For this month’s episode, we spoke with Katherine Crew, MD, an associate professor of medicine and epidemiology at the Columbia University Herbert Irving Comprehensive Cancer Center. Crew discusses her recent research on genetic testing in young women with breast cancer. While she was happy to see that the testing rates were not much different between ethnic groups, there were some differences when it came to the results.

Crew also offers advice for nurses in discussing genetics with their patients, as well as easing the worry of not knowing what some genetic testing results may mean.

Articles

Genetics: Discovering the Unknown in Breast Cancer

Genetic alterations could mean different (and more effective) treatment choices for patients with gastrointestinal (GI) cancers, according to Tanios S. Bekaii-Saab, MD.

Bekaii-Saab, medical oncologist, and medical director of the Cancer Clinical Research Office, vice chair and section chief of Medical Oncology in the Department of Internal Medicine, at Mayo Clinic, said that all patients with GI cancers should undergo next-generation sequencing (NGS), at the very least.

The filed of cancer overall is moving toward more universal next-generation sequencing, and even in some instances, in our institution for example, we try to get even beyond NGS to more whole-genome [sequencing].

Every colon cancer patient, every biliary cancer patient, every gastric patient, and I would argue every [pancreatic] cancer patient, and every GI cancer patient should be screened for alterations through, at least, next-generation sequencing. Why is this important? Well, it's important because of a lot of reasons. One, what's approved, and two, what's being studied.

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The results of genetic testing could change a patient's treatment regimen.

All Patients With GI Cancers Should Undergo NGS

The presence of the proteins p16 and p21 has shown to be predictive of treatment response in patients with osteosarcoma, a disease that previously had no identified biomarkers to indicate whether or not patients would benefit from therapy, explained C. Parker Gibbs, MD.

“We may finally have a way to predict how well a patient is going to do with osteosarcoma prior to initiating any therapy,” said Gibbs.

In a study, 104 patients with osteosarcoma were evaluated to determine if p16 and p21 expression are able to serve as predictive biomarkers for this patient population. All patients received standard neoadjuvant chemotherapy after initial diagnosis followed by surgical resection. Immunohistochemistry (IHC) for the cell cycle checkpoint regulator proteins p16 and p21 was performed on paraffin-embedded chemotherapy-naïve biopsy specimens.

The study showed that >90% expression of p16 in the initial biopsy is strongly related with good histologic response to neoadjuvant chemotherapy (P <.0001), a lower rate of metastasis (P = .0118), and a higher rate of survival (P = .0294).

Meanwhile, tumors that had p21 expression at <1% or >50% were related to poor chemotherapy—induced tumor necrosis (P = .025), a higher rate of metastatic disease (P = .002), and overall poor survival (P = .0305). Higher expression of both markers showed a stronger relationship to predicting necrotic response to chemotherapy, metastasis, and survival versus each biomarker alone.

Overall, the findings showed that p16 alone as well as p16 plus p21 combined are independent predictors of response to chemotherapy, overall survival (OS), and metastatic disease in patients with osteosarcoma.

, Gibbs, a Eugene L. Jewett Professor of Orthopaedic Surgery, Division Chief of Orthopaedic Oncology and Chief Medical Officer of University of Florida Health Department of Orthopaedics and Rehabilitation College of Medicine, discussed the research behind p16 and p21 as predictive biomarkers for treatment response in patients with osteosarcoma.

: What are the current unmet needs of osteosarcoma?

: Osteosarcoma is a highly malignant disease in both children and adolescents. Currently, there are very few prognostic markers to tell us how a child or an adolescent is going to do long-term after chemotherapy and surgery. The gold standard for predicting how well a patient will do with this disease is looking at the tumor after chemotherapy and after surgical resection to determine how necrotic the tumor is. We don't have a way to predict response to chemotherapy or risk of metastatic disease or death prior to the initiation of chemotherapy or surgery.

What are the findings of the study looking at p16 and p21 as predictive biomarkers?

Our study looked at 2 cell cycle checkpoint regulators—p21 and p16&mdash;that had previously shown promise for indicating biologic aggressiveness in our cell culture studies. When we looked at these 2 biologic markers in over 100 osteosarcoma cases, we found a strong correlation between their expression, metastatic disease, and OS in children and young adults with osteosarcoma. We believe this is a major advance because it gives us the opportunity to stratify patients going forward prior to therapy, as opposed to submitting them to terribly toxic chemotherapy upfront with no real indication of whether or not it will help them.

How does the testing of p16 and p21 occur?

The testing for p16 and p21 is done on the biopsy tissue. When a patient presents with osteosarcoma, we always do a surgical or a needle biopsy to obtain tissue to learn the diagnosis and how to treat it. Right now, we take a piece of that tissue and we stain it via IHC for p21 or p16, which are cell cycle checkpoint regulator proteins. We are able to determine what the relative risk of metastatic disease or death is in these patients by how much [these proteins] are expressed.

How can physicians implement this information into their practice?

The potential for including this information in individual surgeon or pediatric oncologist practice is that we may be able to change what chemotherapy drugs we offer upfront. Instead, we may offer surgery upfront rather than after chemotherapy, as well as counsel patients regarding how well they may or may not do, depending on the results of this test that we perform on the biopsy tissue. This is an early study and needs to move on to a much larger prospective analysis before I would incorporate it in daily practice.

The next steps of the study are to incorporate other institutions to validate the statistical significance of our results across other groups of patients and the hands of other surgeons and oncologists.

Nasri E, Vasilopoulos T, Knapik J, et al. Cell cycle checkpoints p16 and p21 — strong predictors of clinicopathologic outcome in high-grade osteosarcoma. Presented at: 2019 Musculoskeletal Tumor Society Annual Meeting; October 2-4, 2019; Portland, OR. Abstract 37.

This article originally appeared on OncLive as, "

P16, P21 Biomarkers Linked to Treatment Response in Osteosarcoma

The presence of the proteins p16 and p21 has shown to be predictive of treatment response in patients with osteosarcoma, a disease that previously had no identified biomarkers to indicate whether or not patients would benefit from therapy, explained C. Parker Gibbs, MD.
 

Biomarkers Predict Osteosarcoma Treatment Response

Not all patients with advanced non—small cell lung cancer (NSCLC) are recommended for genomic testing when treated in a community setting, and are therefore not being appropriately tested for potential molecular drivers of their disease, explained Nathan Pennell, MD, PhD.

In a retrospective study of 1203 patients with stage IIIb or IV NSCLC treated since January 1, 2017, records were manually reviewed to find evidence of molecular testing and targeted treatment. Between 11% and 54% of the identified patients had any evidence of testing for at least 1 of 7 genes recommended for testing by the National Comprehensive Cancer Network at the time: EGFR, ALK, ROS1, BRAF, RET, MET, and ERBB2 (HER2). The genes EGFR, ALK, ROS1, and BRAF can be targeted with FDA-approved treatment options while the rest have investigational agents being tested in ongoing studies.

Overall, 54% of patients received testing for EGFR mutations and the rates decreased for the rest of the genes.

 Testing for all 4 genes with FDA-approved treatment options were given to 22% of patients. Furthermore, 48% of patients received testing for PD-L1 expression.

However, liquid biopsies have the potential to increase the number of patients who receive molecular testing with a quicker turnaround time and less-invasive approach than standard tissue biopsies, according to Pennell.

“The benefit is you can test a larger number of people, you can get all the testing that's necessary, and it can be done fast,” said Pennell. “You also don't need to do repeat tissue biopsies, making it very low risk.”

Additionally, results of the Noninvasive versus Invasive Lung Evaluation (NILE) study showed that a liquid biopsy test detected all of the guideline-recommended biomarkers in newly diagnosed patients with metastatic NSCLC at a similar rate but faster turnaround time compared with tissue genotyping. The 73-gene next-generation sequencing panel Guardant360 increased biomarker detection rate by 48%, from 60 patients identified with ≥1 guideline-recommended biomarker using tissue-based tests alone to 77 patients with liquid biopsy (21.3% vs 27.3%; P <.0001). Moreover, the time it took to receive results after ordering was 9 days for liquid biopsy versus 15 days for tissue biopsy.

In an interview with OncLive®, a sister publication of 

Oncology Nursing News®, Pennell, director of the Lung Cancer Medical Oncology Program at the Cleveland Clinic Taussig Cancer Institute, discussed the emerging widespread role of liquid biopsies in lung cancer and how to best utilize the approach in clinical practice.

: Why is molecular testing underutilized in practice?

 It's a number of things. There is certainly an aspect of education and need for people to understand that testing is necessary, but most biomarker testing for cancer is not done at the oncologist level; rather, it's done at the pathologist level. For example, if someone does a biopsy and is diagnosed with breast adenocarcinoma, then the pathologists automatically order a panel of important biomarker tests, such as estrogen receptor, progesterone receptor, and HER2 expression. With lung cancer and a lot of cancers, on the other hand, [biomarker testing] is only done when requested by an oncologist. However, even when oncologist makes a request, the kind of testing done is determined by the hospital's pathology department, whether they do their own internal testing or whether they have contracted an outside vendor to get it done.

There is a wide variety of how [biomarker testing] is done. There are some places, such as Cleveland Clinic, where it's done reflexively at the time of diagnosis. However, for most places, there has to be a request and then it will be sent out and done from a commercial company that does broad testing or a series of hotspot tests—where they do single gene tests in a combination. That same process could also be done internally, either with a broader, next-generation sequencing test that covers all targets of interest, or a series of single-gene tests. It's a big mess of how testing is done, which is not a good way to systematically design something that's important.

If you look at the most common genetic tests for EGFR mutations, we do a respectable job at testing for that. Probably between 80% and 90% of eligible patients get tested for EGFR mutations in the United States, depending on what study you look at. It's been a decade since that has been recommended, making it in everyone's mind. Additionally, for more than 8 years, we have had treatments for ALK-positive lung cancer, making its prevalence close behind at 70% to 80% of patients getting tested for ALK.

Beyond those 2 biomarker tests, there is PD-L1 testing. Other genetic markers, such as ROS1, BRAF, MET, RET, KRAS, HER2, and NTRK, are done at a much lower rate, either because they're not ordered or because the [tissue] is used up. After the first 2 single-gene tests, there is a major drop off in the ability to do any further testing because the [there is no more available tissue]. For patients with metastatic lung cancer, many weeks, or a month, have gone by when they get the results of this test and a lot of them may have proceeded to other treatments, such as immunotherapy, because they may not feel they can wait for the results.

Additionally, they may not have tissue available, and they may not be able to be biopsied in an area that's easily accessible. Even if they have [tissue], there may not be enough to do all the testing and the patient might require another biopsy. The patient may not want to go through that or the doctor may not feel it's safe or there is enough time. There are lots of different process-related reasons for why testing is inadequate.

How can liquid biopsies improve these testing rates?

The major advantage of plasma testing or liquid biopsy, which is a blood test, is that you can get blood from every single patient. You don't have to worry about where the biopsy was done, if there's enough material from the biopsy, or if it was done properly. The major commercial vendors for plasma testing do a comprehensive multiplexed test that covers all of the targets of interest. You can get testing on every patient and when you order the testing, you can get all of the targets of interest upfront. That immediately takes away a lot of the issues with it. That's something that you can automate: to make it standard to test everyone [upon diagnosis].

The other big advantage with liquid biopsy is the timing because, with preparation of material in order to perform the test, [results take a lot] longer [to come back] with tissue. First, you have to locate the tissue and cut sections. Then, you either have to process them to extract the DNA and RNA or send it to another company. If you send it to another company, you have to consider shipping and logistical processing times before they can extract the material and you can get those results.

With something like plasma testing, the median time for testing results in the NILE trial was 9 days, which was significantly faster than the turnaround time for tissue. Those are the big advantages and has the potential to dramatically increase the number of people who get tested for the appropriate genetic markers for lung cancer.

How else do liquid biopsies compare with standard tissue biopsies?

People have spent a lot of focus on the disadvantages of the liquid biopsy, including the sensitivity. If you're extracting DNA from an actual tumor and you have a piece of the tumor, you're getting DNA that's coming from that cancer. If you test it, you have a high likelihood that you'll accurately be able to assess if there's a mutation or a gene fusion in that cancer because you're testing the cancer itself.

If you're looking at circulating-free DNA in the blood, then you're relying on some of the DNA from the cancer cells, which is not in the blood and is usually in the lung, bone, or wherever the tumor is, to leak into the bloodstream and become detectable amid a huge amount of DNA that is not tumor DNA; it's normal DNA from the person. The technology has gotten phenomenally better at being able to detect extremely low amounts of circulating tumor DNA and being able to filter it out to detect the difference between the tumor and normal DNA from a person.

However, not every cancer is going to be detectable in that way. Some cancers don't shed DNA as much as others. Some patients who have a relatively low amount of cancer and a low tumor burden may not have as much detectable DNA. The sensitivity is always going to be a relative disadvantage of doing liquid biopsies compared with an actual tumor biopsy. If you look at comparisons between tumor biopsies and plasma biopsies, for example, in the NILE study, you probably get somewhere in the range of about 80% sensitivity of mutations and other genetic alterations that are known to be in the tumor from a tumor biopsy that are detectable in the blood, meaning you may miss 20% of actual findings that are there by solely doing a blood test.

What targets can be identified via liquid biopsy?

In 2019, there are 4 must-have biomarker tests for genetic testing in lung cancer. You have to test for EGFR, ALK, ROS1, and BRAF V600E in every patient with lung adenocarcinoma and nonsquamous non—small cell lung cancer. Then, there are a number of tests that should be done on everyone but we don’t yet have FDA-approved treatments for—including RET and MET exon 14 skipping mutations. Therefore, you could argue that they are not necessary, but getting very close [to being necessary].

Similarly, the FDA is reviewing data from drugs for approval in this space. HER2 activating mutations are still investigational, but there are promising drugs and trials. KRAS mutations, historically, have not been targetable, but that's changing with multiple drugs now in early-phase trials. KRAS is also very valuable because it’s very common, and these drivers are mutually exclusive. If you find it, there likely are not any other targetable oncogenes present.

There are also NTRK fusions, which are extremely rare but have extremely effective treatments if you identify them. When you're doing a broad multiplex test, you can test for all of these at around the same cost as testing for any of them [individually].

The NILE trial looked into the impact of liquid biopsies in lung cancer. Could you highlight the findings from this study?

This is a very simple test. They took 282 patients with lung cancer who were going to undergo standard tissue testing. All of them had their blood drawn and sent for plasma testing at the same time. In the end, they described the success rate for identifying guideline-recommended biomarkers with the plasma testing compared with the tissue testing. This was a nice, real-world study because they were using a commercially available, FDA-approved plasma test and whatever was done by local testing centers for tissue testing, which is a very realistic real-world way of doing it.

In one aspect, this is a glaring way of illustrating that with many biomarkers to test, using a combination of single-gene tests is completely ineffective. There's no practical way to test for 8 different biomarkers using single-gene tests. If you just looked at EGFR and ALK, for example, more than 80% of patients were tested, which is pretty close to what literature has described regarding patients who were tested for EGFR and ALK nationwide. However, even 80% for ALK 83% for EGFR, compared with 95% of patients getting tested with plasma testing, shows that liquid biopsy captures a much larger group of eligible patients and ensures they have at least some testing done.

The disadvantage [of liquid biopsy] is the sensitivity. Although a relatively small number of patients had all of the tissue testing done, the plasma testing results in patients who had tissue testing showed they had about an 80% sensitivity. In other words, 80% of the genetic alterations that were found in tissue were also found in the plasma. The flipside is if you had done plasma and not tissue testing, you probably would have missed about 20% of those.

However, since only 18% of people got all the tissue testing done, you probably picked up a lot more actionable alterations by doing the plasma testing than you would have if you had solely done tissue testing. In a way, they are complementary. The perfect solution would be to do tissue testing and get it done correctly on 100% of patients. However, since that's impractical currently, plasma testing has a huge role to play in improving the number of people getting testing.

Is there any pushback regarding the payment aspect liquid biopsies?

A major outstanding question when it comes to plasma testing is reimbursement for paying for these tests. There are FDA-approved plasma tests. Hopefully, payers understand the importance of the role of testing and are covering this. We as a field have to be careful about routinely recommending double testing using plasma and tissue for every patient. We have to set up an algorithm that optimally try to identify [optimal testing] for patients without doing wasteful testing. I'm encouraged by what I've seen, at least in the last couple of years, with payer coverage for plasma testing when it's appropriate.

What steps can we take as a community to make liquid biopsies more widespread?

[We must work on] education and letting people know about plasma testing, including the advantages and disadvantages. I do not want to put out the message that, “Plasma testing should replace tissue testing universally, that it's every bit as good, and that the result of plasma testing is adequate if it shows you don't have an actionable result.” If you have good tissue testing and you're going to get the [results from plasma too], then that's adequate. If you have any questions about your tissue testing, then doing plasma testing upfront makes perfect sense. However, if you get a negative result and there are no actionable results from your plasma test, you have to follow up with tissue testing because you may have missed some [alterations].

1. Gierman HJ, Goldfarb S, Labrador M, et al. Genomic testing and treatment landscape in patients with advanced non-small cell lung cancer (aNSCLC) using real-world data from community oncology practices. J Clin Oncol. 2019;37(suppl; abstr 1585). doi: 10.1200/JCO.2019.37.15_suppl.1585.

2. Leighl N, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA (cfDNA) analysis to identify genomic biomarkers in newly diagnosed metastatic non-small cell lung cancer (mNSCLC) [published online ahead of print, April 15, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-0624.

Liquid Biopsies Are Link to Increasing Molecular Testing in Lung Cancer.

Not all patients with advanced non–small cell lung cancer (NSCLC) are recommended for genomic testing when treated in a community setting, and are therefore not being appropriately tested for potential molecular drivers of their disease, explained Nathan Pennell, MD, PhD.

Expert Talks Liquid Biopsies, Molecular Testing in Lung Cancer

The American Cancer Society estimates that 5%-10% of cancers are connected with mutations in the DNA that are inherited through generations.

 For millions of patients in the United States, genetic testing allows for a deeper understanding of one’s risks, prompting more comprehensive screening and services in an effort to prevent the onset of a disease or detect cancer at an earlier stage. Despite heightened awareness of the BRCA gene, breast cancer is far from the only cancer associated with inherited risks. Melanoma, pancreatic, prostate, colon, ovarian, stomach, and brain cancers may be associated with family cancer syndromes caused by inherited genetic mutations.

Most insurance companies that pay for genetic testing do so at the request of a primary care physician or genetic counselor who has agreed that there are enough immediate family relatives with cancer diagnoses to warrant a genetic test on the patient. Patients often have to recite a painful list of family members who have had cancer diagnoses, and this in itself is unsettling, given that they may have lost family members from the disease and may still be grieving. The emotional context of a family medical history is compounded by the implication that patients themselves may be diagnosed with cancer in the future.

For people with genetic mutations that lead to an increased risk of cancer, occupying the same clinical spaces designed for people with cancer diagnoses may be challenging. The protocol for many genetic mutations involves annual or biannual scans or follow up on concerns.

 As a result, patients can form lasting relationships with oncology nurses without ever having a diagnosis of cancer. The discovery of a genetic mutation allows people to take power over an uncertain future, but places them in the same medical setting they are hoping to avoid. For those living in more rural areas, access to genetic counseling may be limited. Patients will look to oncology nurses for assurance that their screenings or preventive measures will be effective, and may feel discomfort at being treated as though they are already a person with cancer.

Because most patients with genetic mutations will have family members who have been diagnosed with cancer, it can be a fine line between patient and caregiver. When working with clients who compare their diagnoses and experience with cancer to those of similarly diagnosed family members, it is important to remember the individuality of patient experience. Working with caregivers can present unique topics, as their concerns are both for the patient and for their own futures. It is important as oncology nurses to remember that patients identified with family cancer syndromes usually have a lengthy personal narrative that includes multiple losses of family members. This creates the need for a delicate balance in which oncology nurses have to be aware of their patients’ need for support while not assuming that the patient will become ill themselves. 

People with genetic mutations are often confronted with an abundance of screening protocols that can be overwhelming. Oncology nurses have the rare chance to form long-term relationships with patients and help contextualize the data behind what “increased risk” means. Various cancer syndromes can have different timelines; one may involve an  increase in cancer diagnoses for those under the age of 30 while another might involve a lifetime of gradually increasing risk. Oncology nurses can help put these things into context. For example, oncology nurses can help patients understand that a high risk of cancer by the age of 70 only remains true if nothing is done to lessen risks associated with cancer

 and that increased screening, changes in diet, reduction in alcohol and avoidance of tobacco can prevent or reduce chances of cancer.

Oncology nurses are at the front lines of meeting a patient where they are emotionally. If a patient comes to an oncology center for screenings, oncology nurses can treat them with care and empathy while being mindful that the patient might not need the same degree of support as someone with a cancer diagnosis. In the same vein, a patient with a family cancer syndrome may experience increased anxiety due to previous scans and tests and require more information and reassurance.

It is essential to remember that people with family cancer syndromes may never receive a cancer diagnosis. This may be due to preventive surgeries to remove organs and body tissue or prophylactic medication.

 For those patients who are unable to take preventive surgeries and rely on increased screening measures, there may eventually be a cancer diagnosis. The emotional comparison to other family members challenges the notion that everyone’s experience with cancer is unique, and oncology nurses can help contextualize and support a patient who transitions from screenings to cancer care. Oncology nurses are often in a prime position to validate the patient experience and provide essential support in long-term relationships with patients and caregivers.

The American Cancer Society. Family Cancer Syndromes. 

https://amp.cancer.org/cancer/cancer-causes/genetics/family-cancer-syndromes.html

 January 4, 2018. Accessed December 10, 2019

Schmeler KN, Lynch HT, Chen L, et. al. Prophylactic Surgery to Reduce the Risk of Gynecologic Cancers in the Lynch Syndrome. 

. Jan. 9, 2006. DOI: 10.1056/NEJMoa052627

 Garber JE, Offit K. Hereditary Cancer Predisposition Syndromes. 

People with genetic mutations are often confronted with an abundance of screening protocols that can be overwhelming.

Genetic Testing and Inherited Increased Risk of Cancer

Single-agent vorasidenib or ivosidenib (Tibsovo) led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor 

 mutations, according to updated data from an ongoing, 2-cohort, perioperative study (NCT03343197) that were presented at the 2019 Society for Neuro-Oncology Annual Meeting.

Findings were available from 42 efficacy-evaluable patients on vorasidenib (n = 21) or ivosidenib (n = 21). Among those who received postoperative vorasidenib at 50 mg, 4 (31%) patients achieved objective tumor responses, which comprised 2 partial responses (PRs) and 2 minor responses, according to the investigator by Response Assessment in Neuro-Oncology for low-grade glioma (RANO-LGG).

The objective response rate was also 31% for patients who received 500 mg of ivosidenib in the postoperative setting, also according to investigator by RANO-LGG. This included 2 PRs and 2 minor responses. Moreover, stable disease was achieved in 15 and 16 patients on vorasidenib and ivosidenib, respectively, which led to respective disease control rates of 90% and 95%.

Vorasidenib is an investigational, oral, selective IDH1/IDH2 inhibitor that is designed to enhance brain penetrance and has been in clinical development in 

Ivosidenib is currently approved by the FDA for the treatment of adult patients with relapsed/refractory 

-mutant acute myeloid leukemia (AML), and for the first-line treatment of adult patients with 

-mutant AML, as detected by an FDA-approved test, who are ≥75 years old or are ineligible to receive intensive induction chemotherapy.

In the ongoing trial, vorasidenib and ivosidenib are being evaluated as single agents in patients with 

-mutant grade 2/3 glioma. Patients are randomized to receive 500 mg of ivosidenib once daily, 50 mg vorasidenib once daily, or the control arm of no treatment in cohort 1. In the second cohort, patients receive either 250 mg of ivosidenib twice daily or 10 mg of vorasidenib once daily. Patients are treated for 4 weeks prior to surgery and can continue postoperative treatment until disease progression.

The primary endpoint is 2-HG concentration in tumors resected following neoadjuvant treatment with vorasidenib and ivosidenib compared with the untreated control tumors.

As of the July 26, 2019, data cutoff, 49 patients were randomized before surgery and 39 remain on treatment. The median duration of postoperative treatment for all doses was 5.42 months (0.9-13.5) for vorasidenib and 6.93 months (1.0-13.2) for ivosidenib.

The baseline characteristics were similar across arms in each cohort. Overall, 88% of patients had World Health Organization classified grade 2 tumors; less than one-third of patients had prior radiation therapy and approximately half of patients previously received systemic therapy.

Results also showed that vorasidenib and ivosidenib each demonstrated brain penetrance. The mean brain-plasma ratios were 3.16, 1.74, 0.13, and 0.10 for the 10-mg vorasidenib, 50-mg vorasidenib, 250-mg ivosidenib, and 500-mg ivosidenib arms, respectively. The mean percent reduction in 2-HG were 92.6% (95% CI, 76.1-97.6) in the 50-mg vorasidenib group and 91.1% (95% CI, 72.0-97.0) in the 500-mg ivosidenib arms, relative to untreated samples.

A safety analysis was conducted for all 49 patients as of the data cutoff, which showed that both vorasidenib and ivosidenib had favorable safety profiles. In the vorasidenib arm, the most common adverse events (AEs) occurring in >25% of patients were diarrhea (29.2%), fatigue (29.2%), and nausea (29.2%). The most common AEs on the ivosidenib arm were headache (32%), diarrhea (28%), and anemia (28%).

A total 8.3% of patients on vorasidenib developed transaminase elevations, including one grade 3 transaminase elevation at 50 mg daily; this was resolved with dose interruption. Grade ≥3 AEs occurred in 6 (25.0%) vorasidenib-treated patients and 4 (16.0%) patients on ivosidenib; the majority of these were related to postoperative complications. No patients discontinued treatment due to AEs.

“Having now demonstrated brain penetrance, robust 2-HG suppression and an encouraging disease-control rate with vorasidenib, we’re confident in our ability to make a difference for patients with 

 mutant low-grade glioma and are on track to initiate the phase III INDIGO study next month.” Chris Bowden, MD, chief medical officer at Agios Pharmaceuticals, Inc., the developer of these agents, stated in the press release.

The double-blind, phase III INDIGO study will randomize 366 patients with 

-mutant, grade 2 non-enhancing glioma 1:1 to receive either 50 mg of vorasidenib once daily or placebo. The primary endpoint of the trial, which is expected to initiate at the end of 2019, is progression-free survival.

A version of this article originally appeared on OncLive

Vorasidenib, Ivosidenib Show Encouraging Activity in IDH1-Mutant Low-Grade Glioma

Agios presents new pharmacodynamic and response data from both cohorts of the perioperative study of vorasidenib and Tibsovo (ivosidenib) in patients with IDH1 mutant positive low-grade glioma. Agios Pharmaceuticals. Published November 22, 2019. https://bit.ly/34lHPL7. Accessed November 25, 2019.

Two new single agents led to brain penetrance and 2-hydroxyglutarate (2-HG) suppression in patients with low-grade glioma who harbor IDH1 mutations, according to updated findings.

New Agents Show Promise in Treating Patients with IDH1-Mutant Low-Grade Glioma

As the use of next-generation sequencing (NGS) in lung cancer increases, ongoing research is focusing on new therapeutics to target less-common mutations that can be identified, explained Michael D. Offin, MD.

 alterations tend to be some of the rarer alterations in lung cancer,” said Offin, a medical oncologist at Memorial Sloan Kettering Cancer Center. “However, there are approved and emerging data of definite targetable options in that setting.”

, Offin discussed ongoing research focusing on some of the less-common targetable mutations in non—small cell lung cancer (NSCLC).

: What are the current treatment options for patients with NSCLC who harbor 

: The current standard of care would be crizotinib (Xalkori), which is in the National Comprehensive Cancer Network (NCCN) guidelines. Capmatinib, tepotinib, and savolitinib are all emerging targetable applications. Each one had a slightly different adverse event profile, [which was reported at the] 2019 ASCO Annual Meeting. The overall response rates (ORRs) were in the 40% to 60% range, depending on which drug we looked at. It's a bit premature to say that one is necessarily better than the other, but we're all very excited to see the data as more patients enroll and they are on these medications longer [to better evaluate] progression-free survival (PFS).

What are some therapeutic updates in the 

space right now, there are NCCN guideline recommendations, but I would say that they are relatively toxic with response rates that are lower than what we would hope for. With selpercatinib, as well as BLU-667, there is hope for a better targetable option here. Both medications are well tolerated. Selpercatinib had a bit of a signal for a slightly better ORR, but it's unfair to say that in a cross-trial comparison. Overall, everyone is very excited and hoping that the breakthrough designation will [quickly] lead to an approval to provide patients with better options.

How has treatment evolved for patients with 

 fusions, larotrectinib (Vitrakvi) and entrectinib (Rozlytrek) are in that space now. Larotrectinib was a landmark approval because it was both age and histology agnostic, which is the first time that has occurred. While 

fusions are exquisitely rare [and are identified] in less than 1% of all tumors and in about 0.2% of all lung cancers, response rates with [these two agents] are robust and toxicity profiles are reasonable with mostly grade 1/2 adverse events. These medications have changed the way we treat patients with those rare tumors harboring 

 setting, some medications are in the guidelines and others are under further investigation. There is activity with afatinib (Gilotrif) as well as ado-trastuzumab emtansine (T-DM1; Kadcyla). The antibody-drug conjugate (ADC) in the HER2 space showed activity in research that was recently published by Bob T. Li, MD, MPH, and his colleagues. Other medications, including novel ADCs, are under investigation now. The HER2 space is a growing field with many new options [emerging].

If a test comes back positive for 1 mutation, what is the likelihood that a patient also harbors another mutation?

In the specific drivers we're discussing, which are RET, MET, NTRK, and BRAF, they are somewhat exclusive. However, I was involved in a project where we looked at MET exon 14 splice site alterations and found concurrent KRAS alterations—both de novo and acquired. There is no hard and fast rule to this. We have to question the paradigm that these [mutations] only happen in a vacuum.

Is there any new research regarding more difficult-to-target mutations, such as EGFR or HER2 exon 20 insertion mutations?

For EGFR, colleagues of mine, such as Gregory J. Riely, MD, PhD, are looking into novel medications. There are ongoing clinical trials evaluating novel tyrosine kinase inhibitors; there are good data on their efficacy that was presented recently. There is some [anecdotal] evidence, as well, for doubling the dose of osimertinib in that setting, which is not approved.

The ongoing clinical trials are very exciting, and we all look forward to more data. For the HER2 exon 20 insertion mutation, Li is working in that space to try and figure out what combination strategies could be tested [and found effective] clinical trial settings.

A version of this story appeared on OncLive

Research Abounds in Targeting Rare Mutations in Lung Cancer

With the help of NGS, new research is emerging for targeted therapies of rare mutations in lung cancer.

Next-Generation Sequencing Sets Sights On Rare Mutations in Lung Cancer

, Elham Nasri, MD, resident, and pathologist at the University of Florida’s College of Medicine, discussed the procedures oncology professionals should take before determining whether patients with osteosarcoma should begin chemotherapy.

What they do is, they usually biopsy a patient's tumor and the tumor comes to us as a pathologist. We diagnose it to see if it is osteosarcoma or not, if the physicians and especially the oncologists are aware that they can use a specific markers at a time of diagnosis to help them to gauge the treatment of the patients because they will have started the chemo already, it will be helpful.

So, they can ask us to do it, because it's not a routine or a standard thing to do nowadays, and it's still a method under investigation, but what we do is that they perform immunohistochemistry on the piece of tissue that they gave us. Based on our evaluation of the percentage of the cells in that slide of tissue that express that marker, we can give them if this tumor is a high expression for 

To extend the quality of life for patients with osteosarcoma, researchers are looking for ways to identify before chemo whether or not they need that treatment.

Searching for Prognostic Markers in Patients with Osteosarcoma

Wnt could be a prime target and immune agonist in colorectal cancer (CRC), given that the protein is present in the majority of patients with the disease. However, investigators are still in the early stages of identifying and developing compounds capable of targeting mutations that activate the pathway, said Lukas E. Dow, PhD.

“The goal is to understand what we can do to [increase responses to] immunotherapy. One potential option is targeting the Wnt pathway,” said Dow. “Good preclinical evidence [in liver cancer and melanoma] suggest that suppressing Wnt in tumor cells allows T cells and other components of the immune system to target tumor cells more effectively.”

, Dow, an assistant professor of biochemistry and medicine at Weill Cornell Medicine, highlighted ongoing research evaluating Wnt as a potential target in CRC.

: Could you discuss the potential applications of targeting the Wnt pathway in CRC?

: The Wnt pathway is activated or mutated in more than 95% of CRC cases. I discussed potential ways to target it. At the moment, there is no clinical compound that has received FDA approval. We're operating on preclinical models to understand where [Wnt-targeted therapies] would be effective and what we can do to make it more effective.&#8239;

Could you expand on some of the combinations that are being evaluated?

There is a phase I trial that's no longer recruiting and is evaluating a porcupine inhibitor, which blocks Wnt ligand release from cells. The inhibitor was tested in CRC that have 

 fusions because they rely on the Wnt ligand, as do 

 mutations. Therefore, they were combined with BRAF inhibitors as well as an EGFR inhibitor to try to block MAPK activation.

There are two other trials that are actively recruiting and are examining similar porcupine inhibitors. However, these are early-phase, dose-escalation trials that are being conducted to look at safety. Once safety is established, it is likely that these compounds will be combined with existing therapies that we know target relevant pathways.

Could you highlight the impact of immunotherapy in this space?

In general, immunotherapy is great. However, its use in CRC is pretty limited. There are FDA-approved immunotherapies for patients with microsatellite instability-high or hypermutated CRC. In general, these therapies show relatively good responses. However, for 95% of patients with microsatellite stable disease, immunotherapy has a very poor response rate.

We have reason to be hopeful about strategies targeting the Wnt pathway, but we need to pay close attention to the types of mutations that activate this pathway as well as other cancer-associated mutations that occur in those cells, as they could impact the way the cell responds to Wnt suppression.

Wnt Pathway Emerges as Attractive Target in CRC

Wnt emerges as an exciting and favorable pathway for the treatment of patients with CRC.

New Pathway Emerges as A Favorable Target in CRC

At the 2019 Prostate Cancer Consensus Conference, prostate cancer experts gathered along with genetic counseling experts to discuss the implementation of genetic testing for treating patients with inherited prostate cancer.

During one of the presentations Curtis A. Pettaway, MD, presented on germline predisposition in males from racially diverse populations. Highlighting the importance of more research needed to be down in these populations to understand how to prevent and treat their illness better.

Pettaway, a professor of medicine at The University of Texas MD Anderson Cancer Center, Houston, Texas, had the chance to sit down with 

, and discuss genetic testing recommendations in patients from racially diverse populations.    

You know, there are testing recommendations now, certainly through the National Comprehensive Cancer Network, and men are being referred for testing, specifically prostate cancer patients are being referred. And when we look at the set of genes that would be remit recommended by the NCCN, we see that these same genes are seen in racially diverse populations.

They're seen in African American patients they're seen in Hispanic patients; they're seen in Asian patients. Some of the mutations look like they might be a little lower, in fact, in African American and Hispanic patients such as mutations and 

Genetic testing in cancer care is a relatively new element of the field, but some experts are looking to it to help prevent and understand prostate cancer in racially diverse populations. 

Genetics