase (20%), pyrexia (20%), gamma-glutamyltransferase increase (13%), neutropenia (13%), and white blood cell count decrease (13%). There were no treatment-related deaths. Due to AEs, 27% of patients discontinued at least 1 of the therapies.

A randomized phase II portion of the KEYNOTE022 study is ongoing (NCT02130466), with a primary endpoint of progression-free survival (PFS). This portion of the study has enrolled 120 patients, and results are expected in the second quarter of 2018, according to Ribas.

Two phase III studies are exploring other combinations of BRAF and MEK inhibition with a PD-1 or PD-L1 inhibitor. The TRILOGY trial is investigating the MEK inhibitor cobimetinib (Cotellic) plus the BRAF inhibitor vemurafenib (Zelboraf) and the PD-L1 inhibitor atezolizumab (Tecentriq), and the COMBI-i trial is examining dabrafenib plus trametinib with the investigational PD-1 inhibitor spartalizumab (PDR001), which is being developed by Novartis.

In the TRILOGY trial, the triplet will be compared with cobimetinib, vemurafenib, and placebo for patients with previously untreated 

-mutant metastatic melanoma. The study, which is currently accruing patients, hopes to enroll 500 participants, and the primary endpoint is PFS. Results are expected by the end of 2019 (NCT02908672).

The COMBI-i trial has a similar schema, with the immunotherapy-containing triplet being compared with dabrafenib, trametinib, and placebo. The trial is currently accruing with a goal of enrolling about 500 patients. The primary endpoint is PFS, and the results are expected to report in the fourth quarter of 2020, Ribas said (NCT02967692).

Additionally, several smaller phase I trials are exploring novel combinations. The National Cancer Institute is testing several experimental regimens in an 8-arm trial that seeks to enroll 40 participants with metastatic or unresectable melanoma (NCT01940809). The regimens include dabrafenib plus trametinib followed by ipilimumab (Yervoy), a CTLA-4 checkpoint inhibitor; dabrafenib plus trametinib followed by both nivolumab (Opdivo), a PD-1 inhibitor, and ipilimumab; and trametinib or dabrafenib with nivolumab plus ipilimumab.

In a phase Ib study, Genentech is examining the combination of atezolizumab with vemurafenib and cobimetinib in an expansion cohort of patients with 

-mutant metastatic melanoma who have experienced disease progression after receiving prior checkpoint inhibitor therapy (NCT01656642). The study, which is active but not recruiting participants, has an estimated completion date of November 2018, according to ClinicalTrials. gov. Meanwhile, MedImmune, which is part of AstraZeneca, is conducting a phase I/II study with a cohort in which participants received dabrafenib plus trametinib and durvalumab (Imfinzi), a PD-L1 inhibitor (NCT02027961). The trial also is active but no longer recruiting participants.

Although the prospect of triplet therapy for patients with melanoma remains experimental, dual regimens have become the standard of care in recent years.

The combination of nivolumab plus ipilimumab was initially approved in October 2015 to treat patients with 

 V600 wild-type, unresectable or metastatic melanoma, which was based on findings from the phase II CheckMate-069 study. This indication was expanded in January 2016 to include patients with 

In updated analyses presented at the 2017 American Association for Cancer Research Annual Meeting, the combination was associated with a 12% reduction in the risk of death versus nivolumab monotherapy in patients with treatment-naïve advanced melanoma. The median overall survival (OS) was not reached in the nivolumab/ipilimumab arm or for patients who received nivolumab alone and was 20 months for those who were treated with ipilimumab.

 Toxicities have been a concern with the combination. Grade 3/4 treatment-related adverse events were reported in 58.5% of patients in the combination arm, 20.8% in the nivolumab arm, and 27.7% in the ipilimumab arm.

In 2014, the FDA granted accelerated approval to the combination of dabrafenib and trametinib for patients with unresectable or metastatic melanoma with a 

 V600E or V600K mutation after demonstrating a higher objective response rate of 76% and a duration of 10.5 months compared with 54% and 5.6 months, respectively, for singleagent dabrafenib. The following year, the agency approved vemurafenib and cobimetinib for the same patient population based on gains over single-agent vermurafenib in progression-free survival (12.3 vs 7.2 months, respectively) and median OS (not reached vs 17 months).

Meanwhile, the FDA is scheduled to make a decision by June 30, 2018, on a new drug application for the combination of encorafenib, a BRAF inhibitor, and binimetinib, a MEK inhibitor. Dual use of the experimental therapies demonstrated an OS improvement compared with single-agent vemurafenib, according to updated findings from the phase III COLUMBUS trial.

The combination of encorafenib at 450 mg daily and binimetinib at 45 mg twice daily reduced the risk of death by 39% versus vemurafenib monotherapy (HR, 0.61; 95% CI 0.47-0.79; P <.001). The median OS was 33.6 months versus 16.9 months, respectively.

McArthur GA, Ribas A. Targeting oncogenic drivers and the immune system in melanoma.

2013;31(4):499-506. doi: 10.1200/ JCO.2012.45.5568.

Hu-Lieskovan S, Mok S, Homet Moreno B, et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. 

 2015;7(279):279ra41. doi: 10.1126/scitranslmed.aaa4691.

Ribas A, Hodi FS, Lawrence D, et al. KEYNOTE -022 update: phase 1 study of first of first -line pembrolizumab plus dabrafenib and trametinib for BRAF-mutant advanced melanoma. Abstract presented at: ESMO 2017 Congress; September 8-12, 2017; Madrid, Spain. Abstract 1216O. cslide. ctimeetingtech.com/library/esmo/browse/search/2eda#2Bb3U0Ka.

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Overall survival results from a phase III trial of nivolumab combined with ipilimumab in treatment-naïve patients with advanced melanoma (CheckMate-067). Abstract presented at: 2017 AACR Annual Meeting; April 2-5, 2017; Washington DC. Abstract CT075. abstractsonline.com/pp8/#!/4292/presentation/12341.

Encorafenib and binimetinib combination treatment demonstrates 33.6 month median overall survival (OS) in patients with BRAF-mutant melanoma in phase 3 COLUMBUS trial [press release]. Boulder, CO, and Castres, France: Array BioPharma Inc; February 6, 2018. prn.to/2GU3BdI. Accessed February 6, 2018.

The past decade of drug discovery has brought a dramatic expansion in the number of new therapies to treat patients with advanced or metastatic melanoma in 2 modalities: checkpoint blockade immunotherapies and molecularly targeted drugs.

Triplet Therapy May Be on the Horizon for BRAF-Mutant Melanoma

The use of next-generation sequencing (NGS) to diagnose cancers and guide therapy decisions is expanding as more therapies are linked to genomic abnormalities. But advances in molecular testing face headwinds in the near term as clinicians struggle to manage the wealth of data produced by tests and payers balk at covering expensive assays backed by sparse evidence for improved outcomes.

The debate over the future of testing centers on broad-spectrum panels that evaluate tumor tissue for dozens or hundreds of genes at once, as opposed to standard in vitro diagnostics that test for a single aberration such as HER2, to predict response to trastuzumab (Herceptin) in breast cancer, and EGFR, to guide the use of tyrosine kinase inhibitors for lung cancer. Spurred by a 2013 US Supreme Court decision that genes are not patentable, along with the plunging cost of sequencing and the convenience of using 1 tissue sample to check for multiple abnormalities, private labs, academic hospitals, and cancer centers have developed panels that examine as many as 500 genes at once in the last 5 years.

The growing significance of NGS was illustrated in December 2017 by the first FDA approval of a large panel, Foundation Medicine’s FoundationOne CDx (F1CDx), which detects mutations in 324 genes and 2 genomic signatures in any tumor type. CMS conducted a parallel review that led to a proposal for limited Medicare coverage of the test.

Last year, the FDA also granted authorization for MSK-IMPACT, a 468-gene assay developed by Memorial Sloan Kettering Cancer Center (MSK) in New York, New York. The decision created a new pathway for regulatory analysis of large gene testing panels (FIGURE). The authorization could promote test adoption and cooperation with pharmaceutical companies, possibly payer coverage as well, while potentially paving the way for future approvals of other similar products.

Figure. FDA's Approach to NGS Tumor-Profiling Tests

However, the federal review process also underscores the hurdles that laboratories face as they seek broader acceptance of their products. Although testing companies and oncologists have applauded CMS for addressing the question of NGS coverage, many have also expressed dismay at the accompanying restrictions. Under the draft policy, CMS would only pay for tests that are FDA approved or cleared or are being used in National Cancer Institute-sponsored trials and would not cover retesting using the same test, among other limitations.

The policy specifically mentions 5 tests that the FDA has approved so far (TABLE). Additionally, the draft identifies the patient population elgible for test coverage as those who have recurrent, metastatic, or advanced stage IV cancer.

Table. FDA-Approved NGS Tumor-Profiling Tests

“What it would basically do is deny payment for the vast majority of assays currently being offered, unless they follow our lead and obtain FDA clearance. Even then, it’s a rather restrictive subset of cancer types that would be covered,” said David S. Klimstra, MD, chair of the Department of Pathology at MSK. He said he is also concerned that CMS’ proposed policy would essentially expand FDA authority over the assays without the usual congressional oversight. Such assays are currently considered laboratory-developed tests (LDTs) that do not need FDA approval.

“The draft policy is also only directed toward next-generation sequencing assays,” Klimstra noted. “CMS would continue to support existing payment structures for single-gene assays, which are less broad-spectrum, less tissueefficient, and less sensitive, but it would refuse to pay for the best assays out there. In a sense, that is a clear step backward.”

The dominant technologies for molecular marker testing include immunohistochemistry, fluorescence in situ hybridization, and NGS methods. Use of all of these types of assays is increasing due to the expansion of targeted therapies, but the number of multigene NGS tests ordered annually appears to be rising particularly quickly. NGS assays represented 27% of molecular tests in the National Institutes of Health’s Genetic Testing Registry in February 2016, up from 10% 2 years earlier.

 Panels of at least 5 genes accounted for 16% of NGS tests. In addition, the number of oncology genetic tests of all types in the registry had jumped 153% over 12 months.

Multigene panels arose in response to the discovery of various molecular pathways that may be active in a tumor site. At Moffitt Cancer Center in Tampa, Florida, pathologists began developing larger panels when it became necessary to test for multiple abnormalities in non—smallcell lung cancer (NSCLC), including 

, said Anthony M. Magliocco, MD, FRCPC, FCAP, chair of the Department of Anatomic Pathology at Moffitt.

“You have to test several different genes simultaneously to be able to determine the correct treatment for these patients. The test gets used very routinely for patients with advanced lung cancer.”

Thermo Fisher’s Oncomine Dx Target Test, which evaluates 23 genes associated with NSCLC and serves as a companion diagnostic for 1 combination regimen and 2 single-agent therapies, became the first NGS-based panel to win FDA approval last year. The company says it is working with more drugmakers to add indications for the test.

Labs are constantly assembling new panels or expanding existing ones. Moffitt has a 55-gene myeloid malignancy panel and a 170-gene solid tumor panel; the University of California San Francisco Medical Center (UCSF) has a 500-gene test, one of the larger panels in regular use. Nationally, tens of thousands of such tests are conducted every year, said Richard L. Schilsky, MD, senior vice president and chief medical officer of the American Society of Clinical Oncology (ASCO).

Broad-spectrum tests not only encompass the best-known mutations that are commonly evaluated through single-gene or small-panel tests, but they also allow for the detection of rare, actionable abnormalities. “

 V600E, which is a mutation common in melanoma, shows up in a couple percent of a lot of different kinds of cancer. You would never sequence every different cancer for 

, but it’s included in these large panels, so you get the information anyway and it allows you to catch those uncommon patients who could have a dramatic benefit. Those rare mutations would never be studied by individual gene assays,” Klimstra said. Findings from a recent study support the utility of broad-spectrum gene screening. The ProfiLER study in France sequenced 69 genes in patients with advanced cancer and found at least 1 clinically actionable alteration in 52% of samples tested.

The 5-year overall survival (OS) rate was higher among 143 patients who received recommended treatments than it was among 533 who did not (34.8% vs 28.1%, respectively). The PI3K/ mTOR pathway contained the most common actionable mutations. Investigators are planning a follow-up trial to compare their test’s outcomes with those of a commercial 315-gene test.

Researchers are hoping for further insights from TAPUR, a nonrandomized, phase II basket trial sponsored by ASCO that provides patients with targeted drugs matched to the genomic profiles of their tumors. The study has enrolled 510 patients at 83 clinical sites in 20 states and provides 19 drugs for 16 therapy options. Results have not yet been released.

The advent of tumor-agnostic targeted therapies could help make large NGS-based assays more routine, at least for patients with advanced cancers or who otherwise lack satisfactory treatment options. Last year, the FDA approved pembrolizumab (Keytruda) for the treatment of patients with unresectable or metastatic microsatellite instability—high or mismatch repair deficient–solid tumors, marking the first time a drug gained an indication based on its efficacy against a molecular target rather than on the primary tumor site.

“Because the drug is now FDA approved to use in any tumor that has high microsatellite instability, and because many tumors have that but at relatively low frequency, almost every patient at some point will likely get their tumor tested to see if they could get that drug on label,” Schilsky said. “The more we see these kinds of things coming along, the more the nature of the testing is going to change. I’m sure we’ll begin to see testing for these specific alterations incorporated into the large-panel tests, because otherwise you just end up having to continue to test for multiple one-offs and that starts to get very inefficient after a period of time.”

Schilsky said he also expects the shift in testing practice to gain steam from the anticipated approval this year of larotrectinib (LOXO-101) for TRK fusion—positive cancers, which would make the drug the first targeted therapy developed in a tumor-agnostic manner. The oral drug has shown high response rates in both adult and pediatric patients with TRK fusions, with an objective response rate (ORR) of 76% (95% CI, 62%-87%) and consistent results across tumor types.

Other TRK fusion drugs in development include Ignyta’s entrectinib, which has demonstrated efficacy against cancers with 

-positive NSCLC, the ORR with entrectinib was 68.8%, which included 2 complete responses (6.3%).

The FDA granted a breakthrough therapy designation last year for entrectinib as a treatment for adult and pediatric patients with TRK fusion—positive, locally advanced, or metastatic solid tumors who have either progressed following prior therapies or have no acceptable standard therapies.

Additionally, Loxo Oncology, the maker of larotrectinib, is developing LOXO-195 for patients with cancers that have acquired resistance to initial TRK therapy, which may emerge due to TRK kinase point mutations.

 on Gastrointestinal Cancers which was held in January, Luis Diaz, MD, head of the Division of Solid Tumor Oncology at MSK, said these new targeted therapies should demonstrate to community oncologists the importance of genetic testing.

“What I would like them to start realizing is that genomics is not just ‘nice’ to have. It is soon to become a ‘must have.’ Understanding some of the underlying principles, such as the advantages and disadvantages, will be important for the community oncologist,” Diaz said.

A major obstacle to wider adoption of large-panel gene tests is their cost, which can be 10 times higher than for a single-gene assay. Magliocco said a commercial test of 1 gene costs $300 to $400 while big panels come in at $3000 to $6000. FoundationOne has a $5800 list price and FoundationOne Heme costs $7200, although actual payments are often smaller, according to the company. The 500-gene tumor-profiling panel at UCSF runs about $4000, according to Eric Collisson, MD, an associate professor at UCSF School of Medicine.

The costs are covered through various means. Schilsky said some labs cap payments or agree not to bill patients. At MSK, philanthrophic support pays for MSK-IMPACT testing, Klimstra said. In general, Medicare and private payers sometimes pay for smaller panels but do not cover the broad-spectrum tests, with some exceptions. Palmetto GBA, a regional Medicare contractor based in South Carolina, last year began approving payments for FoundationOne testing for patients with advanced NSCLC. Magliocco said Moffitt can sometimes obtain partial payment by focusing on genes with billing codes.

“There are frequent denials on the larger panels. Payers view them as being research rather than diagnostic assays—even though they’re clearly diagnostic&mdash;so we certainly have challenges there. For some tumors, we can break down the billing for the specific genes. We may break it out and bill for 

 and so on separately, and those tend to be reimbursed. But it’s very challenging,” Magliocco said.

Schilsky said labs have rationales for including many nonactionable genes in their panels, based on data showing they are important in molecular pathways known to be activated in cancer cells. However, much of the resulting data is not useful to most physicians. “The broader that the panel goes, the more and more information you get that you frankly don’t know what to do with. That sets up this whole conundrum that is facing oncology these days. How do I interpret this information? How do I act on it? How do I get a therapy that potentially benefits my patient based on these findings? This potentially leads to lots of off-label prescribing without really, in many cases, a sound basis, and no mechanism by which to collect data as to whether patients benefit from this approach,” he said.

Off-label prescribing based on the molecular profiling of tumors has not been shown to improve outcomes. In the phase II SHIVA trial conducted in France, patients with metastatic solid tumors refractory to standard therapies were randomly assigned either to molecularly targeted therapies or treatment of physician’s choice. After a median followup of 11.3 months, median progression-free survival was similar in the experimental and control groups (2.3 vs 2 months, respectively).

 Grade 3/4 toxicities were more common among those who received targeted therapies (43% vs 35%). Findings from an updated analysis of the SHIVA population showed that patients with targetable mutations who were randomized had better OS outcomes than those with no druggable mutation, but the benefit did not reach statistical significance (HR, 0.85).

Against concerns about the cost and utility of broad-spectrum NGS tests, proponents argue that they will inevitably be used much more frequently because of their greater efficiency and comprehensiveness. The true cost difference between differently sized panels is not significant enough to limit access to the larger ones, they argue. “We know that we never need to know 300 genes. That’s absolutely a true statement,” Collisson said. “But at the same time, that’s not really the issue. The issue is, you’re probably going to need to know more than 2, and once you get into low doubledigits, it’s way more economical to just do 300 and not have to guess which the right 200 are.”

Collisson also argued that it does not make sense to suppress easily available gene data because it is not prospectively actionable, as some labs do. “We don’t hold anything else in medicine to that criterion. When I order a chemistry panel, I get 12 things back that I mostly don’t want, but that’s because they all come together. We just have to get past this ‘I’m going to pay $1000 but not $4000.’ They should just argue about price rather than what the content is, and the market will probably figure out the sweetest spot of serving the most people for the least amount of money.”

Klimstra and others said large-panel testing is also an important tool for recruiting patients for clinical trials. MSK has a system that tracks genomic abnormalities as they are detected and notifies oncologists who are studying relevant novel therapies so they can enroll the patients in the trial, he said.

Schilsky said the use of NGS testing in oncology will continue to grow as the technology continues to advance and costs keep falling. At the same time, he said oncologists and other participants in the cancer ecosystem have a responsibility to make progress in key areas in order improve testing.

More basic research is required to understand the functional consequences of the abundance of genetic alterations that assays uncover, he said. Doctors need better test reporting and clinical decision support tools so they can quickly determine whether and how to act on test data.

In addition, precision medicine must proceed through a learning-systems approach that captures test data, interventions, and outcomes to help refine testing and ensure that patients benefit, Schilsky said. A number of data-collection and data-sharing efforts are under way, including programs sponsored by ASCO, the National Cancer Institute, and the American Association for Cancer Research.

Proposed decision memo for next generation sequencing (NGS) for Medicare beneficiaries with advanced cancer (CAG-00450N). CMS website. cms.gov/medicare-coverage-database/ details/nca-proposed-decision-memo.aspx?NCAId=290&TimeFrame=90&DocType=All&bc=AAAAIAAAQAAA&#Top. Published November 30, 2107. Accessed February 5, 2018.

Rubinstein W, Malheiro A, Kattman B, et al. Landscape scanning of cancer gene panels: A report from the NIH Genetic Testing Registry (GTR). 

2016; 34(suppl). ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.e13120.

Tredan O, Corset V, Wang Q, et al. Routine molecular screening of advanced refractory cancer patients: an analysis of the first 2490 patients of the ProfiLER study. Abstract presented at: 2017 American Society of Clinical Oncology Annual Meeting; June 2-6, 2017; Chicago, IL. Abstract LBA100. meetinglibrary.asco.org/record/152168/abstract.

Hyman DM, Laetsch TW, Kummar S, et al. The efficacy of larotrectinib (LOXO-101), a selective tropomyosin receptor kinase (TRK) inhibitor, in adult and pediatric TRK fusion cancers.

 2017;35(suppl; abstr LBA2501). abstracts.asco. org/199/AbstView_199_195112.html.

Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 14.06. https://s3.amazonaws.com/iaslc/pdf/WCLC2017_Abstract_Book_Web.pdf.

Le Tourneau C, Delore JP, Goncalves A, et al; SHIVA investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicenter, open-label, proof-of-concept, randomised, controlled phase 2 trial. 

 2015;16(13):1324-1334. doi: 10.1016/S1470-2045(15)00188-6.

Dureau S, Ricci F, Alt M, et al. SHIVA: Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer—Overall survival (OS) analysis. Poster presented at: 2017 American Society of Clinical Oncology Annual meeting; June 2-6, 2017; Chicago, IL. Abstract 11515. meetinglibrary.asco.org/record/152961/abstract.

The use of next-generation sequencing to diagnose cancers and guide therapy decisions is expanding as more therapies are linked to genomic abnormalities.

NGS Testing Hits Clinical Practice

Approximately 30% to 40% of patients with non—small cell lung cancer (NSCLC) have stage III locally advanced disease at diagnosis.

Stage III NSCLC is a highly heterogeneous disease that encompasses locally advanced primary tumors that have infiltrated mediastinal organs, involve mediastinal lymph nodes, or are larger than 7 cm.

Patients are categorized as stage IIIA, IIIB, or IIIC, depending on tumor size and localization.

No consensus exists on the best treatment approach for stage III NSCLC, but a combination of chemotherapy and radiotherapy is typically used.

 Currently, the 5-year survival rates for stage III NSCLC range from approximately 36% for stage IIIA to 26% for stage IIIB to 13% for stage IIIC.

 Although the past 2 decades saw an abundance of targeted agents and immunotherapies emerge for metastatic NSCLC, progress in locally advanced disease remained stagnant until recently.

The Promise of Immunotherapy for Locally Advanced NSCLC

In September 2017, at the annual European Society for Medical Oncology (ESMO) Congress, researchers presented positive data from a phase III trial of durvalumab (Imfinzi) in patients with stage III NSCLC.

 Durvalumab is an inhibitor of programmed cell death ligand-1 (PD-L1) approved in the United States for urothelial carcinoma. In an 

, Everett E. Vokes, MD, moderated a panel of some of the world’s foremost experts on immunotherapy in lung cancer to discuss durvalumab and other emerging approaches for stage III NSCLC.

Immunotherapy has changed the paradigm for managing metastatic NSCLC. In took just a few years from the approval of checkpoint inhibitors as a second-line option to their integration into first-line management.

Naiyer A. Rizvi, MD, recalled the first patient with lung cancer he treated with the anti— PD-1 antibody nivolumab (Opdivo) in 2009; the patient had an adrenal mass that was so painful, he went to the emergency department for pain medication right after his first nivolumab infusion. “It’s 8 years later, and he still has no evidence of disease. That’s why I think we’re so excited about incorporating immunotherapy into our treatment,” Rizvi said.

The hope is that the success of immunotherapy in the metastatic setting will be repeated in the locally advanced setting. Although the approach for stage III locally advanced NSCLC has shifted from palliative to curative, Vokes said only one-quarter to one-third of patients survive 3 years. Rizvi said none of the approaches tried after chemoradiation—including consolidation chemotherapy or adjuvant vaccine therapy&mdash;has “moved the bar” for stage III patients.

Roy S. Herbst, MD, PhD, suggested that immunotherapy is poised to make a real difference for this population. Rizvi agreed, saying that many patients would be affected.

For PACIFIC, an ongoing phase III trial, investigators have enrolled approximately 700 patients with untreated, unresectable stage III NSCLC.

 Participants underwent standard chemoradiotherapy before being randomly assigned to durvalumab or placebo at a 2:1 ratio.

 Interim data presented at the ESMO 2017 Congress and simultaneously published in the 

 showed an approximately 11-month difference in median progression-free survival (PFS) that favored the durvalumab arm (16.8 vs 5.6 months; stratified HR for disease progression or death, 0.52; 95% CI, 0.42-0.65;

 Compared with placebo, durvalumab was also associated with a higher rate of 1-year PFS (55.9% vs 35.3%, respectively), 18-month PFS (44.2% vs 27.0%), and overall response (28.4% vs 16.0%; 

Among patients who responded, significantly more in the durvalumab arm than in the placebo arm were still responding at 18 months (72.8% vs 46.8%). At the time of the interim analysis, data on overall survival (OS) were not yet mature.

 “[As far] as PFS goes, this is really a novel and impressive finding,” Vokes said. He added that the PFS data were unmatched by anything published for stage III NSCLC during at least the past 15 years.

“Another point that came out from the trial was that programmed death ligand 1 [PD-L1] expression didn’t seem to matter— patients with low and high PD-L1 expression benefited from getting the durvalumab maintenance or consolidation therapy,” Suresh S. Ramalingam, MD, said. PACIFIC investigators measured PD-L1 expression level prior to chemoradiotherapy. The HR for PFS in durvalumab-treated patients with a baseline PD-L1 expression level <25% was 0.59 (95% CI, 0.43-0.82) compared with 0.41 (95% CI, 0.26-0.65) for patients with a PD-L1 expression level ≥25%.

 “I think that these results come as a very refreshing step forward in a disease where we have been stuck with stagnation, and I think it will be incorporated into clinical practice,” Ramalingam said.

Rizvi agreed that the results were impressive. “To see a trial with 11-month difference in PFS—that’s massive. I think it’s going to be a new standard of care,” he said.

Fred R. Hirsch, MD, PhD, said although he concurred with the panel members that the PACIFIC findings were encouraging, he was unsure about prescribing it to patients based on the data presented. “I would like to see the OS data...and the quality of life [QOL] data. Does the improvement in PFS also lead to a better performance for the patients? We don’t know that yet,” he said.

“Although the data are not mature enough to have OS data, it is almost impossible in my mind to think that there isn’t going to be an OS benefit,” Rizvi countered. “If you hit PFS with an immunotherapy agent, you’re going to hit OS,” he said.

Nothing in the safety data suggested durvalumab would negatively affect QOL, according to Vokes. “I think the cough rate was a little bit higher, and maybe [there was] a higher pneumonitis rate [in the durvalumab arm],” he said. Approximately 35% of patients in the durvalumab arm developed cough compared with 25% of patients in the placebo arm.

Just 0.4% of patients in each arm developed a grade 3 or 4 cough. In the durvalumab arm, 34% of patients developed pneumonitis compared with 25% of patients in the placebo arm.

 Rates of grade 3 or 4 pneumonitis were 3.4% with durvalumab therapy versus 2.6% with placebo.

 The study investigators described the treatment-related adverse effects as manageable.

Herbst said that although patients in PACIFIC were a select, relatively fit group, which might affect toxicity outcomes, the study was randomized and the groups were balanced. He called the results historic and said he would recommended the drug to patients “as soon as there’s an approval and reimbursement available.” Herbst added that he does want to see OS data to “make sure that it’s trending in the right direction.”

Based on results of the PACIFIC trial, the FDA a granted priority review to a supplemental biologics license application for durvalumab to treat patients with stage III unresectable NSCLC that remains stable after at least 2 cycles of chemoradiation; a decision is pending.

 The decision deadline is April 17, 2018. The National Comprehensive Cancer Network updated its guidelines for NSCLC to recommend durvalumab in the same setting.

A panel of several of the world’s foremost experts on immunotherapy in lung cancer discuss durvalumab and other emerging approaches for stage III NSCLC.

Vol. 19/No. 4 | Oncology Live®

How Elbow Grease and Inspiration Forged a Winning Career

Immunotherapy Combination Explored in Unresectable HCC

CTCs Demonstrate Predictive Power in Prostate Cancer

Triplet Therapy May Be on the Horizon for BRAF-Mutant Melanoma

NGS Testing Hits Clinical Practice

Immunotherapy Poised to Move Forward Into Stage III NSCLC

MSK Pioneers Interventional Pulmonology Techniques in Lung Cancer Field

Decision Support Is Lacking in Flood of New Data