A theme of the 2019 NCCN Annual Conference was the expansion of biomarker testing to guide treatment, and a review of brand-new changes for guidelines in colorectal cancer (CRC) was no different.

Wells A. Messersmith, MD, co-director of the developmental therapeutics program at the University of Colorado Cancer Center, said work in this area is needed to fill the knowledge gaps in metastatic CRC, which has a 5-year survival rate of just 11%.

Complex genetics define metastatic CRC, which Messersmith said has 4 consensus subtypes, known as CMS1, CMS2, CMS3, and CMS4, with varying lengths of overall survival (OS).

 Messersmith explained that while there are 13 FDA-approved drugs for CRC, until recently only 4 were biomarker-driven. The 2019 update adds treatment based on BRAF, MEK and NTRK fusion targets.

The cost of expensive combination therapy is driving the quest for better biomarkers, Messersmith explained, citing data from his university’s pharmacy that showed 24 to 30 months of combination therapy in metastatic  CRC exceeded $300,000 by 2013. At the same time, OS has increased incrementally. Spending more for better biomarker studies makes more sense than spending billions on therapies that don’t work or could be harmful, he said.

With that, he reviewed studies and key updates for 2019:

 an additional option was added for unresectable stage IV mCRC: mFOLFOXIRI plus the EGFR inhibitor panitumumab (Vectibix) for KRAS/NRAS/BRAFwild-type and left-sided tumors only.

In the VOLFI trial 96 patients with RAS wild-type metastatic CRC were randomized in a 2:1 ratio to mFOLFOXIRI plus panitumumab (n = 63) or mFOLFOXIRI alone (n = 33). The objective response rate (ORR) with the addition of panitumumab was 85.7% compared with 54.5% with mFOLFOXIRI alone.

Although microsatellite instability (MSI) and mismatch repair (MMR) is usually not inherited, this does not rule out Lynch syndrome, which is seen in 1% of cancers with BRAF V600E.Germline testing is indicated if there is a strong family history.

The latest guidelines also include additional explanation of MMR immunohistochemistry testing for the 4 genes known to be mutated in Lynch: MLH1, MSH2, MSH6, and PMS2.

New frontline immunotherapy treatment options listed in the NCCN guidelines for advanced or metastatic CRC are nivolumab (Opdivo) or pembrolizumab (Keytruda), or a combination of nivolumab and ipilimumab (Yervoy), both in dMMR and MSI-H only. These recommendations are category 2B and are intended for patients who are not appropriate candidates for cytotoxic combination regimens. These same immunotherapy options are also listed in the guidelines as second- and third-line recommendations for dMMR/MSI-H patients.

Larotrectinib (Vitrakvi) is now a second-line treatment option for patients with metastatic CRC that is NTRK gene fusion positive, based on a pivotal 2018 paper published in the 

 The pivotal analysis was also the basis of the FDA’s November 2018 approval of larotrectinib for the treatment of adult and pediatric patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no satisfactory alternative treatments or that have progressed following treatment. The pivotal trial included 4 patients with CRC, 1 of whom achieved an objective response.

Combination therapies added to the guidelines as second-line options are: (1) dabrafenib (Tafinlar; BRAF) plus trametinib (Mekinist; MEK), plus cetuximab or panitumumab (EGFR mAb), (2) encorafenib (Braftovi; BRAF) plus binimetinib (Mektovi; MEK) plus cetuximab or panitumumab (EGFR mAb).

The regimen of encorafenib/binimetinib and an EGFR inhibitor is supported by findings from the safety lead-in phase of the phase III BEACON trial. In 30 patients with BRAF V600E-mutant metastatic CRC, the estimated median progression-free survival with encorafenib/binimetinib plus cetuximab was 8.0 months and the estimated median OS was 15.3 months with a median duration of follow-up of 18.2 months.

 The ORR was 48% by local assessment, with 3 patients achieving a complete response.

Testing, Treatment Options Added to NCCN CRC Guidelines

1. Messersmith WA. NCCN Guidelines Updates: Management of Metastatic Colorectal Cancer Presented at: 2019 NCCN Annual Conference; March 21-23, 2019; Orlando, FL.

2. Lenz HJ, Ou FS, Venook AP, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2017;35(15 suppl):3511 DOI: 10.1200/JCO.2017.35.15_suppl.3511.

3. Geissler M, Riera-Knorrenschild J, Tannapfel A, et al. mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild- type metastatic colorectal cancer m(CRC): A randomized phase II VOLFI trial of the AIO (AIO- KRK0109). J Clin Oncol. 2018;36(15 suppl):3509. DOI: 10.1200/JCO.2018.36.15_suppl.3509.

4. Drilon A, Lactsch TW, Kummar S, et al. Efficacy of lacrotrectinib in TRK fusion—positive cancers in adults and children. N Engl J Med. 2018;378:731-739. DOI: 10.1056/NEJMoa1714448.

5. Kopetz S, Grothey A, Yaeger R, et al. Updated results of the BEACON CRC safety lead-in: Encorafenib (ENCO) + binimetinib (BINI) + cetuximab (CETUX) for BRAFV600E-mutant metastatic colorectal cancer (mCRC). Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19; San Francisco, CA. Abstract 688.

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NCCN Expands Guidelines for Colorectal Cancer Treatment

 A study of patients with metastatic melanoma found that those who spent more time in hospice care lived almost four months longer than similar patients who had little or no hospice care, and that end-of-life costs dropped for those with more time in hospice.

, led by Jinhai Huo, PhD, MD, MPH, examined data involving 862 Medicare patients who died between 2000 and 2009 of metastatic melanoma, which has a 5-year survival rate of only 15 percent (compared with 95 percent for melanoma caught at early stages). Until the recent introduction of new therapies for late-stage metastatic melanoma, prospects for long-term survival for these patients were grim, even after following steps including radiation, surgery and chemotherapy.

Thus, end-stage metastatic melanoma patients offered a window into one of the most difficult but essential debates in healthcare today: Does it make sense to continue invasive, expensive treatments that offer little hope, or are patients and the healthcare system better off if palliative care is pursued earlier?

The authors used the Surveillance, Epidemiology, and End Results (SEER) Medicare-linked database to cull results involving 862 patients over age 65, and divided data into three groups: those with no hospice care, those with one to three days, and those with at least four days of hospice care. Among the findings:

		Patients with at least four days of hospice lived an average of 10.2 months (114 patients), while those with no care lived 6.5 months (225 patients) and those who received up to three days of hospice lived 6.1 months (523 patients).

		Patients with at least four hospice days had lower healthcare costs in their final three months, with the cost dropping between $9576 and $14,680, depending on the calculation method used. Besides the amount of hospice care, only the patient’s age made a significant difference in healthcare costs.

“Our study has current policy relevance given that the proportion of Medicare expenditures during the last year of life has been stable for 20 years, with 26.9 percent to 30.6 percent of all Medicare expenditures occurring during that interval,” the authors write.

The article notes that the data used reflects a period before the arrival of game-changing therapies such as ipilimumab and vemurafenib, which have been shown to dramatically extend survival for patients with metastatic melanoma.

A study of patients with metastatic melanoma found that those who spent more time in hospice care lived almost four months longer than similar patients who had little or no hospice care, and that end-of-life costs dropped for those with more time in hospice.

More Hospice Care Meant Longer Survival, Lower End-of-Life Costs for Metastatic Melanoma Patients

As a senior program officer for The John A. Hartford Foundation, Amy Berman, BS, RN, has devoted her career to spreading the word about better ways to deliver healthcare. Three years ago, she became her own case study when she discovered she had inflammatory breast cancer, a rare form of the disease with poor odds of 5-year survival. Berman’s story of embracing palliative care and an active life embodies the movement toward “person-centered” care that will become essential as the population with cancer ages.

For Amy Berman, BS, RN, today’s cancer care delivery system is a lot like the sound of 1 hand clapping: It can be out of sync and unproductive, because it fails to touch the patients it treats.

Creating a better system for delivering cancer care means creating a new value proposition, Berman said; it means making a new business case for cancer.

Berman, a senior program officer at The John A. Hartford Foundation, predicts that demographics will drive change. “We have 10,000 people turning 65 every day,” she said, and this group is getting older. The sexy senior on the tennis court who takes a pill for high blood pressure is increasingly joined by the extremely old person, aged 85 years or above, who suffers from multiple chronic conditions or dementia. This latter group, Berman said, is accounting for more and more of today’s cancer diagnoses. Understanding the demographic realities is key to grasping—and avoiding &mdash;the 2 top cost drivers in cancer care, she said. First, the top cost driver of cancer care are treatments that don’t meet patient goals. The second cost driver is a lack of community-based support services. “We have a system that is perfectly designed for someone to show up in the emergency department (ED), where we don’t want them to show up,” Berman said. Improving the value proposition means working to keep people away from the ED, in part by trimming the twin pillars of runaway cost.

Berman presented the concept of the “triple aim,” which she said refers to better health, better care, and lower costs. “Another way to look at value is gaining the same or better quality care at the same or lower cost. You want to improve quality as you decrease cost,” she said. “That is the improvement of a value proposition.”

Professionally, Berman’s focus has been to find ways to avoid hospital readmissions. She has a nurse’s eye and heart. But 3 years ago, the red spot that appeared on her right breast put Berman on the “patient” side of the table. Even before her test results came back, Berman knew what she was facing, and the look on her primary care physician’s face only strengthened her suspicion of inflammatory breast cancer.

As Berman explained to the conference attendees, inflammatory breast cancer is a rare form of a common disease; its 5-year survival rates are only about 40%. Survival rates are so much worse than for most breast cancers that its patients drag down rates for breast cancer generally (where improvements in treatment have raised survival to 90%).

“Inflammatory breast cancer looks different— it’s not a tumor or a lump that can be picked up early,” Berman said. When it clumps up, it appears on the skin and looks like the peel of an orange. Given her background, Berman spent the night before her biopsy reviewing the literature: Who was treating inflammatory breast cancer? Who has funding? Where are the best treatments being offered? What does the National Cancer Institute say about different approaches? Berman found an expert oncologist in her search and resolved to visit that person.

After her biopsy, there was more sobering news from a body scan: Her lower spine had a “hot spot” of activity—it could be an old surfing injury, but it could mean the cancer had already spread. Berman had a bone biopsy, and she traveled out of state with her 70-year-old mother in tow to see the specialist she had identified.

During their trip, she was walking with her mother when she received a call from her oncologist: the cancer was in her lower spine. At diagnosis, she was already at stage IV. Her 5-year survival prognosis was now 11%.

“It was raining out, and hearing those words, my mother and I dropped our umbrellas, and we hugged on the street and cried. We cried the whole way home, and it felt like the entire world was crying with us.

“It was absolutely devastating, but we stopped crying pretty quickly, and I’ll tell you why. It is really important to know that for whatever time I have left, I didn’t want to be spending it in tears—or not doing.”

The next day she visited the specialist. The oncologist wanted aggressive treatment: a mastectomy, radiation, chemotherapy.

Knowing the cancer was already in her spine, Berman asked, “Why?” The treatment would rob Berman of her ability to work, to write, to enjoy time with her family. It would compromise her immune system and leave her open to infections. So Berman said, “No.”

“I probably have saved my payer about $500,000,” Berman told the gathering. More important, however, are the experiences Berman has gained: “I jet-skied to the Statue of Liberty this summer. I’ve climbed the Great Wall of China twice. I work, I play; I have a very good life, and I am getting treatment.”

Berman has opted for palliative care, and lower-dose chemotherapy that holds her cancer in check. She takes an oral medication—a single pill&mdash;at night; once a month, she has an infusion to keep her bones strong.

The literature supports Berman’s approach.

“People actually do live longer when you focus on pain and symptoms and quality of life,” she said, citing a study in the New England Journal of Medicine (

 The question, asked Berman, is why doesn’t this happen more often?

“How can care be patient-centered when we don’t discuss serious illness with patients?” she asked. “I don’t think people are trying to do bad things, even that physician who would have suggested that I throw everything at it.”

That physician, Berman said, laid out his plan before asking what her goals were—because that’s the way he practiced medicine. Care that is truly patientcentered, she said, “Considers the patient’s cultural traditions, their personal preferences, values, their family situation, and their lifestyle.”

The value proposition, she said, comes when the patient gets all the information and is part of the decision, “because studies show that people actually choose less aggressive care when they understand the totality of their situation.”

Cancer care has not done this historically. “Oncology chooses to look in a narrow way at the cancer, and we have to begin addressing the person.”

Data show physicians often don’t give patients the full story.

 Yet the American Medical Association code of ethics, revised in 2006, states that they must. This is, as Berman put it, the “nut” of the issue in the rising cost of cancer care: physicians must start embracing palliative care, which Berman defined as that “layer of support” that can go alongside curative treatment, not just at the end of life. Palliative care exists for other ailments: congestive heart failure, dementia, and other conditions with pain. It also covers advance planning, or “the stuff that oncology typically does not want to do.” What the data show, Berman said, is that physicians want to do less just as informed patients do, but what happens instead is “liability-driven care.”

She presented numbers for what drives up the cost of cancer care, as well as the 5 elements of the “Choosing Wisely” initiative produced by the American Society of Clinical Oncology.

 They focus on symptom relief and palliative care, and are:

		Do not give patients starting on a chemotherapy regimen that has a low or moderate risk of causing nausea and vomiting anti-emetic drugs intended for use with a regimen that has a high risk of causing nausea and vomiting.

		Do not use combination chemotherapy (multiple drugs) instead of chemotherapy with 1 drug when treating an individual for metastatic breast cancer, unless the patient needs a rapid response to relieve tumor-related symptoms.

		Avoid using PET or PET-CT scanning as part of routine follow-up care to monitor for a cancer recurrence in patients who have finished initial treatment to eliminate the cancer, unless there is high-level evidence that such imaging will change the outcome.

		Do not perform prostate-specific antigen (PSA) testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live less than 10 years.

		Do not use a targeted therapy intended for use against a specific genetic aberration unless a patient’s tumor cells have a specific biomarker that predicts an effective response.

The Institute of Medicine’s recent report, “Delivering High-Quality Cancer Care: Charting a New Course for a System in Crisis,” reported the obvious: When cancer strikes older people, who have more than just cancer, “value” takes on new meaning, and it may not be the same thing for each person.

“The number 1 goal was to engage your patient, and you can read the reasoning behind it,” Berman said. Starting palliative care—that “extra layer” of support&mdash; at the onset of a serious disease, rather than at the end of life, will bring cost savings and greater quality of life, she said.

Palliative care keeps people from showing up in the ED; patients may be able to resolve issues over the phone. It keeps people from ending up without advance directives. “For those of you who are in the managed care environment, in ACOs, working under new patient methodologies, you have the ability to offer it all to your patients,” she said. “If you are in a capitated environment, you will benefit from this. It will reduce liability.”

“This is everything that you want. It’s everything that people like me want.”

		Figure. Palliative Care Shifts Care Out of Hospital to Home

		ED indicates emergency department; SNF, skilled nursing facility. Source: NEJM, 2010, Temel JS, Greer JA, Muzikansky A, et al.

			Temel JS, Greer JA, Muzikansky A, et al. Palliative care for patients with metastatic non-small-cell lung cancer. 

			Seoane L, Bourgeois DA, Blais CM, Rome RB, Luminais, HH, Taylor, DE. Teaching palliative care in the intensive care unit: how to break the bad news. 

			Schnipper LE, Lyman GH, Blayney DW, et al. American Society of Clinical Oncology 2013 Top Five List in Oncology. 

For Amy Berman, BS, RN, today's cancer care delivery system is a lot like the sound of 1 hand clapping: It can be out of sync and unproductive, because it fails to touch the patients it treats.

Mary Caffrey

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NCCN Expands Guidelines for Colorectal Cancer Treatment

More Hospice Care Meant Longer Survival, Lower End-of-Life Costs for Metastatic Melanoma Patients

Person-Centered Care: The New Business Case for Cancer