Caroline Seymour

received a diagnosis of colorectal cancer (CRC), it’s crucial to ask for testing to determine the tumor’s genetic mutations or other aberrations.

That’s because CRC is a very heterogeneous group of cancers, meaning it differs greatly among patients. Testing allows for individualized therapy by helping to inform doctors about which drugs to use and which to avoid.

The many subsets of CRC include those with and without the BRAF and RAS family of mutations. Then there are CRCs that overexpress the protein HER2, which helps drive the cancer. Another crucial aberration: mismatch-repair deficiency or microsatellite instability (MSI)-high status. This means that the cancer has trouble repairing its own DNA when damaged; over time, these tumors develop a large number of mutations that render them sensitive to immunotherapy. Although a type of immunotherapy known as immune checkpoint blockade does not work for all CRCs, mismatch-repair/MSI-high tumors are more sensitive to it, and this subset has a Food and Drug Administration (FDA)-approved treatment.

Previously, some of these mutations were only useful in determining prognosis. Now, there are treatment options for patients with BRAF V600E gene mutations and also those with NTRK gene fusions, and clinical trials are testing anti-HER2 drugs, according to Pashtoon M. Kasi, M.D., M.B.B.S., M.S., an assistant professor of oncology and medi&shy;cine at the University of Iowa. “We’re increasingly moving toward individualizing therapy for each patient,” he said.

In practice, genetic testing of these patients typically involves sampling and analyzing tumor tissue in a standard biopsy procedure. But liquid biopsies, which test blood for circulating tumor DNA, are increasingly used both in clinical trials and in practice and are expected to play a growing role in guiding treatment for people with CRC. Already, liquid biopsies are helping to identify both clini&shy;cally relevant mutations and changes that happen over time, which can direct future treatment decisions, Kasi said.

®, Kasi discussed the potential for liquid biopsies and provided an overview of treatment advances being made for CRC based on the molecular makeup of tumors.

Liquid biopsies, or circulating tumor DNA testing, have rapidly made their way into research and now into practice. The most recent guidelines, issued by a panel of experts from the American Society of Clinical Oncology and the College of American Pathologists in March 2018, summarized the promising ongoing research and studies on circulating tumor DNA. However, they’re not ready for prime time: The only FDA-approved indication for liquid biopsies is in the sphere of lung cancer.

Still, if you look at all the papers and abstracts that came from the 2018 American Society of Clinical Oncology Annual Meeting and now the 2019 ASCO Gastrointestinal Cancers Symposium, there is a great enthusiasm for the approach because of its sensitivity and specificity — at least in the metastatic setting. For early-stage cancers, it’s still early in research. In the metastatic setting in CRC, these biopsies are able to pick up the presence of all the relevant mutations &mdash; BRAF V600E and non-V600E, RAS family or its absence, as well as HER2, which can be present at base line or acquired. Additionally, these assays are now reporting on microsatellite instability.

Employing liquid biopsies as part of practice to help complement tissue-based testing is useful and practical in many ways. First, often we see patients whose tissue biopsy is not available. Next, it is not uncommon to encounter situations where tissue biopsy is not sufficient or safe to be done or repeated. Additionally, we know that these tumors, while on therapy, especially targeted therapies, evolve and change over time, explaining why these treatments may stop working.

Specifically, liquid biopsies help us identify tumors that initially don’t have RAS or EGFR mutations or HER2 or MET amplifications but acquire them during treatment. Those are things you can pick up on a liquid biopsy that you wouldn’t be able to pick up on tissue testing. That’s because a standard biopsy is done at the outset of treatment, and it’s not feasible to do these again and again. Liquid biopsies, on the other hand, are noninvasive blood tests and, therefore, can be repeated periodically as treatment progresses.

It is also important to know that not all actionable aberrations are detected by all assays and that the timing of circulating tumor DNA testing is key. Ideally, for patients with metastatic CRC, doing a liquid biopsy at base line when they have not begun treatment is the most informa&shy;tive and reliable time. It also serves as a base line with which to compare results down the line.

Could you elaborate on ongoing research efforts in this area? 

One of the most exciting things, in terms of using this approach in the metastatic setting, is clinical trials. One of them is a master protocol called COLOMATE (NCT03765736), or Colorectal Cancer Liquid Biopsy Screening Protocol for Molecularly Assigned Therapy, where each treatment arm may be determined by the patient’s liquid biopsy results. The study is being led by many academic institutions, with each arm being a separate clinical trial.

As of right now, different arms, or testing groups, are being developed based on the aberration found in each patient. We already have the HER2 arm open (NCT03043313), where tucatinib (ONT-380) and Herceptin (trastuzumab) (a kinase inhibitor and an antibody, respec&shy;tively, that work in different ways to inhibit the activity of the HER2 protein) will be given together to patients based on HER2 amplification detected in circulating-tumor DNA testing.

Other ongoing research, more for patients with stage 2 or stage 3 CRC, involves the use of liquid biopsies to determine which patients will benefit from chemotherapy after surgery and which may not need it. However, the sensitivity of these assays has to be very high, since the stakes are a lot higher in the curative-intent setting for earlier-stage patients.

Are there other ways that under&shy;standing gene mutations can be used to guide treatment? 

Pharmacogenomics — or genetic testing of the indi&shy;vidual, not the tumor &mdash; is underused in CRC patients; it can guide treatment dosing and adjustment based on variations in genes that affect the metabolism of various drugs. Historical analyses have shown that some patients do far worse in terms of side effects when they get chemo&shy;therapy because they harbor an aberration in certain genes. One of the barriers is that it’s underestimated how many patients have these aberrations.

Additionally, previously there was a delay — usually weeks &mdash; in getting back some of these results. We have shown that incorporating this testing into practice is feasible. Now you can get the results back within three to five days and make a treatment decision in real time.

The other barrier was figuring out how to interpret these results. Now there are guidelines available from Clinical Pharmacogenetics Implementation Consortium that tell you how much chemotherapy should be considered if a patient has an aberration in a certain metabolism gene.

By using pharmacogenomics testing preemptively rather than reactively, we could avoid severe side effects in patients. For patients with CRC and other gastrointestinal cancers, it is particularly of value since the genes that metabolize the two most commonly used chemotherapies are already known and well described. It’s going to help bridge that gap in terms of individualizing care. That will be very helpful, because chemotherapy is still the mainstay for first-line therapy and beyond for all of our patients. To be able to give them treatment in a way that is safer and more tolerable without compromising efficacy would affect the care of these patients.

The BEACON CRC trial is one of the most exciting trials that we had updates for at the 2019 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. It is focused on patients with BRAF V600E-mutated CRC and is led by Scott Kopetz, M.D., Ph.D., FACP, of The University of Texas MD Anderson Cancer Center, and Axel Grothey, M.D., of West Cancer Center. These patients represent an unmet need; their survival in the second-line setting or beyond is about four to six months. Outcomes in these patients are up to three times worse than those of patients who don’t have the BRAF V600E mutation. Historically, BRAF inhibitors didn’t work. The combination of BRAF inhibitors with MEK inhibitors did not show much promise, either.

Those efforts showed that we had to block the cell-signaling pathway at three levels due to the upregulation of the protein EGFR and overac&shy;tivation of that pathway. Doing so with the BRAF protein inhibitor Braftovi (encorafenib), MEK inhib&shy;itor Mektovi (binimetinib) and the anti-EGFR monoclonal antibody Erbitux (cetux&shy;imab) has demonstrated remarkable results. The median estimated overall survival is now around 15 months, and about 48 percent of patients with BRAF V600E-mutated CRC responded to the regimen. In this subset, even stable disease is an important clinical end point, because these patients would otherwise die of their disease. Even the progression-free survival (the time from first treatment until disease progression) is outperforming some of the historical overall survival rates.

Many patients who respond tend to show (relatively long-lasting) responses, and the regimen is well-tolerated. It received an FDA breakthrough therapy designation (to speed development) in August 2018 for the treatment of patients with metastatic BRAF V600E-mutant metastatic CRC after one or two lines of treatment. Hopefully, this will become an option this year. A sister trial, ANCHOR, will evaluate for the use of the combination in the first-line setting.

What is the ongoing research in the HER2 space? 

One of the key advances in CRC is looking at these aberra&shy;tions at base line and what happens to these tumors over time. One of the classic examples is the evolving recognition of HER2-positive CRC. At base line, it confers resistance to some anti-EGFR therapies. It’s not part of guidelines yet, but HER2 may be another aspect to check for in patients before considering anti-EGFR therapies. If found, we may not consider an anti-EGFR therapy for them. HER2 can also be an acquired mechanism of resistance; you can pick it up later either through liquid biopsy or tissue testing. For those 3 to 4 percent of patients, you can enroll them in anti-HER2- based therapy trials.

Data with the anti- HER2 and EGFR drug Tykerb (lapatinib) and the anti-HER2 monoclonal antibody Herceptin (trastuzumab) look promising. There are data and ongoing trials with the dual anti-HER2 blockade that combines Herceptin and another HER2-targeting antibody, Perjeta (pertuzumab). These are studies where it is important to know HER2 status at base line and also at progression so that we can pick the right trials for patients. It won’t be long before a biologic becomes available for these patients, in addition to anti-VEGF and anti-EGFR agents. Antibody-drug conjugates such as trastuzumab deruxtecan (DS-8201), which links an anti-HER2 drug to a chemotherapy, are also being used to treat CRCs with HER2 expression; a trial of this conjugate (NCT03384940) is in progress. Meanwhile, the MOUNTAINEER study (NCT03043313) of tucatinib (ONT-380) and Herceptin employs the addition of a novel small-molecule HER2 inhibitor and is also open and (accepting patients).

Articles

An expert discusses genetic profiling and other advances in the treatment of colorectal cancer.

Looking Beneath the Surface in Colorectal Cancer

Split dosing with Darzalex (daratumumab) was found to be comparable with a standard dosing schedule in terms of safety and efficacy in patients with multiple myeloma in first infusion, suggesting greater convenience for patients and providers alike.

In a retrospective, observational analysis that was presented at the 2018 ASH Annual Meeting, patients who had started on Darzalex therapy within any US Oncology Network practice between November 2015 and June 2017 were eligible for evaluation. Descriptive analyses revealed that the majority of patients were male (54.2 percent) and Caucasian (78.3 percent), with a median age of 63.6 years. Aside from Karnofsky performance status, which was higher in patients who received split dosing than in those who received standard dosing, no other differences in baseline characteristics were observed.

Of the 622 patients included in the analysis, 58.5 percent (364 patients) received split dosing and 41.5 percent (258 patients) received a standard first dose of one infusion at 16 mg/kg. Split dosing, as outlined in the US Oncology Network protocol, was given at 50 mL/hour. If no infusion events occurred within the first hour, the infusion rate was increased in 50-mL/hour increments every hour, not exceeding 200 mL/hour.

A shorter infusion duration was noted on day one in the split dosing cohort than in the standard dosing cohort, with respective median infusion lengths of 4.5 hours (range, 0.1-8.1) and 6.5 hours (range, 0.7-9.9). However, the median total infusion time with split dosing (8.7 hours) exceeded that of standard dosing (6.5 hours).

Though not statistically significant, split dosing resulted in a lower rate of infusion reactions than with standard dosing. In a random sample of infusion reactions taken from both cohorts (302 patients), 47.8 percent of patients (88 patients) who received split dosing and 48.3 percent of patients (57 patients) who received standard dosing experienced at least one infusion reaction. The most common infusion reactions were lower-respiratory (26.1 percent), upper-respiratory (17.2 percent), gastrointestinal in nature (12.5 percent), chills (8.9 percent) and flushing (6.6 percent).

Notably, more patients received split dosing as opposed to standard dosing over the course of the study. Though standard dosing was more common among patients between the first two quarters of Darzalex administration (2015/Q4: 6/22; 2016/Q1: 33/48), split dosing superseded its use in the latter portion of the study (2016/Q2: 34/31; 2016/Q3: 48/35; 2016/Q4: 44/37; 2017/Q1: 101/55; 2017/Q2: 98/30).

“We hope going forward, this will be a direction we move toward in multiple myeloma, so that we are not just looking at all the hard, clinical data, but the convenience of infusion and its impact on patients and their caregivers,” said lead study author Robert M. Rifkin, M.D.

, Rifkin, attending physician, Rocky Mountain Cancer Centers, research lead, Multiple Myeloma, The US Oncology Network, highlighted the results of this trial evaluating the safety of split-dosing administration of Darzalex in patients with multiple myeloma.

: How did split dosing with Darzalex compare with its traditional infusion?

: This is a very important time in multiple myeloma with the advent of many new agents. In the presentation [at the 2018 ASH Annual Meeting], we discussed making the administration of Darzalex easier in the clinic and in the community. In the initial studies that were done with Darzalex, the first infusion took around 10 hours or so. In our poster, we studied patients who received this single infusion versus splitting the dose over the course of two days. We showed that there's a decrease in infusion reactions with split dosing. It was also much more convenient for patients and their caregivers.

We went back and looked at [the data] from a health economics and outcomes research standpoint using our electronic medical records, as well as some other tools. In this case, we were able to present very nice, real-world evidence on splitting the dose of Darzalex.

What are the next steps that should be taken?

The next steps will be to let the data mature. Then, we'll start to look at integrating this approach with Darzalex split-dose infusions into other research and open studies.

This article was originally published on 

Real-World Evidence Supports Split Daratumumab Dosing in Myeloma

Splitting up Darzalex dosing had comparable results to standard dosing schedules in patients with myeloma.

Split Dosing Has Comparable Results in Myeloma Treatment 

There are now 3 FDA-approved PARP inhibitors in the maintenance setting —  Zejula (niraparib), Lynparza (olaparib), and Rubraca (rucaparib) &mdash; for patients with ovarian cancer who are in a complete or partial response to platinum-based chemotherapy.

The April 2018 approval of Rubraca was based on the results of the phase 3 ARIEL3 trial, in which 10 patients saw complete responses with Rubraca compared with 1 patient on placebo, leading to an overall response rate of 18 percent.

Results showed that the median progression-free survival (PFS) in the overall study population was 10.8 months with maintenance Rubraca versus 5.4 months with placebo. Moreover, patients with germline or somatic 

 mutations saw a more impressive median PFS of 16.6 months versus 5.4 months, respectively. This subset of patients experienced a 77 percent reduction in the risk of progression or death with Rubraca versus placebo.

“PARP inhibitors have certainly shown a statistically significant and very meaningful impact on PFS in patients with platinum-sensitive recurrent ovarian cancer in the maintenance setting without any deleterious impact on quality of life,” said Lyndsay Willmott, M.D. “In general, PARP inhibitors are well tolerated. The percentage of patients who have to come off the medication due to toxicity is relatively low.”

Though PARP inhibitors have been shown to confer a benefit in PFS, they are not immune to resistance. In addition to understanding the mechanism of action behind these inhibitors, research now has a vested interest in understanding their mechanisms of resistance.

 State of the Science Summit™ on Ovarian Cancer — just prior to the FDA’s approval of the maintenance indication for Rubraca &mdash; Willmott, a gynecologic oncologist at Arizona Oncology, discussed the use of PARP inhibitors in patients with ovarian cancer and detailed the mechanisms of resistance that have been identified so far.

What are the differences among the three approved PARP inhibitors in ovarian cancer?

The first commercially available PARP inhibitor is Lynparza. The current indications for Lynparza are in treatment and maintenance. The treatment indication is for patients who have had three prior regimens and who have a germline 

mutation. The maintenance indication is for patients with ovarian cancer who had a platinum-sensitive recurrence who have had at least a partial response to their chemotherapy.

The second inhibitor is Zejula; that has a maintenance indication for patients with platinum-sensitive recurrent ovarian cancer with at least a partial response, as well. The third is Rubraca, which has a treatment indication after at least two prior regimens. Those patients need to have either a somatic or germline

[Editor's Note: This interview took place prior to the 

For the maintenance indications, it does not matter what their 

 status is. Every patient is eligible as long as they meet the platinum-sensitive recurrent parameter.

What has the impact of these PARP inhibitors been in the maintenance setting?

Clinical trials have demonstrated PFS improvement in all three drugs. The clinical trials showed statistically significant benefit in PFS with impressive hazard ratios in all three drugs. We can’t say anything about overall survival; the studies weren’t designed that way, nor have the events accrued yet to report on that. However, these drugs certainly have improvement over placebo from a PFS standpoint.

What mechanisms of resistance have been identified?

There is a really good article that was published in 

 at the end of 2017 looking into this issue. There is this idea of reversion mutations, which means that tumor cells can revert to

wild-type and can confer resistance to PARP inhibitors. There can also be upregulation of other types of cell cycle repair such as nonhomologous end joining, which is a type of alternative repair in cells with 

defaults. Halting the replication fork can also lead to PARP inhibitor resistance.

There can be other acquired types of resistance, such as increased efflux of the PARP inhibitor out of the cell, so that it’s no longer available for its mechanism of action. PARP inhibitors can sometimes exploit these abnormalities in cell cycle regulation. If we can alter some of these things, with treatments such as cyclin-dependent kinases, that may enable increased PARP activity. Certainly, a number of mechanisms are being evaluated to see if we can shut down or turn up other systems to allow the inhibitor to remain effective.

Are there next-generation PARP inhibitors being studied?

Other PARP inhibitors have certainly been evaluated in clinical trials that looked at their use with cytotoxic chemotherapy. The viability of those PARP inhibitors in the current marketplace is relatively low. However, yes—there are other PARP inhibitors that may or may not show benefits. That remains to be seen.

What other clinical trials have explored combinations of chemotherapy and immunotherapy?

That’s the next step in research. The idea behind combining PARP inhibitors with checkpoint inhibitors in the maintenance setting is to see if we can portend a better PFS. Chemotherapy plus PARP inhibitors is a little bit more challenging. There is a lot of toxicity, which makes simultaneous administration prohibitive. That’s where the idea of maintenance therapy came about.

What are the main points of your presentation?

Many toxicities are well managed with either supportive medications or dose reductions. This makes for an excellent maintenance setting because patients don’t want to feel ill when they have no evidence of disease. They want to be able to live their lives. These well-tolerated oral PARP inhibitors allow them to do that.

Are PARP inhibitors being used in other fields?

There have been questions about whether that could be evaluated. Lynparza carries an indication in 

-associated breast cancer. If there are other tumor types with similar errors in homologous repair, it could potentially be useful. A number of tumors are submitted for tumor profiling, and sometimes you will see errors in the homologous recombination pathway that come up on profiling. That may warrant its off-label use.

There are now three PARP inhibitors approved for the treatment of ovarian cancer, improving outcomes of many of the women who take them.

Author | Caroline Seymour

Looking Beneath the Surface in Colorectal Cancer

Split Dosing Has Comparable Results in Myeloma Treatment

PARP Inhibitors Continue to Impress in the Ovarian Cancer Space