Many patients with non–small cell lung cancer (NSCLC) achieve much better outcomes with targeted therapy compared with chemotherapy, according to Beth Sandy, MSN, CRNP.

For example, findings from Singal G et al found that the median overall survival (OS) was 18.6 months for patients with NSCLC who received targeted therapy for their driver mutation.

 In comparison, among those who received standard-of-care chemotherapy when they had a driver mutation, the median OS was 11.4 months.

However, with many new targeted therapies receiving FDA approval, it can be difficult to stay up to date on the various options.

School of Nursing Oncology Annual Meeting

 Sandy, who is a thoracic oncology nurse practitioner at the Abramson Cancer Center with the University of Pennsylvania, gave a brief overview on the treatment landscape for patients with NSCLC who have actionable driver mutations. She highlighted which agents were approved for which mutations, compared their efficacy and safety profiles, and noted if any promising new generation agents were under investigation for the driver mutation.


Throughout the presentation Sandy noted that patients are only eligible for targeted treatments if have 

 was never more important than it is now in NSCLC,” Sandy noted. “Up to 40% to 50% of patients with adenocarcinoma are going to have some kind of actionable mutation, where we can give them a targeted therapy instead of chemotherapy or immunotherapy, to manage their disease—usually with better outcomes and less toxicity.”

-mutated NSCLC, including the first-generation agents gefitinib (Iressa), and erlotinib (Tarceva), and the second-generation agents afatninib (Gilotrif), osimertinib (Tagrisso), and dacomitinib (Vizimpro).

Osimertinib is the preferred agent recommended by the National Comprehensive Cancer Network guidelines based on its superiority over the first generation agents, and its favorable toxicity profile.

In the first-line metastatic setting, osimertinib was associated with a 38.6-month median OS (95% CI, 34.5-41.8), compared with 31.8 months with a comparator 

tyrosine kinase inhibitor (95% CI, 26.6-36.). The hazard ratio was 0.80 (95.05% CI, 0.64-1.00; 

Moreover, in light of recent data showcasing the agent’s value in the adjuvant setting, osimertinib is now an option for patients following surgery and chemotherapy.

There are 2 approved agents for patients with exon 20 insertions: amivantanib (Rybrevant) and mobocertinib (Exkivity).

Amivantitanib is given intravenously (IV) once per week for 4 weeks, and then once every other week. Relevant adverse effects (AEs) include infusion reaction with the first dose (66%) and rash (74%).

Mobocertinib is an oral agent and patients take 4 tablets a day. Major reported AEs included diarrhea (93%), 20% of which was grade 3 or greater, and heart rate corrected prolongation or cardiomyopathy, which is rare.

Both agents can cause interstitial lung disease, which was reported among 3.1 % and 4.3% of patients, respectively.

mutations are the most common oncogenic drivers in NSCLC and present in approximately 25% of nonsquamous and 3% of squamous cases. Patients who are likely to have a 

mutation include younger, female, and Caucasian patients, as well as those with a smoking history. Among 

 mutations, G12C is the most common variant representing approximately 40%-50% of 

 mutations and is evident in about 13% of adenocarcinomas.

In 2021, the first targeted therapy for patients with a 

 G12C mutation, sotorasib (Lumakras), was approved for locally advanced or metastatic disease which had progressed after at least 1 prior platinum-based regimen and/or immunotherapy based on findings from CodeBreaK 100 (NCT03600883).

Sotorasib is administered at 960 mg once daily either with or without food.

The tablets are sold as 120 mg and patients will take 8 tablets. The most common laboratory abnormalities associated with this targeted treatment are decreased lymphocytes, decreased hemoglobin, increased aspartate aminotransferase, increased alanine aminotransferase, decreased calcium, increased alkaline phosphatase, increased urine protein, and decreased sodium.

Patients taking sotorasib should avoid the concomitant use of proton pump inhibitors and H2 blockers. Over the counter acid reducing mutation, such as TUMS, are OK.

Adagrasib, another oral therapy targeting 

 mutations, is under investigation. The agent has shown encouraging clinical activity; however, as of August 2022, it is not approved.

 exon 14 skipping mutations have 2 approved treatment options: capmatinib (Tabrecta) or tepotinib (Tepmetko).

exon skipping–mutated NSCLC treated with capmatinib, the overall response rate (ORR) was 44.0%, the median duration of response (DOR) was 9.7 months, and the median progression-free survival (PFS) was 5.5 months. In the treatment naïve cohort (n = 60), the median ORR was 66.7%, the median DOR was 12.6 months, and the median PFS was 12.3 months.

Oral doses of capmatinib can be given at 400 mg twice daily with or without food.

 Commercially available doses are sold at 150 mg and 200 mg. The most common AEs associated with this treatment include peripheral edema, fatigue, nausea, vomiting, dyspnea, and decreased appetite. The most common laboratory abnormalities (greater than 20%) include decreased albumin, increased creatinine, alanine transaminase increase (ALT), alkaline phosphatase, amylase, gamma-glutamyl transferase, lipase, and aspartate transaminase increase (AST).

The agent includes a box warning for interstitial lung disease/pneumonitis, hepatotoxicity, photosensitivity, and embryo-fetal toxicity. Nurses prescribing this drug to patients should ensure that patients are avoiding strong to moderate CYP3A inducers.

exon skipping–mutated NSCLC who were treated with tepotinib, the ORR was 44.6%, the median DOR was 11.1 months, and the median PFS was 10.9 months. In the treatment-naïve cohort (n = 69), the median ORR was 44.9%, the median DOR was 10.8 months, and the median PFS was 8.5 months.

Tepotinib should be taken with food once daily at 450 mg.

 Tablets are 225 mg. The most common AEs associated with this agent include edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. Common laboratory abnormalities include decreased albumin and sodium, as well as increased creatinine, alkaline phosphatase, ALT, AST, potassium, amylase, and gamma-glutamyltransferase.

This agent shares the same warnings as capmatinib, except it is not associated with photosensitivity. Patients taking this drug should avoid strong CYP3A and P-glycoprotein inhibitors as well as strong CYP3A inducers.

-mutated NSCLC is 2%, making it an uncommon mutation with this disease, Sandy noted. This mutation is more common among smokers.

The combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) was approved for patients with 

 V600E–mutant NSCLC. According to data from the 2022 International Association for the Study of Lung Cancer (IASLC) Targeted Therapies conference, 20% to 50% of patients with a 

It is slightly more common among female nonsmokers. The most common toxicity associated with this treatment is a noninfectious fever.

Other drugs under investigation for this setting include encorafenib (Braftovi) plus binimetinib (Mektovi), as well as vemurafenib (Zelboraf) and cobimetinib (Cotellic). These agents are not approved.

An RNA-fusion panel is the most sensitive test for identifying fusions and gene arrangements, Sandy said. However, next-generation sequencing, immunohistochemistry (IHC), and fluorescence in situ hybridization testing, can be useful as well.

There are 5 approved drugs for patients with 

fusions in NSCLC, all of which have different toxicity profiles, administration, and schedules, she noted.

For example, crizotinib (Xalkori) is taken at 250 mg twice a day and is available in 250-mg and 200-mg capsules;

ceritinib (Zykadia) is taken at 450 mg daily and is available in 150-mg capsules;

 alectinib (Alecensa) is taken at 600 mg twice a day, and is available in 150-mg capsules;

 brigatinib (Alunbrig) is taken at 90 mg daily for the first week, and then at 18 mg daily for the following, and is available at 30-mg, 90-mg, and 180-mg capsules;

 and lorlatinib (Lorbrena) is taken at 100 mg daily and is available at 25-mg and 100-mg tablets.

Of these, alectinib, brigatinib, and lorlatinib, have demonstrated excellent intracranial penetration.

, there are 2 approved drugs: crizotinib and entrectinib (Rozyltrek). The 2 agents have demonstrated similar response rates, although entrectinib has considerably better intracranial penetration. Both drugs are associated with excellent and durable responses. Patients are often able to live a long time with these treatments.

 gene rearrangements have 2 treatment options available to them, selpercatinib (Retevmo) and pralsetinib (Gavreto). Both drugs have similar efficacy data, including excellent response rates and long durable responses for 1 to 3 years. Selpercatinib may be given to patients who weigh 50 or more kg at a dosage of 160 mg twice daily. Associated AEs include elevated transaminase, hypersensitivity reactions, hepatotoxicity, hypertension, skin rash, electrolyte abnormalities, abdominal pain, constipation, diarrhea, nausea, vomiting, xerostomia, and fatigue.

Pralsetinib must be given on an empty stomach. This drug is given at a dose of 400 mg and its associated toxicities include elevated transaminases, neutropenia, anemia, thrombocytopenia, hypertension, dysgeusia, diarrhea, constipation, increased creatinine, pneumonitis, and hyponatremia.

 gene fusions are best found on a fusion panel. These are rare, and among the gene fusions, 

 represent the most common expressions. There are 2 first generation agents available: entrectinib and larotrectinib (Vitraki). The response rate with these agents was 70%.

Another agent, repotrectinib (TPX-005), is under investigation.

-mutated NSCLC is not to confuse it with IHC+, or overexpression, or amplification, Sandy stressed. As of 2022, antibody-drug conjugates have demonstrated the most clinical activity with this biomarker, with fam-trastuzumab deruxtecan-nxki (Enhertu) leading the way in terms of clinical activity, but no agents are approved.

Data from the DESTINY-Lung01(NCT03505710) trial showed that among 85 patients the best percentage change of tumor size was 54.9% (95% CI, 44.2%-65.4%).

-mutated NSCLC is an emerging field, Sandy noted.

Sandy B. Molecular testing and targeted therapies in lung cancer. Presented at: 

 School of Nursing Oncology®; July 29-30, 2022; San Diego, CA.

Singal G, Miller PG, Agarwala V, et al. Association of patient characteristics and Tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. 

. 2019;321(14):1391-1399. Published correction appears in 

Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology. 

. 2022;20(5):497-530. doi:10.6004/jnccn.2022.0025

Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. 

. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137

Articles

At the 6th Annual SONO meeting, Beth Sandy, MSN, CRNP, reviewed available treatment options for patients with identified driver mutations in non–small cell lung cancer.

Targeted Therapy Approvals Improve Outcomes, Expand Options for Patients With NSCLC

Understanding the role of maintenance PARP inhibitor therapy and the importance of germline testing for all women with a diagnosis of ovarian cancer are 2 areas of importance for oncology nurses, according to Paula Anastasia, RN, MN, AOCN.

Maintenance therapy with PARP inhibitors has been documented to improve progression-free survival (PFS) in women with stage III-IV ovarian cancer following a complete response (CR) or partial response (PR) to platinum-based chemotherapy. Three agents are approved by the FDA for the treatment of ovarian cancer: olaparib (Lynparza), rucaparib (Rubraca), and niraparib (Zejula).

Treatment adverse effects [AEs] of anemia, nausea, and other hematological effects should be monitored with continued communication between patients and nurses.

“When I started [nursing] 30 years ago, my patients who [had] stage 3 [disease], on average, lived 2 years,” said Anastasia, a gynecologic Oncology Clinical Nurse Specialist for UCLA Health. “Now my patients are living 5 years, 10 years, and longer. They may be on chemotherapy on and off for the long term, but there are long-term remissions and treatment breaks, because we have more and more treatments available. The PARP inhibitors are really providing PFS [benefit] and with the recent data from olaparib in SOLO-1 [NCT01844986] and SOLO2 [NCT01874353], we are seeing our patients [remain] on frontline maintenance olaparib post chemotherapy [and are] disease free for 3 to 5 years.”

Anastasia added that there is still a long way to go with defining the role for PARP inhibitors. “Long-term survival has expanded with the use of PARP inhibitors and maintenance therapy. We didn’t have maintenance therapy 3 years ago. Now with all these studies we’re [in the stage of] tweaking and finding the right dose and the right concoction for the right patients.”

®, Anastasia discussed how multipanel testing is key for identifying patients who have a germline mutation and are therefore at risk of developing other cancers and how customization of care, such as changing of dosing, is importance in determining appropriate PARP inhibitor treatments.

Please highlight how PARP inhibitor therapies are changing the field?

[There were updates at] the Society of Gynecologic Oncology and at ASCO. [These] were very exciting…but they’re not ready for primetime. There’s a lot of new information with combination therapy using PARP inhibitors with the goal to extend survival benefit for patients.

The rucaparib study [ATHENA-MONO; NCT03522246], is looking at frontline maintenance therapy, comparing rucaparib with placebo. Right now, there are 2 PARP inhibitors [approved] for frontline maintenance therapy—olaparib and niraparib. Rucaparib is not approved for frontline [maintenance] yet.

[In ATHENA-MONO] rucaparib showed a median PFS [improvement] in patients who have a homologous recombinant–deficiency [HRD] compared with placebo. [The study] was talked about, saying [it would support] a new FDA indication, but fortunately, or unfortunately, the FDA is being very cautious. They are now saying no, we’re not going to provide approval until [the data] reach 50% maturity and that can take another 2 years. These data are still premature [at] 25%. Time is of essence, but it’s also important to have safety data and look at overall PFS and then in addition, overall survival.

What are some key considerations when selecting a PARP inhibitor for your patient?

Eligibility [for the 2 approved PARP inhibitors] is different based on whether they have a germline or a [genomic] tumor mutation. It’s important that if patients don’t have a germline mutation, they should have tumor testing to see if there’s a deficiency in the homologous recombination pathway. If patients have a deficiency, they would be eligible for a PARP inhibitor, [and studies have shown that] patients who have a germline or an HRD-positive tumor have a better clinical benefit with a PARP inhibitor.

Niraparib is approved for all comers, whether they have a germline or tumor mutation. That’s important in determining a PARP inhibitor and personalized and individualized care is important to pay attention to the patient’s prior AEs from chemotherapy.

As we go forward, after frontline therapy, if patients are in a clinical remission or partial remission—which [we expect] 80% of patients will be—[they] will be offered a PARP inhibitor. Most patients who received 1 line of chemotherapy have sturdy bone marrow, but there is a percentage who don’t, so we want to know, how did patients do with their frontline therapy? Did they require growth factors? Were there dose reductions? Do they have a history of hypertension, which may indicate whether they would tolerate niraparib? All those questions personalize care.

What is the nurse’s role in genetic testing and helping patients understand the importance of it, interpreting results, and helping them make sense of what's going on?

I can't emphasize enough that all patients should have genetic testing.

When we talk about genetic testing, germline testing, now we want panel testing because in addition to the 

 pathogenic variants, there are other pathogenic variants in that family [such as] 

. Sometimes, if clinics aren’t experienced in doing genetic testing, then these targets may be missed. We’re fortunate [at UCLA] that we have a genetic counselor on site, and I know that every [practice] does not have that luxury. There are online genetic counselor services and in addition to testing, all patients should also have counseling [and the opportunity] to ask what does this information mean?

If a patient carries a germline mutation there are other cancer risks: breast cancer, pancreatic cancer, melanoma, etc. In addition, if we’ve identified a germline mutation in our patients, we want to do cascade or family testing—siblings, parents, aunts, uncles, cousins. If we can help prevent cancer by testing a family member, we’ve done a very good thing. I think a lot of that is very helpful and there are support groups, for patients who have germline mutations. I think part of our role as nurses is letting them know that this is part of standard of care.

The other thing that we don’t talk enough about is health care disparities. There is so much data out there and not all ethnic groups are having genetic testing. We do a disservice to our patients if we’re not testing, because then they may be missing out on receiving a PARP inhibitor as a maintenance therapy, or in a recurrent setting. Not only is it a hindrance to the patient, but we’re also not doing cascade testing on their family members, and therefore preventing cancers for them as well.

[We also need to be] aware of our own practices and instill trust in our patients because we want what's best for them [and we must discover] what is important to the patient.

What data are available surrounding tolerability and dose changes for patients receiving PARP therapy? What have you found useful in helping patients who may be experiencing toxicities with continued treatment?

I always tell my nurses…you may not be an expert on knowing the doses. That’s what the package inserts are for, that’s what the pharmacist is for. 

Looking at [data from studies of] niraparib, patients who weighed less than 77 kg and/or have platelet [counts] less than 150,000, should be started at 200 mg daily, as opposed to FDA-approved dose, which is 300 mg. I [was involved in] the original studies and saw a tremendous grade 4 thrombocytopenia when these patients were receiving the 300-mg dose. It was almost counterintuitive because we had dose delays and patients couldn’t receive the therapeutic drug on time.

We check their [complete blood count] CBC every week when we first start niraparib. If they’re on olaparib, we check it monthly. The goal is to see their tolerability; we are looking for any hematological changes. 

I remind patients that when they get [intravenous] IV therapy, we are basing those doses on their height and weight, but with oral medications, it’s one size fit all. If we need delay or dose reduce, again, that’s [based on] their body’s metabolism. I remind them that we are individualizing and personalizing their care.

What AEs should patients be looking for when they’re on a PARP inhibitor?

With the first line maintenance patients do so much better and communication is key.

The classic effects are fatigue, nausea, and then hematological AEs. We oversee the hematological AEs and that’s why we really mandate that they have their labs drawn [more frequently at the start] so we can tweak things. 

Nausea is more like underlying queasiness, and I tell patients to take an antinausea medicine at bedtime, just to see if we can mitigate [it].

Are there any patients who may not be a good fit for PARP inhibitors, even when it is standard of care?

I think most patients are fit to have PARP inhibitors; however, sometimes we must start at a lower dose. Just because we’re starting at a lower dose does not mean it’s going to be sub therapeutic. [It’s important to consider] if the patient is able to take oral medications [and if] they are going to be adherent.

There may also be patients who have a poor performance status and have comorbidities. There is a very small percentage of patients for whom [PARP inhibitors] might not be the right fit. But for the majority, paying attention to individual AE profiles, chemotherapy response, and if they benefit from having a lower dose than the FDA approved starting dose [are important considerations].

What kind of conversations need to happen between patients and providers before starting these therapies?

Something we don’t talk about is the financial [burden]. These medications can be very expensive, and I’ve [seen] copays of $0 and I’ve [seen] copays of $5000 to $10,000. There are copay assistance programs, and I don't think we utilize them enough, but I’ve been able to get grants for patients and the pharmaceutical companies have been very helpful.

It can sometimes be time consuming, but the copay assistance programs, and access groups will do some of the legwork for us.

Pthuri B, O’Cearbhaill R, Eskander R, Armstrong D. Frontline PARP inhibitor maintenance therapy in ovarian cancer: a Society of Gynecologic Oncology practice statement. 

 2020;159(1):8-12. doi:10.1016/j.ygyno.2020.07.097

 Paula Anastasia, RN, MN, AOCN, discusses the value of germline testing 
and the role of maintenance PARP inhibitor therapy in optimized ovarian cancer treatment. 

Nurses Play Key Role in Facilitating Maintenance Therapy With PARP Inhibitors in Ovarian Cancer

Biomarker testing in lung cancer has never been more important, according to Beth Sandy, MSN, CRNP. Targeted treatments are associated with better outcomes and fewer toxicities for patients with select mutations, and although there are multiple barriers to testing, she urges all oncology nurse practitioners to order molecular tests for all newly diagnosed patients with lung cancer.

“It is really important that we are doing the testing,” Sandy, who is a nurse practitioner at Abramson Cancer Center at the University of Pennsylvania, said in an interview with 

®. “Recent studies have shown that we’re not testing at great rates—less than 50% of [individuals] are getting the full next-generation sequencing [NGS] panel, which is testing for all these things. We need to make sure we’re doing a good job.”

Current National Comprehensive Cancer Network recommendations for biomarker testing say that, whenever feasible, providers should recommend a broad panel-based, molecular test. NGS is the most common way to complete this. These can be performed either in-house or through a commercial company. If no biomarkers are uncovered, providers should consider an RNA sequencing panel to detect RNA fusions.

In addition, all patients with metastatic NSCLC with nonsquamous histologic subtypes and NSCLC not otherwise specified should be tested for biomarkers. Testing should be considered in any patients with squamous disease. Further, as of 2022, patients with IB-IIIA NSCLC should be tested for 

 mutations when they are being considered for adjuvant therapy, and patients with II-III NSCLC being considered for adjuvant therapy should be tested for PD-L1.

In addition, patients with stage II-III NSCLC being considered for neoadjuvant therapy should be tested for 

 mutations prior to receiving immunotherapy/chemotherapy, because the presence of the biomarker renders the treatment less effective, Sandy noted.

Sandy recently presented on the value and practicalities of 

® ahead of the conference, Sandy discusses some of the challenges for nurses to consider when ordering the tests.

“There are barriers,” she said. “First of all, you have to make sure that [the test] has been ordered and that the patient has quality tissue for it. For example, sometimes you will order an NGS panel, and it comes back as an “S,” which means quality or quantity is not sufficient to run the test. What do you do then? Do you retest [the patient]? There are a lot of [questions] there.”

“[Further], a lot of these reports are going to an outside company,” Sandy added. “So [you need to check] for a result. Did it go to a portal online that you have to look it up? Did it come across a fax machine, and it’s sitting on a fax machine, and no one’s looked it up? At the University of Pennsylvania, we do in-house testing and even I sometimes can’t find [the results] in our electronic medical records. If it’s embedded in the pathology report, it [may be] hard for me to find—I may overlook it—I [may] have an unconscious bias [and think] a patient isn’t going to have a mutation.”

It is key to ensure that all patients receive molecular testing and that the results find their way into the electronic medical report. Once this has been completed, the next barrier is understanding the results, Sandy said, adding that collaboration with the molecular pathologists is crucial.

“There’s a whole line of numbers and letters that don’t make any sense to me,” she admitted. “I recommend calling the molecular pathologist, whether it’s in your institution or an outside institution, they love to talk about this stuff. I call them and say: What does this mean? Is this targetable? Is there something approved? Is there something in clinical trials? Does it mean that that’s actually actionable?”

Moreover, Sandy noted that the oncology nurse plays a vital role in ensuring that these processes are completed and the test was done. Once it’s been ordered, the oncology nurse ensures the report has been received, deciphered, and explained to the patient. Then, once the report has been conducted, the team can see whether there are any approved targeted therapies that correlate with the mutations.

When it comes to ordering liquid vs tissue biopsies, Sandy noted that there are advantages and disadvantages associated with each.

“Everyone has lung tissue,” she said. “But sometimes tissue come back as QMS: quality not sufficient.”

Blood biopsies are less invasive, and results come back quicker; however, if the tumor did not shed DNA on the day the blood was drawn, the mutations might not show on the report. In addition, these tests cannot detect histology, and cannot therefore determine a “small cell transformation” from 

“[Individuals] who don’t have a big disease burden might not have [tumor] shedding that day. But if you [don’t] actually find a mutation [via liquid biopsy], that doesn’t mean they don’t have a mutation,” she said.

To address these concerns, Sandy recommended ordering both tests. “I would make an argument to do both from the beginning,” she said. “At my institution, the day the patient comes to see me, we do both [tests].”

Because the tissue biopsy takes longer but may be more accurate, by ordering both at the same time, you are providing you patient with the best chance to start treatment sooner, she explained.

“The blood [tests] comes back in less than 5 days. It’s really quick. In comparison, the tissue 2 to 3 weeks,” she said. Further, if something actionable is detected in the liquid biopsy, the patient can be treated right away. If nothing appears in the blood, by already having ordered the solid biopsy, the patient is still waiting for a shorter amount of time to received treatment.

‘By doing both together [liquid] and tissue, you’re going to find more results, and cover all the bases you can to try to find one of these actionable mutations” she concluded.

Sandy B. Molecular testing and targeted therapies in lung cancer. Presented at: 

 School of Nursing Oncology®; July 29-30, 2022; San Diego, CA.

Ettinger DS, Wood DE, Aisner DL, et al. Non-small cell lung cancer, version 3.2022, NCCN Clinical Practice Guidelines in Oncology. 

Beth Sandy, MSN, CRNP, discusses some of the challenges that may be associated with molecular testing, and how oncology nurses can help play a role in ensuring that the reports are received. 

Sandy on the Practicalities of Molecular Testing in Newly Diagnosed Lung Cancer

Recommendations for the use of liquid biopsies to detect circulating tumor DNA (ctDNA) were recently released by the European Society for Medical Oncology (ESMO). Investigators reviewed available evidence to provide tumor-specific and general consensus on the use of ctDNA and clarify quality standards required for decision-making.

The assay, which is minimally invasive and can provide more convenient and rapid results compared with tissue samples, has become increasingly used in clinical practice to molecularly profile tumors. The release of ctDNA is believed to be proportional to tumor growth with more ctDNA being shed as a tumor grows.

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response. Of note, the guideline authors state there is a lack of clinical evidence to support the recommendation of ctDNA assays in these areas.

“New technologies currently in development, such as methylation pattern-based sequencing, fragmentation pattern-based sequencing or novel ultra-sensitive mutation detection methods, have the potential to optimize utility in these new settings,” the study authors wrote. “Multiple clinical trials are underway that may provide the evidence base to adopt ctDNA assays for decision making in multiple clinical scenarios.”

However, ctDNA assays have a larger role for patients with advanced disease as it can be used to guide adoptive adjuvant strategies upon clinical relapse, identify biomarkers to guide therapy and monitor response to therapy, and, upon disease progression, ctDNA assays can be used to identify acquired resistance mechanisms and the emergence of driver and resistance clones.

The evaluation of ctDNA varies and a single ctDNA assessment is fit for all purposes. Investigators noted that the ctDNA fraction changes based on tumor features such as extent of necrosis, disease burden, tumor location, inflammation, rates of proliferation and apoptosis, tumor microenvironment and host-related phenomena. Treatments such as chemotherapy, targeted therapy, radiation, and immunotherapy can also affect levels of ctDNA and ctDNA fraction.

Liquid genotyping consists of polymerase chain reaction (PCR)-based technologies and many studies have shown positive predictive values between ctDNA liquid biopsy and tissue-based PCR and next-generation sequencing testing in advanced malignancies (95%-99%). High accuracy of liquid biopsy in breast, gastrointestinal and lung cancer for single-nucleotide variants have been reported in large prospective studies of liquid biopsy.

The ESMO guidelines include tumor-specific recommendations for tier 1 and tier 2 variants across tumor types including the following:

 ctDNA genotyping recommended in treatment-naïve patients with cancer with resistance to prior TKIs. ctDNA testing may not have adequate sensitivity to detect 

 true high copy number gain as resistance mechanism to osimertinib (Tagrisso) or lorlatinib (Lorbrena). Further, amplification and fusion detection is suboptimal with ctDNA assays, and should be repeated in tissue where possible.

mutations should preferentially be tested in ctDNA. 

fusions only when advanced tissue biopsy not available.

 ctDNA testing if tissue not available or when fast turnaround time is needed for urgent therapeutic decision-making.

 V600E/microsattelite instability for chemotherapy-naïve metastatic colorectal cancer is recommended when tissue testing is not feasible or urgent therapeutic decision-making. 

 pathogenic or likely pathogenic somatic variants may be carried out if tissue not available.

 for potential PARP inhibitor therapy. Caution is needed when interpreting results of ctDNA assays due to false-positive CHIP mutations in DNA repair genes.

Pancreatic, hepatocellular, endometrial, urothelial, thyroid, and soft tissue sarcoma

In terms of general tumor site recommendations, the ESMO guideline committee noted the occasions where tissue testing may provide confirmatory or more accurate guidance for treatment decision-making. These include interpretation of pathogenic variants such as 

; retesing results that are deemed “not detected” by ctDNA; and for the detection of fusions and copy number events. Further, liquid biopsy should not be taken when a tumor is responding to treatment.

Liquid biopsy may have limitations for the detection of specific deviations, and they risk false negative results and the authors recommend that clinicians take these into consideration when evaluating the results. A false negative result may occur when a patient’s plasma sample does not have sufficient levels of ctDNA or ‘non-shedding’ happens, preventing the detection of a variant. False positive results may occur when clonal expansion takes place in apoptotic hematopoietic cells, where plasma DNA mainly originates; the frequency of clonal hematopoiesis of indeterminate potential (CHIP) increases with age, previous systemic cancer treatment and smoking. False positives can be minimized with either the sequencing of white blood cell DNA or the pairing sequencing of a tumor tissue sample. Additional limitations of ctDNA testing include a low tumor fraction presence in the sample, which prevents reliable assessment of variant allele fraction and limits copy number alteration analysis.

The guidelines recommend that clinicians consult a molecular tumor board for to assess results.

Pascual J, Attard G, Bidard FC, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: a report from the ESMO Precision Medicine Working Group. 

. Published online July 6, 2022. doi:10.1016/j.annonc.2022.05.520

In early-stage cancers, ctDNA has a role in screening, neoadjuvant monitoring, identification of molecular residual disease (MRD), molecular relapse monitoring, and early assessment of treatment response.



ESMO Guideline on Liquid Biopsy Address Quality Standards for Clinical Implementation

Certain immune-cell related parameters in patients with advanced or metastatic clear cell renal cell carcinoma (RCC) may be tied to stronger responses with the combination of nivolumab (Opdivo) and ipilimumab (Yervoy), according to an analysis of the phase 2 TITAN-RCC clinical trial.

Results from the study were presented by Marc-Oliver Grimm, MD, of Jena University Hospital at the 2022 Genitourinary Cancers Symposium, and revealed that having 4-1BB or LAG-3–expressing T cells at baseline correlated with response to nivolumab induction. Moreover, nivolumab/ipilimumab boosts were associated with a high proportion of PD-L1-expressing myeloid cells and plasmacytoid dendritic cells (pDC) during boost cycles.

Response to immune checkpoint inhibitors in patients with RCC appears to vary from patient to patient. There is a need in the field to identify key predictors of response to immunotherapy. With consideration that a boost of nivolumab plus ipilimumab improved response compared with nivolumab monotherapy in patients with RCC treated in the TITAN-RCC clinical trial,

 investigators assessed characteristics of blood-circulating immune cell subsets within the study population to identify the markers of response.

TITAN-RCC included 207 patients with clear cell RCC whose disease was metastatic or locally advanced according to histologically confirmation. Patients were required to have intermediate or high International Metastatic RCC Database Consortium (IMDC) risk, be either untreated or previously treated with 1 prior tyrosine kinase inhibitor, and have measurable disease per RECIST v1.1, and a Karnofsky performance score ≥ 70.

Baseline characteristics of the intention-to-treat (ITT) population of 207 patients showed a median patient age of 65 years (range, 20-87), and the population was predominantly male (71%). Fifty-three percent of patients entered the study while in the first-line treatment setting and the remaining 47% were second line. In terms of IMDC risk factors, 18% of the ITT population had a Karnofsky performance score of < 80%, 65% had an initial RCC diagnosis < 12 months, and laboratory values including hemoglobin, platelet count, neutrophil, and calcium were adequate. Overall, 70% of the ITT population had intermediate-risk disease, 25% had poor-risk disease, and 4.3% had favorable-risk disease.

Among the 137 patients who received an immunotherapeutic boost during the study, the median age was 64 years (range, 20-86), and the cohort was also 71% male. Forty-eight of the patients were the first line and 52% were second line. IMDC risk factors were adequate and similar to the ITT population. Overall, 74% of the boost group had intermediate-risk disease, 21% had poor-risk disease, and 5.1% has favorable-risk disease.

“Patients received nivolumab induction until week 16 and continued with nivolumab maintenance upon remission. Patients who had stable disease or progressive disease or early progressive disease at week 8 continued up to 4 cycles,” explained Grimm during the presentation. The 4 cycles included immunotherapeutic boosts of nivolumab 3 kg/mg with ipilimumab 1 kg/mg in patients who were stable after 4 cycles. Nivolumab maintenance was then continued in these patients at multiple time point during induction and before each boost cycle.

Investigators looked at 198 samples from patients with RCC, 105 of whom were treated in the frontline setting, and 93 of whom were second line. The samples were evaluated using multiparametric flow cytometry for frequency and phenotype of T cell, monocyte, myeloid-derived suppressor cell (MDSC), and dendritic cell (DC) subsets. Further, uni- and multivariable logistic regression modeling was used to look into the association between treatment response and immune parameters.

By flow cytometry, immune response in the Mo, MDSC, CTL, Th, and Treg cells were evaluated. Further, single marker models that were adjusted for age and gender. Data showed that most of the markers investigated had some correlation with immune response except for CD8-positive T cells like TIM-1, VISTA, OX40, CD69, and CD28 compared with PD-1, LAG-3, CTLA-4, and others. In the CD4-positive T-cell category, only VISTA and CD69 were not associated with immune response.

Results for responders to nivolumab induction were split into 3 categories. First, of those with 4-1BB-positive, CD8-positive T cells at baseline, 41 responded to therapy while 106 did not respond (odds ratio [OR] 1.03; 95% CI, 1.01-1.07). Among the patients with 4-1BB-positive, CD4-positive T cells at baseline, there were 43 responders and 106 non-responders (OR, 1.05; 95% CI, 1.02-1.08). In the last category of patients with LAG-3-positive, CD4-positive T cell at baseline, 41 patients had a response to nivolumab induction while 106 did not respond (OR, 1.03; 95% CI, 1.01-1.05).

Looking at CD14-positive monocytes and pDC, at the time of the first boost cycle, patients with CD86-positive cells were most likely to respond to therapy compared with those with CD40-positive cells or PD-L1-positive cells. Also, ICOS positivity did not correlate with response to the nivolumab/ipilimumab boost.

Across the board in CD14-, e-MDSC-, and pDC-expressing cells, PD-L1 expression correlated with non-response to immunotherapy with nivolumab plus ipilimumab boost at cycle 1. Only 4 patients with PD-L1 expression in CD14-positive cells responded compared with 41 nonresponders (OR, 1.22; 95% CI, 1.06-1.58). In patients with PD-L1 expression in e-MDSC, there were 4 responders and 30 nonresponders (OR, 1.44; 95% CI, 1.02-1.41). Finally, in patients who have PD-L1-expressing pDC, there were only 7 responders versus 40 nonresponders (OR, 1.08; 95% CI, 1.01-1.17).

“These immune cell parameters may represent novel predictive biomarkers for the response to nivolumab and or nivolumab/ipilimumab therapy in clear cell RCC,” stated Grimm.

Grimm MO, Kesselmeier M, Leucht K, et al. Novel predictive biomarkers of response to immune checkpoint blockade with nivolumab ± ipilimumab in the TITAN-RCC phase 2 trial. 

. 2022;40(6):367-367. doi:10.1200/JCO.2022.40.6_suppl.367

Grimm MO, Esteban E, Barthelemy P, et al. Efficacy of nivolumab/ipilimumab in patients with initial or late progression with nivolumab: Updated analysis of a tailored approach in advanced renal cell carcinoma (TITAN-RCC) .

. 2021;39(suppl 5): 4576-4576. doi: 10.1200/JCO.2021.39.15_suppl.4576

Patients with 4-1BB or LAG-3–expressing T cells at baseline, or a high proportion of PD-L1–expressing myeloid cells and plasmacytoid dendritic cells during boost cycles, may be more likely to benefit from the combination of nivolumab and ipilimumab.

 Nivolumab/Ipilimumab Efficacy in Clear Cell RCC May Be Tied to Certain Immune-Cell Related Parameters

Ongoing research efforts are designed to understand cisplatin-induced hearing loss in young children in order to proactively prevent it, according to Bruce Carleton, PharmD, FCP, FISPE.

Specifically, Carleton, University of British Columbia, Department of Pediatrics, Division of Translational Therapeutics, and his colleagues, are investigating how cisplatin interacts with other drugs, as well as the role of genetics, in impacting the extent of 

hearing loss in children under the age of 5

 Carleton highlights how this area of research can have a profound and lasting impact on a child’s quality of life.

“Sometimes, we refer to adverse [events] (AEs), as “side effects.”I really think that minimizes the harm that is occurring. I'm not suggesting that these drugs are bad; these drugs have wonderful beneficial effects, but they're not [perfect].”

“Automobiles are the same thing. Right? They are wonderful gifts to humanity in terms of moving us from one place to another, and the convenience, but they have a dark side, which is injury that can occur—particularly when they're not operated properly. Drugs are the same way: we need to understand how to operate with them in the best possible way to maximize benefit and minimize harm.”

 that sometimes parents and providers are willing to accept the risk of hearing loss in order to preserve survival, but that it is not a choice he believes should be necessary in the future.

“That’s not the choice I think parents should have to make­—or any of us should have to make,” he said. “Why can't we have the beneficial effects without the adverse effects? That's the [research] that [my lab] is [currently] working on.”

Videos

An expert discusses the consequences of cisplatin-induced hearing loss and ongoing research efforts to eliminate this associated risk for children receiving the treatment.

More Than A “Side Effect”: Why Pediatric Hearing Loss Is So Detrimental

The FDA granted accelerated approval to asciminib (Scemblix) for the treatment of adult patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) who have received prior treatment with 2 or more tyrosine kinase inhibitors (TKIs), as well as for the treatment of adult patients with Ph+ CML-CP and a 

mutation. The novel agent, also known as a STAMP inhibitor, functions by binding to the ABL myristoyl pocket. The accelerated approval program dictates that continued approval is contingent upon verification and confirmatory evidence of clinical evidence.

“The introduction of TKIs 20 years ago revolutionized treatment for CML. However, there remain many patients who do not respond adequately to at least 2 available treatments and often experience challenging [adverse] effects [AEs] that add a burden to their daily lives,” Lee Greenberger, PhD, chief scientific officer of the Leukemia and Lymphoma Society, said in a press release. “The approval of Scemblix may offer hope to patients by addressing gaps in CML care.”

The approval was based on findings from the phase 2 ASCEMBL trial (NCT03106779), which showed that asciminib resulted in a major molecular response (MMR; 25%), double that of bosutinib (Bosulif; 13%) at 24 weeks (

 = .029) in previously pretreated patients with Ph+ CML-CP. In addition, 7% of the 156 patients receiving asciminib needed to discontinue treatment because of AEs, compared with 25% in the bosutinib cohort.

The FDA have granted an accelerated approval to acimibinib, which treats CML by binding to the ABL myristoyl pocket.


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