Caroline Seymour

About one-fifth of patients with malignant pleural mesothelioma were also diagnosed with COVID-19 during the first year of the pandemic at one hospital in Barcelona, which contributed to both high hospitalization and mortality rates, according to recent findings presented at the 2021 World Conference on Lung Cancer.

The results showed that seven patients (18%) were diagnosed with COVID-19; the average overall survival (OS) of these patients was 17.8 months from cancer diagnosis.

Five of these patients died; reasons for death included COVID-19 (four patients) and progressive disease (one patient). The median OS of these patients was 0.4 months since COVID-19 diagnosis.

Patients with thoracic malignancies may be particularly vulnerable to COVID-19, lead study author Dr. Susana Cedres, a medical oncologist in the Thoracic Tumors Unit at the Vall d’Hebron University Hospital and Institute of Oncology in Barcelona, Spain, said in explaining the basis for the study in a virtual presentation of the data.

Although the effect of SARS-CoV-2 infection has previously been evaluated in 200 patients with thoracic malignancies in the TERAVOLT registry, only eight patients with malignant pleural mesothelioma were included in the assessment.

In the United States, tuberculosis, drug use disorder, hepatitis, HIV/AIDS, cardiomyopathy, diabetes and malignant pleural mesothelioma have been associated with worse COVID-19 related mortality outcomes.

Therefore, investigators sought to tease out the effect of COVID-19 infection on patients with malignant pleural mesothelioma at Vall d’Hebron University Hospital.

In the study, investigators compiled the medical records of 38 patients with malignant pleural mesothelioma who had visited Vall d’Hebron University Hospital between March 2020 and March 2021.

The data that was collected included information on demographics, comorbidities, oncological background and course of COVID-19 illness.

Regarding the patient characteristics of those diagnosed with COVID-19, the median age was 62 years (range, 62-87). The study population comprised four men (57%) and four women (43%). Four patients were non-smokers (57%), and three patients were current or former smokers (43%).

All seven patients (100%) had epithelioid histology. Five patients (71%) were not receiving cancer treatment at COVID-19 diagnosis vs two (29%) patients who were.

Additionally, investigators stratified patients by six characteristics at COVID-19 diagnosis: comorbidity, concomitant treatment, clinical onset, laboratory, hospitalization and respiratory symptoms.

Regarding comorbidities, four patients (57%) had a cardiovascular comorbidity, one patient (14%) had a respiratory comorbidity and one patient (14%) had a renal comorbidity.

Regarding concomitant treatments, four patients (57%) were receiving antiplatelet or anticoagulant therapy, 2 patients (29%) were receiving antidiabetic therapy, and one patient (14%) was receiving corticosteroids.

Regarding clinical onset, four patients (57%) had symptomatic onset, and three patients (43%) had asymptomatic onset.

Regarding laboratory results, six patients (85%) had lymphopenia, four patients (57%) had high d-dimer, and four patients (57%) had high IL-6.

Regarding hospitalization, six patients (85%) were hospitalized, and one patient (14%) was not.

Regarding respiratory symptoms, four patients (57%) had bilateral pneumonia, and six patients (85%) had oxygen support.

A version of this article was originally published on OncLive as, “

COVID-19 Leads to High Hospitalization and Mortality in Malignant Pleural Mesothelioma.

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Articles

The average survival for patients with malignant pleural mesothelioma was less than a month after being diagnosed with COVID-19, according to a small study.

COVID-19 Increases Death, Hospitalization Rates in Patients With Mesothelioma

Patients with multiple myeloma had suboptimal antibody response against COVID-19 after being vaccinated, putting them at risk of contracting the virus, even after getting the shot, according to recent findings published in 

Lead study author Dr. Oliver Van Oekelen and colleagues evaluated SARS-CoV-2 spike-binding immunoglobulin G (IgG) antibody levels – which develop after being vaccinated and protect an individual against COVID-19 – in 320 patients with multiple myeloma who received COVID-19 vaccinations in early 2021. Most patients (69.1%) received the BNT162b2 vaccine by Pfizer, 27.2% received Moderna’s mRNA-1273 vaccine and 3.8% received an unknown mRNA vaccine.

Of these patients, 260 (81.3%) had antibody levels measured at least 10 days after receiving the second vaccine dose (range, 11-118). Of the fully vaccinated patients, 84.2% (219/260) developed measurable SARS-CoV-2 spike-binding IgG antibody levels.

“What was more important, and in a way, a little bit more worrying to us, was that more than 15% of the patients had no detectable IgG after receiving two (doses of the) vaccine at least 10 days prior,” Van Oekelen said. Forty-one (15.8%) patients did not develop any SARS-CoV-2 spike-binding IgG antibodies.

“That was somewhat surprising, although it has been confirmed in other cancer types, especially in 

Additionally, 24 (58.5%) of the nonresponders were receiving CD38-directed therapy at the time of vaccination, 13 (31.7%) were receiving BCMA-directed bispecific antibody therapy, and four (9.8%) had received BCMA-directed CAR-T therapy more than three months prior.

“We also saw, at least at (the time of the analysis), that at least 10 patients after partial (seven patients) or complete vaccination (three patient), developed COVID-19, and a handful of these patients were hospitalized. Some of these patients went to the intensive care unit, suggesting that patients that don’t have any IgG antibodies might be at risk for contracting the virus.”

®a sister publication of CURE®, Van Oekelen, a PhD candidate and graduate assistant in the Graduate School of Biomedical Sciences at Mount Sinai, discussed the results and implications of the study, as well as plans for further research.

®: Why was it important to study SARS-CoV-2 spike antibody responses to the COVID-19 vaccine in patients with multiple myeloma?

 Patients with multiple myeloma are immunocompromised, either because of the disease itself, which causes a dysfunction of the immune system, or the treatments that they’re receiving. Very often patients are getting multiple lines of chemotherapy or immunotherapy, and we know that these drugs have an effect on the immune system. At the same time, we have studies now showing excellent efficacy for all the vaccines that are available in the United States. We wanted to see whether that efficacy translated to our patients as well, because we were worried that perhaps they might not have as good of an immune response to the vaccine.

What did the findings show? Did anything come as a surprise to you?

Patients with myeloma had significantly lower levels of IgG to the SARS-CoV-2 protein after vaccination (compared with healthy individuals), which was not that surprising. In general, for other diseases, or for other vaccinations, we don’t tend to measure these IgG levels. We do it now because (COVID-19 is) a new disease, and we want to understand it better. But as I said earlier, (low levels of IgG) can be because of the immunosuppressive effect of drugs or the disease itself.

We also had patients who had COVID-19. One question we had when we saw that 15% of the patients mounted no antibodies or no IgG at all was: Who are those patients? What is their profile? When we looked at which patients were unable to develop antibodies, we saw it was mostly patients that were on a CD38-directed monoclonal antibody and patients that were receiving BCMA-directed treatments. Both drugs are known to affect B cells, so that was not that unexpected, but it’s (an) important (finding), especially as CD38-directed treatment is being used extensively in myeloma at this point and the BCMA-directed treatments are growing rapidly. We’re (now) trying to figure out exactly how to explain the fact that these drugs were most associated with not developing antibodies.

The second question was: Does it matter? Does it matter that patients have no antibodies? (We learned that) that clearly matters.

Could the lack of antibodies indicate a delayed response to the vaccine that may become more apparent with a booster shot?

We have data now that, in some patients, extends up to 100 days after vaccination. Just by waiting, there is very little chance that patients who do not have detectable antibodies will get them over time. The important question is: What should we do about it? How should we approach these patients? There have been some data in transplant patients who are also immunosuppressed because of the drugs they receive against rejection, that giving a third shot at 3 or 6 months, or perhaps giving a different vaccine after getting 2 shots, helps some patients to achieve serial positivity or develop antibodies. It’s really a question of whether this could be translated to patients with cancer. We are looking into options to study this. Some of the companies are exploring booster shots as well. It will be important, especially in high-risk patients such as patients with cancer to see whether that can help some patients mount antibodies and be protected.

Even though the study was done in patients with multiple myeloma, could the findings be extrapolated to patients with solid tumors and other immunocompromised individuals?

Multiple myeloma is a disease of the plasma cells, which are the cells that are producing antibodies in normal circumstances, and so, in a way, it is not surprising to see that they have trouble making antibodies because they receive treatments that suppress (malignant) plasma cells and healthy plasma cells to some extent. We have seen similar results come out, sometimes in smaller cohorts or in more heterogeneous cohorts, where a significant proportion of patients failed to develop antibodies. It’s not always 15%; in some diseases, it’s probably a little bit more, and in others, it might be a little bit less. It’s important to identify these people to give them the proper counseling. That’s the most important approach that we take at Mount Sinai. We try to measure these antibodies at least once in patients after vaccination so that we can give them appropriate counsel. We owe it to our patients. Many of those patients have been taking a lot of precautionary measures, more so than many healthy people. We owe it to them to give them good counsel and good advice and tell them whether they should be careful going forward as the country is opening.

This article was originally published on OncLive

COVID-19 Vaccine Fails to Deliver SARS-CoV-2 Spike Antibody Responses in Multiple Myeloma

Fifteen percent of patients with myeloma did not have detectable antibodies two weeks after receiving the COVID-19 vaccine.

COVID-19 Vaccine May Be Less Effective in Patients With Myeloma 

Treatment with Tecentriq (atezolizumab) following surgery was associated with a significant improvement in disease-free survival among patients with stage 2 to 3A non–small cell lung cancer (NSCLC), compared to the best supportive care.

Moreover, the data — which were presented during a news briefing prior to the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting — indicated that the benefit was particularly pronounced in patients who had a PD-L1–positive tumor.

“Though surgery can cure some patients with early-stage lung cancer, disease recurrence is still very common. Until this trial, the only treatment that was known to help reduce that risk for most patients was chemotherapy, or osimertinib [Tagrisso] for the small group of patients with tumors with an EGFR mutation,” said lead study author Dr. Heather Wakelee, a thoracic specialist and chief of the Division of Oncology at Stanford University Medical Center, in a news release. “These data show that personalized medicine with (Tecentriq) can reduce the chance of NSCLC returning after surgery for patients who have a tumor that expresses the biomarker PD-L1.”

Despite the progress that has been made for patients with early-stage disease who harbor EGFR sensitizing mutations, the standard of care remains platinum-based chemotherapy for most patients with resected NSCLC.

Patients had to have had completely resected stage 1B to 3A NSCLC to be enrolled onto the study. After 1,280 patients received between one and four cycles of the chemotherapy cisplatin plus pemetrexed, gemcitabine, docetaxel or vinorelbine, they were randomized to either Tecentriq every 21 days for 16 cycles (1,005 patients) or treatment with best supportive care (1,005 patients).

Measuring disease-free survival (the time after treatment without signs of cancer) in patients with stage 2 to 3A disease, as well as a PD-L1 expression of at least 1% on tumor cells, was the main goal of the study. Other goals included assessing overall survival and disease-free survival in patients with a high expression of PD-L1.

Among patients whose tumors expressed a PD-L1 expression of at least 1%, the data demonstrated that a median disease free survival (DFS) was not evaluable in 248 patients who received Tecentriq compared to a median DFS of 35.3 months in 228 patients treated with best supportive care. Two-year DFS rates were 74.6% in the Tecentriq group and 61% in the best supportive care group. Additionally, three-year DFS rates were 60% in those who received Tecentriq and 48.2% in the best supportive care group.

Treatment with Tecentriq in the other patients was associated with a median DFS of 42.3 months compared to 35.3 months in those who received best supportive care. Two-year DFS was 70.2% with Tecentriq and 61.6% with best supportive care. Additionally, the three-year DFS was 55.7% and 49.4%, respectively.

In terms of safety, 92.7% of 495 patients who received Tecentriq reported a side effect compared to 70.7% of 495 patients in the best supportive care group. Of note, 21.8% of the side effects in the Tecentriq group and 11.5% of side effects in the best supportive care group were considered serious or severe.

None of the patients in the best supportive care group had to withdraw from treatment because of their side effects, however 18.2% of those who received Tecentriq did.

More analyses of DFS and overall survival data are expected to continue as more data are collected over time.

“For the first time, we are seeing that an immunotherapy is effective when used to treat early-stage lung cancer. The IMpower010 trial demonstrates that, for certain patients, (Tecentriq) can delay progression to advanced disease, and perhaps even the need for more aggressive therapy. This could be an important advance in our understanding of immunotherapy and a step forward for many patients with lung cancer” noted ASCO chief medical officer and executive vice president Dr. Julie R. Gralow in the release.

The data, according to an expert, show that treatment with Tecentriq could delay disease progression to an advanced stage, as well as the need for more aggressive therapy.

Tecentriq Significantly Improves Survival Outcome in Patients with Early-Stage Non-Small Cell Lung Cancer

Treatment with sapanisertib did not result in significant activity or a favorable safety profile in patients with refractory metastatic renal cell carcinoma, according to study results presented at the 2021 ASCO Genitourinary Cancers Symposium.

“Sapanisertib had poor tolerability and minimal activity in patients with treatment refractory metastatic (renal cell carcinoma), and there was no clear benefit among patients with (mechanistic target of rapamycin [mTOR]) or (phosphatase and tension homolog [PTEN]) alterations,” lead study author Dr. Bradley McGregor, clinical director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, said in a virtual presentation of the data.

Thirty-eight patients (median age, 62 years) with clear cell metastatic renal cell carcinoma who had received two or more previous lines of treatment and with non-clear cell metastatic renal cell carcinoma who received one or more previous line of treatment were enrolled onto the multicenter, phase 2 study.

Patients underwent a mandatory baseline biopsy that evaluated PTEN status and more than 477 genes, including TSC1, TSC2, mTOR, PIK3CA, and PTEN, prior to receiving 30 milligrams of oral sapanisertib weekly.

Measuring objective response rate (the proportion of patients who had a complete or partial response to treatment) was the main goal of the study. Additional goals included assessing progression-free survival, overall survival, safety and toxicity of the drug.

Most of the patient population had clear cell disease (73.7%), and the rest had non-clear cell renal cell carcinoma (26.3%). Moreover, most patients had intermediate-risk disease (76.3%), followed by favorable- (13.2%) and poor-risk disease (10.5%).

Treatment options following progression on a checkpoint inhibitor and VEGF tyrosine kinase inhibitor are limited for patients with metastatic renal cell carcinoma. Approved rapalogs (a drug class), which have modest activity in the disease, inhibit only mTORC1 (a specific protein), whereas sapanisertib inhibits the entire mTOR pathway by targeting mTORC1 and mTORC2.

Most patients received four or more prior lines of therapy (39.5%). Though, patients who received one (13.2%), two (21.1%), and three (13.2%) prior lines of therapy were also represented. There were five patients who had an unknown number of prior treatments.

After a median follow-up of 10.4 months, treatment with the study drug induced an objective response rate of 5.3%. Median progression-free survival was 2.5 months and the median overall survival was 11.2 months.

The data showed that two patients experienced an unconfirmed partial response, 15 patients had stable disease, 17 patients experienced disease progression and two were not evaluable.

At the time of data stopped being collected, two patients remained on treatment. Of the remaining 36 who discontinued treatment, 29 occurred because of progressive disease and four reached an unacceptable toxicity.

No clear benefit between mTOR and PTEN alterations and clinical benefit with sapanisertib was reported.

Side effects related to treatment with sapanisertib included, but were not limited to, nausea (50%), fatigue (39%), diarrhea (18%), constipation (11%) and dehydration (8%). There were no grade 4 or 5 (more serious or severe) side effects associated with the treatment.

“Additional work is needed to find new targets for patients with advanced RCC,” concluded McGregor.

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Treatment with sapanisertib was associated with limited activity and poor safety outcomes in patients with refractory metastatic renal cell carcinoma.

Novel Therapy Demonstrates Limited Activity and Poor Safety Outcomes in Patients With Metastatic Renal Cell Carcinoma

Clinical benefit from the addition of chemotherapy to endocrine therapy may be determined by menopause status in women with hormone receptor (HR)-positive, HER2-negative, lymph node-positive breast cancer and a recurrence score between 0 and 25, according to findings from an analysis of the phase 3 RxPONDER trial that were presented virtually during the 2020 San Antonio Breast Cancer Symposium.

In particular, the addition of chemotherapy to endocrine therapy led to an improvement in five-year invasive disease-free survival and overall survival (OS) in premenopausal but not postmenopausal women.

In premenopausal patients, the five-year invasive disease-free survival rate was 94.2% in the chemotherapy/endocrine therapy arm vs. 89% in the endocrine-alone arm. In postmenopausal patients, the five-year invasive disease-free survival rate was 91.6% and 91.9%, respectively.

“Postmenopausal women with one to three positive nodes and recurrence score between 0 and 25 can likely safely forego adjuvant chemotherapy without compromising (invasive disease-free survival),” said lead study author Dr. Kevin Kalinsky during a press briefing.

“This will save tens of thousands of women the time, expense and potentially harmful side effects that can be associated with chemotherapy infusions,” Kalinsky, director of the Glenn Family Breast Center and Breast Medical Oncology at Winship Cancer Institute, added. “(However,) premenopausal women with positive nodes and recurrence scores between 0 and 25 likely significantly benefit from chemotherapy.”

Patients with HR-positive, HER2-negative, lymph node-positive breast cancer have an increased risk for recurrence and are typically treated with chemotherapy.

To prevent potential overtreatment or undertreatment, the 21-gene Oncotype Dx Recurrence Score is used to identify which patients with lymph node-negative, HR-positive, HER2-negative disease can omit chemotherapy.

In lymph node-negative patients, exploratory findings from the phase 3 TAILORx trial suggested that women over the age of 50 with a recurrence score of 25 or less derive no benefit from chemotherapy, whereas patients age 50 or under with a recurrence score between 16 and 25 may derive benefit from chemotherapy. However, whether these results were generalizable to the approximately 20% of patients with nonmetastatic HR-positive, HER2-negative disease and one to three positive lymph nodes in the United States had not been previously defined.

To that end, investigators launched RxPONDER, in which 5,015 patients with a recurrence score between 0 and 25 were randomized to endocrine therapy alone or chemotherapy followed by endocrine therapy. Patients with a recurrence score of more than 25 were treated with chemotherapy followed by endocrine therapy.

Patients in the randomized portion of the trial were categorized by recurrence score (0-13 versus 14-25), menopausal status (pre versus post), and nodal surgery (axillary lymph node dissection versus sentinel lymph node biopsy).

Eligible patients included females 18 years of age or older with at least 1% estrogen receptor and/or progesterone receptor expression, HER2 negativity, one to three positive lymph nodes, recurrence scores of 25 or less without distant metastases and an ability to receive taxane and/or anthracycline-based chemotherapy.

Invasive disease-free survival, defined as local, regional, distant recurrence, any second invasive cancer or death due to any cause, served as the primary end point of the study. OS served as the secondary end point.

Additional results demonstrated that the invasive disease-free survival benefit also translated into an OS benefit in premenopausal patients. In this population, the five-year OS rate was 98.6% with chemotherapy/endocrine therapy vs 97.3% with endocrine therapy alone. However, in postmenopausal women, the five-year OS rate was 96.2% and 96.1%, respectively.

Providing additional perspective during the press briefing, SABCS co-director, Dr. C. Kent Osborne, founding director of the Dan L. Duncan Comprehensive Cancer Center and Dudley and Tina Sharp Chair for Cancer Research at Baylor College of Medicine, said, “The results clearly show no benefit to adding chemotherapy to standard endocrine therapy in postmenopausal patients, despite having positive nodes, emphasizing that node positivity, while an important prognostic marker, is not a predictive marker of chemotherapy sensitivity.”

“In premenopausal patients, a different result was obtained. Is the difference in outcome in this subset due to the endocrine effects of chemotherapy? Unfortunately, we may never know the answer to this question,” Osborne concluded.

Premenopausal women with HR-positive, HER2-negative, lymph node-positive breast cancer and a risk for recurrence experienced benefits with chemotherapy plus endocrine therapy, with improvements in five-year invasive disease-free and overall survival. 

Chemotherapy With Endocrine Therapy Shows Clinical Benefit With Improved Survival in Breast Cancer 

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).

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.