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Primary payer data reported by cancer registries are subject to measurement error and can result in biased estimates of insurance-related policy effects, according to a study by the National Cancer Institute (NCI) presented during the American Society of Clinical Oncology 2022 Annual Meeting.

Findings from the study showed that reporting of primary payer status collected by cancer registries at the time of diagnosis is underreported 38% of individuals enrolled in Medicaid and 42% enrolled in Medicare. Additionally, registry data concordantly identified 61% of patients enrolled only in Medicaid and 58% of patients enrolled only in Medicare.

“This study was motivated by the need to better understand the role of health insurance coverage on cancer-related care and outcomes, and the role of federal and state policy on insurance coverage,” Amy J. Davidoff, PhD, MS, wrote in an email to 

“With new availability of the Medicaid enrollment data, which we consider to be the gold standard, we had the opportunity to examine whether the primary payer measure provided through registry abstraction was subject to errors. We also wanted to assess factors associated with errors in insurance assignment, to try to facilitate improvements or at the minimum, to help guide data users.”

Davidoff is a health economist and program director in the Healthcare Assessment Research Branch of the Healthcare Delivery Research Program at the National Cancer Institute in Rockville, Maryland.

The study used data from the Surveillance, Epidemiology, and End Results (SEER)Medicaid and -Medicare enrollment databases. Investigators examined adult patients aged 19 to 64 years who received a new diagnosis of cancer between 2007 and 2011 (N = 896,031). Study authors also linked in Medicare enrollment data and several state-year policy and insurance pattern measures pulled from the Kaiser Family Foundation, the American Community Survey, or Centers for Medicare & Medicaid Services reports.

The distribution of primary payer at diagnosis was mostly private (68%) among patients in the overall study population. Investigators also reported that patients in the overall population had Medicare (7.8%), Medicaid (10.1%), unknown insurance status (5.6%), uninsured (5.1%), and other government (3.3%) listed as the primary payer at diagnosis (

Additional data from the study showed that older patients had a greater rate of underreporting of Medicaid enrollment compared with younger patients. Patients aged 60 to 64 years underreported at a rate of 58% compared with 46% of patients aged 19 to 39 years. Underreporting was also more common among patients who were eligible through a poverty-related or 1115 waiver expansion (64%) and among men (56%).

“For this age group [19-64 years], there was substantial underreporting or misclassification of both Medicaid and Medicare in the primary payer variable,” Davidoff said. “The misclassification of Medicaid, in particular, was more common for individuals with demographics less commonly covered by Medicaid pre–Affordable Care Act [ACA], [including] men and older adults. Underreporting was more common for Medicaidenrolled individuals who were eligible through a poverty-related or 1115 waiver expansion, and in state-years with heavy reliance on capitated managed care enrollment. This has important implications for using the primary payer variable to examine effects of the ACA on insurance coverage among individuals with newly diagnosed cancer.”

In the poster, the study authors concluded that strategies to enhance registry capture or to link enrollment data may help mitigate concerns of biased estimates of insurance-related policy effects.

Investigators have already examined data for patients younger than 19 years and older than 65 years and will pull together those results for dissemination, Davidoff said, adding that the NCI is extending the SEER-Medicaid data linkage through 2019.

“We expect to use the Medicaid and Medicare enrollment data to impute coverage, potentially editing the primary payer measure for our research,” Davidoff said. “With that new information, as well as a host of other area-level measures of social risk factors [a different research endeavor] we expect to revisit some of the questions regarding [effects] of the ACA on insurance coverage, and the effects of insurance coverage on cancer-related care and outcomes.”

Davidoff AJ, Enewold L, Williams C, Bhattacharya M, Sanchez JI. Reliability of cancer registry primary payer information and implications for policy research. 

. 2022;40(suppl 16):1587. doi:10.1200/JCO.2022.40.16_suppl.1587

Articles

Primary payer data reported by cancer registries are subject to measurement error and can result in biased estimates of insurance-related policy effects. 

Errors in Primary Payer Data Persist in Cancer Registries

In the weeks after 9/11, the Fire Department of the City of New York (FDNY) World Trade Center (WTC) research team was established. The team is led by David J. Prezant, MD, a professor at Albert Einstein College of Medicine and chief medical officer for FDNY. It includes collaborators from FDNY, Montefiore Einstein Cancer Center, and New York University. Research investigating the physical and mental health consequences of being at the WTC site during and after the terrorist attacks has been instrumental in obtaining health care coverage for thousands of individuals. These exposures include known and suspected carcinogens such as asbestos, arsenic, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polychlorinated furans, and dioxins.

Ten years ago, the FDNY WTC research team published the first study investigating cancer risk among FDNY firef ighters who worked at the WTC site.

 Over the past decade, this research has been expanded with nearly a dozen additional manuscripts about FDNY WTC–exposed rescue/recovery workers.

 During this time, additional studies from outside research teams have investigated cancer risk among other non-FDNY WTC-exposed rescue/recovery workers compared with the general population.

 These studies have produced some consistent findings.

In the studies, the incidence rates for all cancers combined were elevated compared with general population rates, although not all were statistically significant. Each study also reported elevated rates of prostate and thyroid cancer, but a reduced rate of lung cancer compared with the general population rates.

 Earlier in 2022, published findings from a study combining all of the WTC-exposure rescue/recovery worker cohorts showed that although the incidence rate for all cancers combined was no longer greater than the general population, the rates of prostate, thyroid, cutaneous melanoma, and tonsil cancer were elevated. Reduced rates were observed for several gastrointestinal, respiratory, and female reproductive cancers.

Being that the FDNY cohort included mostly firefighters who were, on average, healthier than the general population but also exposed to carcinogens during routine firefighting activities, the question of whether the elevated rates were due to their occupational exposures rather than WTC exposures still needed to be answered. As part of the Career Firefighter Health Study, investigators compared FDNY firefighters with a cohort of non–WTC-exposed firefighters from Chicago, Illinois; Philadelphia, Pennsylvania; and San Francisco, California.

 The rate of prostate cancer was approximately 30% higher among FDNY firefighters, and the rate of thyroid cancer was more than 2-fold higher.

Following the initial findings that cancer rates were elevated, the National Institute for Occupational Safety and Health assumed biologic plausibility to add most cancers to the list of conditions covered by the WTC Health Program.

 This addition meant that the WTC Health Program provided treatment of WTC-related cancers at no cost to the patient. It also meant that the WTC Health Program would begin free cancer screenings for eligible WTC-exposed responders and survivors enrolled in the WTCHP. The cancer screenings follow United States Preventive Services Task Force guidelines and include low-dose chest CT, colonoscopy, mammography, and Papanicolaou tests.

 For FDNY firefighters and emergency medical service (EMS) providers, as well as others, chest CT screening and other tests such as prostate-specific antigen (PSA) testing were provided by outside funds before 2012 when cancer was added to the WTC Health Program as a coverable condition. Members of the FDNY cohort still receive PSA testing via outside funding.

As noted above, elevated rates of thyroid cancer were observed.

 However, these data may be influenced by incidental detection related to this medical surveillance among WTC-exposed rescue/recovery workers.

 The elevated rate was only observed among individuals who were enrolled in the WTC Health Program.

 Further, 80% of the thyroid cancers diagnosed in the FDNY participants were asymptomatic at diagnosis and detected incidentally.

 Although the overall cancer rates may be elevated by the WTC Health Program screening, the care provided by the WTC Health Program may also be related to improved survival. Investigators found that among patients with cancer in the WTC Health Program, mortality was lower than the general population of patients with cancer, with cancer-specific mortality being 28% lower and all-cause mortality being 36% lower (

Between 2013 and 2015, investigators collected serum samples from thousands of FDNY WTC-exposed firefighters and EMS providers and created a biobank at Albert Einstein College of Medicine. Using samples from this biobank, investigators found that FDNY firefighters have an elevated rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor disease to multiple myeloma, compared with the general population.

 In particular, the risk of light chain MGUS was 3 times higher, which may have important prognostic implications. Recently investigators expanded the study to include non-FDNY WTC-exposed rescue/ recovery workers. These analyses confirm the initial study and demonstrate an association between WTC exposure and MGUS.

The investigators’ recent study published in 

 also used samples from the biobank as well as samples collected from non–WTC-exposed firefighters.

 In this study, investigators conducted deep targeted sequencing of 237 genes frequently mutated in hematologic malignancies and then evaluated the relationship between WTC exposure and clonal hematopoiesis (CH)–associated mutations. CH is the acquisition of somatic mutations in blood cells in individuals without a hematologic malignancy, dysplasia, or cytopenia. CH-associated mutations with smoking and exposure to genotoxic stimuli increase the risk of leukemia and are associated with higher morbidity and mortality rates from a variety of inflammatory conditions and atherosclerotic cardiovascular disease.

 The results revealed that overall 10% of the FDNY WTC-exposed cohort (48 individuals out of 481 analyzed) had CH-associated mutations, compared with 6.7% (n = 17/255) in the non-WTC–exposed firefighter comparison cohort (

); investigators noted that with each subsequent decade the prevalence of pathogenic somatic mutations increases for both cohorts.

Investigators observed the odds of CH-associated mutations in the WTC-exposed first responders was more than 3-fold greater than in the non-WTC–exposed cohort (odds ratio, 3.12; 95% CI, 1.63-5.99; 

 = .0006) after controlling for age, sex, and race/ethnicity. This relationship between WTC exposure and CH-associated mutations held when investigators also controlled for smoking status. Smoking history was not significantly associated with the prevalence of pathogenic somatic mutations.

Genes implicated in CH-associated mutations and myeloid malignancies were those most frequently found to be mutated in the WTC-exposed cohort. The most identified variants affected 

 (7 of 57). Other genes included those involving the spliceosome machinery, 

 (3 of 57 each), as well as other genes commonly implicated in CH-associated mutations such as 

 (2 of 57 for each gene, respectively). The pattern of CH-associated mutations was observed to be similar in the non–WTC-exposed firefighter cohort. Median variant allele frequency of the significant somatic mutations in WTC exposed cohort was 10%, consistent with other published CH studies. Missense mutations were most frequently identified. The most common base-pair change in the somatic mutations was a cytosine to thymine transition (C->T), considered a somatic mutational signature of aging 4. Analysis of overall mutational signatures in the WTC-exposed cohort demonstrated enrichment for aging, DNA mismatch repair, smoking, and alkylating agent.

This study also included in vivo analyses of wild-type mice exposed to WTC particulate matter. Overall, the genomic alterations observed in WTC particulate matter–exposed mice occurred at low variant allele frequencies throughout the whole genome indicating widespread genotoxic effects of aspirated WTC particulate matter on hematopoietic stem cells in vivo. These results demonstrate that environmental exposure to the WTC disaster site is associated with a higher burden of clonal hematopoiesis and provide rationale for mutational testing of the larger WTC-exposed population.

The team continues to investigate the association between WTC exposures and cancer in this population while also providing WTC health care practitioners study findings, cancer screening, and care. Only by continuing to conduct this kind of research and caring for the heroes who responded and assisted others during 9/11 will we begin to understand why certain first responders experience an elevated risk of certain cancers. These studies also ensure that the individuals who need it most get the most appropriate care.

We would like to acknowledge our team of collaborators including David J. Prezant, MD; Michael R. Savona, MD; Advaitha Madireddy, PhD; C. Ola Landgren, MD, PhD; Charles B. Hall, PhD; Michael D. Weiden, MD; David G. Goldfarb, MD; Mayris P. Webber, DrPh; and Anna Nolan, MD, MSc; as well as all the junior epidemiologists and analysts on our projects. 

These studies were supported by National Institute for Occupational Safety and Health at the Centers for Disease Control and Prevention, Edward P. Evans Foundation, Valvano Foundation, Leukemia and Lymphoma Foundation, and the Jane and Myles P. Dempsey family.

Rachel Zeig-Owens, DrPH, MPH, is director of epidemiology and lead epidemiologist for the World Trade Center Health Program at the Fire Department of the City of New York, as well as an assistant professor in the Department of Epidemiology and Population Health at Albert Einstein College of Medicine in New York, New York.

Amit K. Verma, MBBS, is associate director of Translational Science at Montefiore Einstein Cancer Center and a professor in the Departments of Oncology; Medicine; and Developmental & Molecular Biology at Albert Einstein College of Medicine in New York, New York.

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Webber MP, Singh A, Zeig-Owens R, et al. Cancer incidence in World Trade Center-exposed and non-exposed male firefighters, as compared with the US adult male population: 2001-2016. 

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Maura F, Diamond B, Maclachlan KH, et al. Initial whole-genome sequencing of plasma cell neoplasms in first responders and recovery workers exposed to the World Trade Center attack of September 11, 2001. 

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Research investigating the physical and mental health consequences of being at the World Trade Center site during and after the terrorist attacks has been instrumental in obtaining health care coverage for thousands of individuals. 

New Cancer Study Results Confirm Lasting Effects on 9/11 First Responders

Prevention and mitigation of cardiovascular events, such as thrombohemorrhagic complications, have been the main goal of treatment development for patients with essential thrombocythemia (ET) and polycythemia vera (PV).

 An improved understanding of these myeloproliferative neoplasms, including the identification of driver mutations in 

, has opened the door to treatments that enable the natural history of these diseases to be altered. 

, a panel of hematology cancer experts discussed the diagnosis and management for ET and PV. They reviewed the expanding use of interferons, a treatment class that has shown disease-modifying effects and seen recent advancement with the FDA approval of ropeginterferon alpha-2b-njft (Besremi) for patients with highrisk PV. They also discussed several promising agents in clinical development for ET and PV.

“[ET] is a disorder in which there are too many platelets…. Generally, patients will present with an elevated platelet count, and they get sent to hematology,” Jeanne M. Palmer, MD, said. According to the National Comprehensive Cancer Network (NCCN) criteria, a platelet counts of at least 450 × 10

/L is one of the major criteria for diagnosing ET (TABLE 1).

 She noted that 80% of patients with ET have a driver mutation; however, because 20% do not have these mutations and only bone marrow biopsies can rule out other etiologies, she said biopsies are indicated for all patients. “Patients can sometimes have prefibrotic myelofibrosis or even overt myelofibrosis, and the only presenting sign is thrombocytosis,” Palmer said.

A key treatment for ET across risk groups is aspirin (81-100 mg daily),3 which is used to prevent cardiovascular events. “For most, I consider a baby aspirin. There are some data showing that a baby aspirin twice [daily] in patients who are still a little symptomatic [is beneficial],” Ruben Mesa, MD, said. He noted there is some debate about whether patients with 

 mutations derive sufficient benefit from aspirin to warrant its use because their risk of cardiovascular events is lower. Patients with 

 mutations have been observed to have an approximately 50% lower risk of thrombotic events than their counterparts with 

 Nevertheless, the NCCN guidelines recommend aspirin for all patients with ET, including those classified as very low risk (ie, age ≤ 60 years, no 

 mutation, and no prior history of thrombosis).

In patients with high-risk ET (ie, history of thrombosis, aged > 60 years, and presence of 

 mutation), the NCCN guidelines recommend concomitant cytoreductive therapies, which may include hydroxyurea (NCCN preferred), peginterferon alpha-2a (PEG; Pegasys), or anagrelide (Agrylin). Mesa said that although hydroxyurea is not a disease-modifying agent, it helps control blood counts, adding that some patients may not be able to reach sufficient doses to control their blood counts due to the toxicities associated with this treatment.

Regarding PEG, the NCCN guidelines note it could be considered for younger patients, pregnant patients (because of its reduced risks during gestation), and those who defer hydroxyurea. Although interferon-based treatment for ET in the United States has been with PEG, Mesa said that ropeginterferon alpha-2b is currently being explored as an option for high-risk ET in the phase 3 SURPASS ET study (NCT04285086), introducing the potential for this agent to eventually replace PEG as the preferred interferon-based therapy for these patients. SURPASS ET is initiated at approximately 65 sites across North America, Europe, and Asia and is comparing the efficacy, safety, tolerability, and pharmacokinetics of ropeginterferon with that of anagrelide after 12 months of treatment in patients with high-risk ET who have demonstrated resistance or intolerance to hydroxyurea.

Mesa also said that interferons may eventually replace hydroxyurea as the preferred first-line cytoreductive therapy in patients with high-risk ET because of an increasing body of data showing the potential for these agents to alter the natural course of myeloproliferative neoplasms. “Advantages of interferons over hydroxyurea may have a deeper impact on the stem cell clone. [They] may potentially help decrease the risk of movement toward myelofibrosis longer term,” he said. 

Mesa was an investigator in a phase 3 randomized clinical trial (NCT01259856) that showed benefit with PEG vs hydroxyurea in patients with ET or PV who were being treated in the first-line setting.6 Both agents were found to be effective; however, with longer treatment (> 24 months), PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas hydroxyurea produced more histopathologic responses.

 Both agents had similar efficacy in limiting thrombotic events and disease progression. Based on these findings, Mesa and colleagues concluded that both agents are efficacious and that “the decision to choose one agent over the other must be personalized.”

Despite the NCCN guidelines recommending interferon-based treatments for ET, Mesa noted these agents remain “in a bit of an uncertain state” from a production and regulatory standpoint because PEG has never been advanced for registration as a treatment for ET. Additionally, he said oncologists may have had negative experiences with interferons from the days when they were used to treat other malignancies, such as melanoma and myeloma. He expressed hope that favorable findings in ongoing clinical trials for ropeginterferon, which may eventually lead to its approval for ET, as well as studies showing benefit with PEG, may lead to improved uptake of interferons for patients with ET, particularly by community oncology practices, where PEG has been underutilized.

“Ropegylated interferon at low doses is a dramatically different therapy. If you haven’t tried it, don’t let that prior experience make you hesitate…. It’s quite helpful,” he said. 

Regarding anagrelide, Mesa said it’s a good therapy for lowering platelet levels but that it’s not commonly used in clinical practice. Generally, he said patients with difficult-to-control platelet counts tend to respond better when anagrelide is given as a combination therapy vs as a monotherapy.

In patients with high-risk ET who show an inadequate response or loss of response to the currently recommended cytoreductive therapies, other treatments can be considered, including the JAK inhibitor ruxolitinib (Jakafi) for patients with splenomegaly symptoms.

 Mesa also noted that several promising treatments are in various stages of clinical development for these patients, including LSD1 inhibitors, making clinical trial enrollment an important option.

Positive phase 2 data for the LSD1 inhibitor bomedemstat (IMG-7289) were presented at the European Hematology Association Congress 2022.

 The study included 44 patients (median age, 68 years) who were resistant or intolerant to at least 1 standard cytoreductive therapy. The primary end point was a platelet count of 400 × 10

/L, with secondary end points including durability of response (ie, maintaining primary end point for ≥ 12 weeks), symptom improvement, and reduction in white blood cell (WBC) counts and mutation burden. Among the patients treated with bomedemstat for at least 24 weeks, approximately 80% achieved a durable reduction of platelet counts to less than 400 × 10

/L without thrombotic events. Treatment was also associated with symptom improvements and reductions in WBC counts and mutation burden. Overall, bomedemstat was well tolerated, and the most common adverse events (AEs) regardless of causality included dysgeusia, fatigue, constipation, arthralgia, thrombocytopenia, and contusion. Two serious AEs deemed to be related to treatment included thrombocytopenia and mouth hemorrhage. 

“There are more things coming. Longer term, there will maybe even be targeted approaches toward calreticulin. We’re seeing a growing list of options for ET,” Mesa said.

“We should think about [PV] when someone presents with a high hemoglobin and high hematocrit without a plausible explanation—essentially in someone who doesn’t have any other reason for secondary erythrocytosis,” Jamile Shammo, MD, said. The NCCN criteria for diagnosing PV are summarized in TABLE 2.

When patients present with a hemoglobin level that raises suspicion for PV, Shammo said the first tests she orders are for 

 V617F mutation and serum erythropoietin (EPO). “If the EPO level is low and the JAK2 mutation is positive, then you have a very good reason to believe that this is PV,” she said, adding a confirmatory bone marrow biopsy may not be needed if hemoglobin levels measure higher than 18 g/dL in men and higher than 18.5 g/dL in women. However, she added that biopsy is crucial if the numbers do not correspond with the NCCN criteria. Additionally, if the 

 V617F is negative, then the exon 12 mutation test should be ordered.

“Nowadays, the diagnosis of PV is much easier because 95% of the patients will be positive for a JAK2 mutation,” Shammo said. “If you added exon 12 to that, almost 99% [of patients] will be positive. In cases [for which] you’re entertaining the diagnosis of masked PV, in case there’s iron deficiency, you might want to rely on a bone marrow biopsy to make sure you’re also ruling out other “Nowadays, the diagnosis of PV is much easier because 95% of the patients will be positive for a JAK2 mutation,” Shammo said. “If you added exon 12 to that, almost 99% [of patients] will be positive. In cases [for which] you’re entertaining the diagnosis of masked PV, in case there’s iron deficiency, you might want to rely on a bone marrow biopsy to make sure you’re also ruling out other. 

In patients with PV, aspirin (81-100 mg daily) is a core treatment, regardless of whether the patient is considered at low or high risk of cardiovascular events.3 The benefit of aspirin in PV was established in the European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) study, which showed aspirin to reduce the combined risk of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes by approximately 60%.

Another key treatment for all patients with PV is phlebotomy, which should strive to maintain a hematocrit level of less than 45%.

 “This 45% has been proven in a trial where they looked at keeping it less than 50% or less than 45% and [under] 45% was superior with regard to cardiovascular events,” Palmer said. When treating women, she said she tries to keep their hematocrit level below 42% whenever possible because women tend to have lower hemoglobin and hematocrit levels than men. 

In low-risk PV, which includes patients younger than 60 years who have no history of any significant thrombotic events, Palmer said that aspirin and phlebotomy are generally considered sufficient but that cytoreductive therapies are needed for those older than 60 years and for those with a history of arterial or venous thrombotic events. “When I approach cytoreductive therapy, this is where it becomes a shared decision-making process,” she said. NCCN preferred options for these patients include hydroxyurea and PEG, with the recently approved ropeginterferon alpha-2bnjft being another recommended option.

“The most commonly used therapy is hydroxyurea. It’s easy and quick, and it’s a pill,” Palmer said. As with ET, however, she said the toxicities can be problematic. She also explained that many patients have concerns that hydroxyurea will increase their risk of leukemia, despite this never having been “borne out in well-done studies.”

Of the available options, Palmer was most excited about ropeginterferon. Like PEG, it is given as an injection, but administration is every 2 weeks vs weekly for PEG. She noted that very good clinical data from the PROUD-PV (NCT01949805) and CONTI-PV (NCT02218047) studies support the use of ropeginterferon in Jamile Shammo, MD, discusses diagnostic considerations for polycythemia vera including hemoglobin levels and JAK2 mutation status. patients with high-risk PV.

 In these studies, patients were treated with hydroxyurea or best available treatment (controls) or ropeginterferon. PROUD-PV provided data for the first year of treatment and its extension CONTI-PV provided data for 3 years of treatment, but more than 5 years of data have now been reported.

Among the patients who continued treatment for up to 5 years, hematocrit levels below 45% were maintained without the need for phlebotomy in 81.8% of patients in the ropeginterferon arm vs 63.2% of those in the control arm.

 V617F mutation burden, the median allele burden decreased in the ropeginterferon arm, from 37.3% at baseline to 8.5% at 5 years, whereas it increased in the control arm, from 38.1% at baseline to 44.4% at 5 years (P < .0001). 

“This suggests, as does a lot of preclinical data, that the interferons in general may have a modifying effect on the disease or change the natural history of disease. There are preclinical data suggesting [that interferons suppress] the 

clone, although there’s probably some advantage even in patients who don’t have the JAK2 mutation,” Palmer said.

Because of the potential for disease modification with interferons, Palmer said she also discusses their use with patients who have low-risk PV. In this setting, the NCCN guidelines list ropeginterferon as an “other recommended regimen,” giving it a category 2B recommendation.

 This recommendation was partially supported by data from the Low-PV study (NCT03003325), which found supplementing phlebotomy with ropeginterferon to be safe and effective in steadily maintaining target hematocrit values in patients with low-risk PV.

Another key population for which Palmer said she uses cytoreductive therapy is in patients who may not fall under the high-risk category but who have symptoms related to iron deficiency, which can be exacerbated by phlebotomy. “Iron deficiency has a lot of symptoms. It can cause fatigue and restless leg syndrome. I’ve even found that mood can be impaired. Oftentimes, I’ll choose cytoreductive therapy so I can start to replace the iron very gently and control their hemoglobin and hematocrit through another mechanism,” Palmer said.

In patients with high-risk PV who have an inadequate response or loss of response to their initial cytoreductive therapy, use of ruxolitinib can be considered (NCCN category 1 recommendation).3 Data to support this recommendation came from the RESPONSE (NCT01243944) and RESPONSE-2 (NCT02038036) studies, which showed ruxolitinib to be superior to best available therapy in controlling hematocrit levels, improving splenomegaly and reducing symptoms while providing protection against cardiovascular events.11-13 “Ruxolitinib is definitely an option that I consider, especially in patients who don’t tolerate hydroxyurea or have a large spleen and a significant symptom burden,” Palmer said.

A key area of therapeutic development is the identification of PV treatments that can consistently keep hematocrit levels at target range. “If we’re doing phlebotomy and aspirin, your hematocrit goes up. We phlebotomize, and it goes down. It goes up and down repeatedly,” Mesa explained, adding that it is currently impossible to know how long patients stay within the target range. This has spurred the development of noncytoreductive agents that can provide consistent control of hematocrit levels in phlebotomy-dependent patients. One such agent in clinical development is rusfertide (PTG-300), a hepcidin mimetic. “[Hepcidin mimetics] simulate the anemia of chronic disease to create a state where you control the hematocrit without iron deficiency,” Mesa said, adding that this approach may help iron levels rise so that patients have fewer symptoms. 

Data from 2 phase 2 trials assessing rusfertide in phlebotomy-dependent patients with PV were presented at the 2022 American Society of Clinical Oncology Annual Meeting.14 The first study, REVIVE (NCT04057040), included 63 patients with excessive erythrocytosis despite phlebotomy, and the second study, PACIFIC (NCT04767802), included 20 patients with poorly controlled PV (hematocrit level > 48% at study entry) despite treatment with phlebotomy with or without concomitant hydroxyurea. In REVIVE, patients consistently maintained a hematocrit level below 45%, which essentially eliminated the need for phlebotomy, and had normalization in their iron stores and an improvement in their symptoms; PACIFIC reported similar benefits. Neither study showed changes to WBC counts. 

“[Rusfertide is] going to be moving forward to phase 3 studies,” Mesa said. “The role of rusfertide or other drugs in that pipeline—there are some from Ionis [Pharmaceuticals, Inc] and others that are looking at this pathway—may expand our medical therapy to be more inclusive of all patients with PV.”

Oncology Live®

Prevention and mitigation of cardiovascular events, such as thrombohemorrhagic complications, have been the main goal of treatment development for patients with essential thrombocythemia and polycythemia vera.

Essential Thrombocythemia  and Polycythemia Vera Treatments Are Moving Toward Disease Modification

Recent research has thrust HER3 into the spotlight as a potentially effective therapeutic target for patients with lung cancer for whom limited treatment options exist. HER3 is overexpressed in upward of 40% of patients with lung cancer, including approximately 83% of patients with non–small cell lung cancer (NSCLC), and is associated with poor clinical outcomes.

HER3 is a heterodimeric partner for EGFR and HER2. Additionally, HER3 expression contributes to metastatic development and resistance to EGFR-directed therapies, according to retrospective datasets.

“EGFR and HER2 are both tyrosine kinases [that] need signaling through HER2 for dimerization and cross-phosphorylation to activate downstream, at least in the native forms of the protein—the ones activated by exogenous ligands,” Joel Neal, MD, PhD, an associate professor of medicine, oncology, at the Stanford Cancer Institute in Palo Alto, California, said during an 

 scientific interchange and workshop. “HER2 is important in EGFR-mutant lung cancer, but you can bypass some of that signaling and activate the PI3 kinase and AKT signaling pathways. Both of those [must] be activated for cell growth to happen in an oncogenic way. That heregulin-combined HER3, and then HER2 and HER3, can heterodimerize and bypass EGFR.”

Interestingly, HER3 has been shown to have a small amount of tyrosine kinase activity. This makes it an attractive target for the treatment of patients who have progressed after treatment with tyrosine kinase inhibitors (TKIs), for whom there are currently limited treatment options beyond chemotherapy. Preclinical data have shown that targeting HER3 and EGFR can overcome acquired resistance to EGFR inhibition.

Novel HER3-Targeted Agent Makes an Impression in NSCLC

There are no HER3-directed agents approved by the FDA for the treatment of patients with lung cancer. For patients with 

-mutated NSCLC who have progressed after treatment with EGFR TKIs and chemotherapy, limited treatment options are available. However, patritumab deruxtecan (formerly U3-1402), a novel antibody-drug conjugate consisting of a fully humanized anti-HER3 IgG11 monoclonal antibody, has shown promise in the space.

The monoclonal antibody is covalently linked to a topoisomerase I inhibitor payload via a tetrapeptide cleavable linker. The agent’s design is similar to that of fam-trastuzumab deruxtecan-nxki (Enhertu), another antibody-drug conjugate consisting of a deruxtecan-based topoisomerase I payload.

The ongoing phase 1 U31402-A-U102 trial (NCT03260491) is evaluating patritumab deruxtecan in patients with locally advanced or metastatic NSCLC with and without identified driver genomic alterations. The dose-escalation and dose-expansion study enrolled patients with 

-mutant disease, as well as patients with non-EGFR oncogenic alterations if they had undergone at least 1 prior treatment with targeted therapy, if available.

In the dose-escalation portion of the trial, patients received patritumab deruxtecan once every 3 weeks at a dose of 3.2 mg/kg (n = 4), 4.8 mg/kg (n = 15), 5.6 mg/kg (n = 12), or 6.4 mg/kg (n = 5). The recommended dose level for the dose expansion portion was determined to be 5.6 mg/kg.

In a pooled analysis of efficacy-evaluable patients with disease harboring an 

 mutation who received the recommended dose in the dose-expansion or dose-escalation portion of the trial (n = 57), the overall response rate (ORR) was 39% (95% CI, 26.0%-52.4%), including 1 complete response. The disease control rate (DCR) was 72% (95% CI, 58.5%-83.0%). At a median follow-up of 10.2 months (range, 5.2-19.9), the median progression-free survival (PFS) was 8.2 months (95% CI, 4.4-8.3) and the median duration of response (DOR) was 6.9 months (95% CI, 3.1-not estimable [NE]).

Notably, a subgroup of efficacy-evaluable patients who previously received prior platinum-based chemotherapy and third-generation EGFR TKI osimertinib (Tagrisso; n = 44) also achieved an ORR of 39% (95% CI, 24.4%-54.5%), with 1 patient experiencing a complete response. The DCR was 68% (95% CI, 52.4%-81.4%) and the median DOR was 7.0 months (95% CI, 3.1-NE).

The median age of patients included in the efficacy analysis was 66 years (range, 40-80). The population was heavily pretreated, with a median of 4 (range, 1-9) prior lines of therapy. All patients included in the trial underwent prior EGFR TKI therapy.

Regarding safety, all patients treated at the recommended dose level experienced a treatment-emergent adverse effect (TEAE). Common TEAEs of grade 3 or higher included thrombocytopenia (30%), neutropenia (19%), and fatigue (14%). TEAEs associated with treatment discontinuation occurred in 11% of patients, and TEAEs associated with death were reported in 7% of patients.

Interstitial lung disease, which was previously identified in other studies of trastuzumab deruxtecan as an important risk for this type of agent, was confirmed by an independent adjudication committee in 5 patients. Adjudicated treatment-related interstitial lung disease was reported in 4 patients: two grade 1, one grade 2, and one grade 3.

In December 2021, patritumab deruxtecan was granted breakthrough therapy designation by the FDA for the treatment of patients with metastatic or locally advanced NSCLC harboring an 

 mutation, following disease progression after treatment with a TKI and platinum-based chemotherapy.

Updated findings from the trial that included patients without 

 mutations were presented at the 2022 American Society of Clinical Oncology Annual Meeting.

 At a median follow-up of 19.7 months (range, 13.8-29.2), patients with identified driver genomic alterations (n = 21) achieved an ORR of 28.6% (95% CI, 11.3%-52.2%). The DCR was 76.2% (95% CI, 52.8%-91.8%) and the median time to response (TTR) was 2.8 months (range, 1.3-4.6). The median DOR was 9.4 months (95% CI, 4.2-NE) and the median PFS was 10.8 months (95% CI, 2.8-16.0) (

Similarly, among patients without any identif ied driver genomic alterations (n = 26), the ORR was 26.9% (95% CI, 11.6%-47.8%) and the DCR was 73.1% (95% CI, 52.2%-88.4%). Additionally, the median DOR was 9.6 months (95% CI, 1.6-NE) and the median PFS was 4.2 months (95% CI, 2.5-10.8).

 Patients in both groups were treated with patritumab deruxtecan 5.6 mg/kg intravenously once every 3 weeks.

In terms of safety, 5 patients in the safety population (n = 47) experienced a TEAE associated with treatment discontinuation and there were no drug-related deaths. The most common grade 3 or greater TEAEs included neutropenia (26%), fatigue (17%), thrombocytopenia (15%), and hypokalemia (13%). Any-grade drug-related interstitial lung disease was reported in 5 patients, with a median time to onset of 140 days (range, 43-331).

Neal noted that more data will be needed before HER3 can be fully established in the space. “For HER3, I want to see a predictive biomarker, [and] we don’t have a lot of data [on] HER3 [immunohistochemistry] right now, or H-scores or any of the [other tests],” he said. “If we could see what the predictive biomarker is, [then] ideally we’d like to personalize therapy of resistance of after first-generation EGFR/TKIs. Once we can personalize a little bit, we [can] see [whether] there are dominant mechanisms of resistance or drugs that work across [patients] regardless [of expression]. Then we’ll probably start to move those [agents] into the first-line setting.”

He added that understanding more about the biology of HER3 and whether it is critical to the cell function will inform investigators about whether there’s a role for it moving forward. “[Right now, it appears agents] can destroy HER3 on most lung cancer cells and destroy it in many other parts of the body and not have horrible toxicity,” Neal said. “But are we doing more than just destroying some cells that happen to express HER3? Does EGFR happen to express more of HER3 in a way that’s biologically dependent for the EGFR? Or is it just like CEACAM5 in that it may happen to be around cancer cells? I want to see a high-resolution picture of the cell, with exactly where the HER3 molecules are on the outside.”

In light of the robust findings from the U31402A-U102 trial, investigators have initiated the phase 2 HERTHENA-Lung01 trial (NCT04619004) to further evaluate patritumab deruxtecan. HERTHENA-Lung01 is a randomized, open-label trial that will enroll approximately 420 patients with metastatic or locally advanced NSCLC harboring an activating 

 mutation. Eligible patients must also have progressed during or after treatment, with at least 1 EGFR TKI and at least 1 platinum-based chemotherapy regimen.

Patients will be randomly assigned 1:1 to receive either a fixed-dose regimen of patritumab deruxtecan 5.6 mg/kg or patritumab deruxtecan via an up-titration dose regimen. In the up-titration arm, patients will be treated at a dose of 3.2 mg/kg in cycle 1, 4.8 mg/kg in cycle 2, and 6.4 mg/kg in cycle 3 and beyond.

The primary end point is ORR by blinded independent central review (BICR). Secondary end points include DOR, PFS, ORR by investigator assessment, DCR, and TTR. The study is presently enrolling patients and has an estimated completion date of 2023.

Additionally, patritumab deruxtecan is under investigation in combination with osimertinib among patients with advanced or metastatic NSCLC with an 

-activating mutation who have progressed during or after treatment with osimertinib in a phase 1 clinical trial (NCT04676477). The trial will enroll approximately 252 patients and will consist of dose escalation and dose expansion parts.

During the dose escalation portion of the trial, patients will receive 1.6 mg/kg, 3.2 mg/kg, 4.8 mg/kg, or 5.6 mg/kg of patritumab deruxtecan intravenously every 3 weeks, plus osimertinib 40 mg or 80 mg orally once daily. Patients will be assigned to a given cohort via a Bayesian logistic regression model. The primary objectives of the dose escalation portion are evaluating the safety and tolerability of the combination and to identify a recommended dose.

If investigators find that the recommended dose includes daily osimertinib 80 mg, approximately 30 patients with advanced, treatment-naïve 

-mutant NSCLC will be enrolled in a separate cohort and treated at the recommended combination dose. The primary objective in this cohort will be safety and tolerability.

In the dose expansion part, patients will be randomly assigned 1:1 to be treated with patritumab deruxtecan plus osimertinib at the recommended combination dose or patritumab deruxtecan monotherapy at a dose of 5.6 mg/kg intravenously every 3 weeks. An additional arm could be added by investigators to evaluate 2 provisional recommended doses of the combination. Each arm will consist of approximately 60 patients. The primary objective of the dose expansion portion is to compare the efficacy of the combination with that of patritumab deruxtecan monotherapy.

The primary end point of the trial is ORR by BICR. Secondary end points include ORR by investigator, DOR, DCR, TTR, PFS, and overall survival.

Steuer CE, Hayashi H, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in advanced/metastatic non-small cell lung cancer (NSCLC) without 

 2022;40(suppl 16):9017. doi:10.1200/JCO.2022.40.16_suppl.9017

Yonesaka K. HER2-/HER3-rargeting antibody-drug conjugates for treating lung and colorectal cancers resistant to EGFR inhibitors. 

 2021;13(5):1047. doi:10.3390/cancers13051047

HER3 has been shown to have a small amount of tyrosine kinase activity, making it an attractive target for the treatment of patients who have progressed after treatment with tyrosine kinase inhibitors. Preclinical data have shown that targeting HER3 and EGFR can overcome acquired resistance to EGFR inhibition.

Vol. 23/No. 15 | Oncology Live®

Errors in Primary Payer Data Persist in Cancer Registries

New Cancer Study Results Confirm Lasting Effects on 9/11 First Responders

Essential Thrombocythemia and Polycythemia Vera Treatments Are Moving Toward Disease Modification

HER3 Emerges as Intriguing Treatment Target in Lung Cancer

New Tissue-Agnostic Treatment Options Emerge

A Revolution Is Pending for Real-World Data Use in Cancer Care