Expanding the use of osmertinib (Tagrisso) so that it is efficacious as a frontline treatment will help pave the way for a new era of success in treating lung cancer, said Jonathan W. Riess, MD, MS.

The expert spoke about the EGFR tyrosine kinase inhibitor, and the key to unlocking its potency, at the 22nd Annual International Lung Cancer Congress.

The largest hurdle facing investigators is identifying and overcoming resistance mechanisms. First-and-fourth-generation (TKIs) in combination with osimertinib may prevent the emergence of known resistance mechanisms, particularly C797S; however, the future of care will lean heavily on the identification of more actionable targets.

Riess, associate professor of medicine at the University of California School of Medicine, UC Davis Comprehensive Cancer Center, provided an overview of the available data for osimertinib, establishing its role in the present and future of care for patients with EGFR-mutant non–small cell lung cancer (NSCLC).

“I can’t emphasize enough the need to find these [targets] as early as possible to forestall resistance developing in [patients with] EGFR-mutant lung cancer,” Riess said during a live presentation of the data. “In later lines of therapy, there’s so much clonal heterogeneity, and it becomes really challenging to target [these mechanisms] with only a few [available] targeted therapies.”

Osimertinib made its way into the frontline setting for patients 

with EGFR-mutant NSCLC in 2018 based on data from the phase 3 FLAURA trial (NCT02296125),

 which showed the clinical benefit of the agent compared with standard first-generation EGFR TKIs (erlotinib [Tarceva] or gefitinib [Iressa].

Specifically, a 54% reduction in the risk of progression was observed with a median progression-free survival (PFS) of 18.9 months (95% CI, 15.2-21.4) reported with osimertinib compared with 10.2 months (95% CI, 9.6-11.1) with erlotinib or gefitinib (HR, 0.46; 95% CI, 0.37-0.57; P < .0001). Overall survival (OS) data trended similarly with a reported median OS of 38.6 months (95% CI, 34.5-41.8) and 31.8 months (95% CI, 26.6-36.0), respectively (HR, 0.799; 95% CI, 0.641-0.997; P = .0462).

“You can see here a tremendous improvement in PFS,” Riess said. “And over 3 years, [there is] a 6-month improvement in OS compared with first-generation in EGFR TKIs. But for a 30-year-old patient with children who has EGFR-mutant metastatic lung cancer, it’s a cold comfort to know that there’s a 6-month improvement at 3 years. I’m always reminded that we could always do better, and we need to do better.”

Riess noted that deeper in the FLAURA data, the forest plots demonstrate that there are certain subsets that do not perform quite as well as others indicating that they may provide opportunities for improvement. “[These include] patients with the L85AR mutations, as opposed to those with exon 19 deletions,” he said. “Although [the trial was] underpowered in subset analysis, [osimertinib] did not show any clear benefit vs first-generation [TKIs].”

The identification of patients who perform well with frontline osimertinib begins to stratify the population a bit further, opening avenues to determine new treatment strategies for those who perform worse on first-line EGFR TKIs. Investigators have identified that those patients with EGFR-mutant disease who also harbor TP53 and TP53/RB1 mutations have a shorter time to discontinuation of treatment.1,3 In an analysis of 863 patients, those whose disease only harbored an EGFR mutation discontinued treatment after a median of 36.6 months, those with EGFR/TP53 at 12.3 months, and those with EGFR/TP53/RB1 mutant disease discontinued at a median of 9.5 months.

This extended to a survival analysis which demonstrated a media OS of 56.4 months, 40.5 months, and 20.1 months across the mutations, respectively.1,3 Additionally, investigators noted that patients with the triple mutation are approximately 25% more likely to experience disease transformation to small cell lung cancer.

Although identified in only a small subset of patients in a retrospective analysis, MET amplification was also a marker of poor prognosis with frontline EGFR TKIs, Riess said.

Investigators have also determined that the presence of circulating tumor DNA (ctDNA) as a marker of poor prognosis. In a mutational analysis of the FLAURA trial, patients with ctDNA present at baseline had a median PFS was 15.2 months with osimbertinib vs 9.7 months with standard EGFR TKI. Those with no ctDNA present at baseline experienced a greater benefit regardless of treatment with reported median PFS of 23.5 and 15 months, respectively.

“I would highlight those patients with baseline, detectable ctDNA and those with ctDNA that persists at week 3 and week 6 appear to do worse,” Riess said, who cited data from the analysis of the FLAURA trial in which investigators examined early clearance of plasma EGFR mutations after 3 and 6 weeks of EGFR TKI therapy.5 The median PFS for all patients with detectable EGFR at 3 weeks was 9.5 months (95% CI, 7.0-10.9) compared with 13.5 months (95% CI, 11.1-15.2) regardless of therapy received (HR, 0.50; 95% CI, 0.3-0.8; P = .001). At 6-week analysis, the median PFS was the same for those with no detectable EGFR in plasma analysis, but worsened to 8.3 months (95% CI, 6.8-10.9) for those who maintained measurable EGFR, for an HR of .70 (95% CI, 0.4-1.2; P = .191).

“How can we better use ctDNA to select those patients who are going to do worse with first-line osimertinib and intervene in the first line setting? I think this is an area we really need to improve on.”

Resistance to osimertinib also depends on the line of therapy, Riess explained. In an analysis of 62 patients with EGFR-mutant NSCLC, the most common off-target genetic resistance obeserved in patients treated with first-line osimertinib were MET amplification (7%), RET fusion (4%), BRAF fusion (4%), and KRAS fusion (4%); on-target acquired mutations were EGFR amplification (4%) and EGFR G724S (4%). In later lines of therapy off-target and on-target genomic alterations increased, the most notable of which is the reported incidence of EGFR C797 which was reported for 27% of patients.

“After the first line, you see a high rate of on-target mutations, including C797 and others, whereas with first-line osimertinib, you still see those, but the on-target mutations appear at a diminished frequency,” Riess said.

“EGFR C797 is the primary target resistance mechanism; it impedes covalent bond formation with irreversible EGFR inhibitors, such as osimertinib,” Riess explained, adding that recent data of osimertinib in combination with gefitinib has demonstrated that this strategy may have the potential to stall the development of C797.

In a phase 1 study (NCT03122717) of 27 treated patients, the combination resulted in rapid plasma clearance of EGFR with an objective response rate of 87.9% (95% CI, 71.9%-96.1%) and a disease control rate of 100% (95% CI, 87.5%-100%). The median depth of response was 58.5% (range, 6.5%-94.2%), and no grade 4 or 5 adverse effects were reported with the therapy.

Combination strategies leveraging fourth-generation EGFR inhibitors also have potential to overcome acquired resistance mechanisms. In particular BLU-945 has demonstrated efficacy in patients whose disease harbors activated L858R or exon 19 deletion mutations, plus acquired T790M and C797S mutations. “In xenograph models, the combination of osimertinib with BLU-945 looked to be the most efficacious in terms of tumor growth inhibition,” Riess said. “I think is definitely a promising avenue to reduce these, these on target resistance mechanisms and improve clinical outcomes.”

Other areas for exploration include the ability to inhibit other mechanisms of resistance, in particular RAS/RAF/MAPK alterations. Riess highlighted the phase 2 study (NCT03392246) in which investigators are evaluating osimertinib in combination with the MEK inhibitor selumetinib (Koselugo) for patients with EGFR inhibitor–naïve advanced EGFR-mutant lung cancer.

The future, Riess explained, will depend on treatment selection based on ctDNA analysis to determine indicators of poor prognosis and then finding a window of opportunity to optimal induction of osimertinib in combination with proven effective therapies.

Strategies outlined by alteration may include osimertinib plus carboplatin/etoposide for those with a TP53 mutation; osimertinib in combination with a MET inhibitor for those with a MET amplification; osimertinib plus a MEK inhibitor for those with RAS/RAF/MAPK alterations; and osimertinib plus a fourth-generation EGFR TKI for those with C797 alterations.

First line osimertinib: what can we add to enhance activity? Presented at: 22nd Annual International Lung Cancer Congress; July 29-31, 2021; virtual.

Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. Ann Oncol. 2017;28(suppl 5):V635. doi:10.1093/annonc/mdx440.050

Offin M, Chan JM, Tenet M, et al. Concurrent RB1 and TP53 alterations define a subset of EGFR-mutant lung cancers at risk for histologic transformation and inferior clinical outcomes. J Thorac Oncol. 2019;14(10):P1784-P1793. doi:10.1016/j.jtho.2019.06.002

Gray JE, Okamoto I, Sriuranpong V, et al. Tissue and plasma EGFR mutation analysis in the FLAURA trial: osimertinib versus comparator EGFR tyrosine kinase inhibitor as first-line treatment in patients with EGFR-mutated advanced non–small cell lung cancer. Clin Cancer Res. 2019;25(22):6644-6652. doi:10.1158/1078-0432.CCR-19-1126

Zhou C, Imamura F, Cheng Y, et al. Early clearance of plasma EGFR mutations as a predictor of response to osimertinib and comparator EGFR-TKIs in the FLAURA trial. J Clin Oncol. 2019;37(suppl 15):9020. doi:10.1200/JCO.2019.37.15_suppl.9020

Schoenfeld AJ, Chan JM, Kubota D, et al. Tumor analyses reveal squamous transformation and off-target alterations as early resistance mechanisms to first-line osimertinib in EGFR-mutant lung cancer. Clin Cancer Res. 2020;26(11):2654-2663. doi:10.1158/1078-0432.CCR-19-3563

Rotow JK, Botelho Costa D, Paweletz CP, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9507. doi:10.1200/JCO.2020.38.15_suppl.9507

This article was originally published on OncLive as “Optimizing Osimertinib Treatment Strategies Relies on Identification of Resistance”

Articles

Identifying targets early can help forestall resistance and improve the efficacy of osimertinib, a EGFR tyrosine kinase inhibitor, in the first-line setting.



Early Target Identification Will Help Maximize Osimertinib Treatment

A novel triplet combination of chemotherapy as a first-line treatment has demonstrated better responses from patients with 

 V600-mutant metastatic colorectal cancer (CRC). Although doublet and triplet chemotherapy-based therapies are standard treatment options for patients with 

 V600­–mutant metastatic CRC, this population has traditionally demonstrated poor outcomes with chemotherapy-based regimens. Even so, BRAF inhibitors are not effective enough to overcome the feedback activation of EGFR.

Investigators of the ANCHOR-CRC trial (NCT03693170) hypothesized that targeting multiple nodes in the MAPK pathway may elicit better responses for patients and fill an urgent unmet need for patients whose disease harbors 

Specifically, the study was designed to examine the efficacy of the triplet combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in the first-line setting.

Updated data analysis presented at the 2021 European Society of Medical Oncology Virtual World Congress on Gastrointestinal Cancer demonstrated that the trial met its primary end point of observed confirmed objective response rate (cORR). In total 92 patients were evaluable and the investigator-assessed cORR was 47.8% (95% CI, 37.3%-58.5%); all responses were partial responses for a disease control rate of 88%. Progressive disease was reported in 5.4% of patients.

The analysis combined 41 patients enrolled to stage 1 of the study with an additional 54 patients enrolled to stage 2. At the time of presentation 6 patients (15%) from stage 1 and 14 patients (26%) from stage 2 remained on treatment. For the 75 patients who discontinued therapy, the cited reasons included progressive disease (64%), adverse effects (AEs; 21%), investigator decision (8%), and other (7%).

Patients with treatment-naïve mCRC and a confirmed 

 V600E mutation were treated with oral encorafenib (300 mg daily), oral binimetinib (45 mg orally twice daily), and intravenous cetuximab (400 mg/m2 loading dose, followed by 250 mg/m2 weekly for the first 28 weeks, followed by 500 mg/m2 once every 2 weeks).

At baseline evaluation, the median age was 65 years (range, 30-84) with median time since initial diagnosis of 66 days. Most patients (60%) had right-side or transverse primary tumors and the remaining (40%) had either left-side tumors or tumors located in the rectum. In terms of metastases, most patients (75.8%) had greater than 2 organs involved including the liver (54.7%), lymph node (51.6%), peritoneum/omentum (48.4%), and lung (36.8%).

Secondary end points of the study were progression-free survival (PFS), overall survival (OS), safety, quality of life, and pharmacokinetics.

At median follow-up of 4.8 months the median PFS was 5.8 months (95% CI, 2.6-6.4) for patients treated with the triplet. At a median follow-up of 14.4 months, the median OS was 17.2 months (95% CI, 14.1-21.1). For 95 patients included in the OS analysis the OS rates at 12, 18, and 24 months were 65%, 49%, and 29%, respectively.

Investigators noted that most patients were able to receive active subsequent therapies. The median time to subsequent therapy was 6.9 months (range, 5.9-8.4). Specifically, 43.2% of patients went on to receive antineoplastic therapy of either oxaliplatin-based doublet with or without bevacizumab (Avastin), FOLFOXIRI with or without bevacizumab, or immunotherapy.

In terms of safety, the results reported for the triplet combination were similar with those reported for recommended chemotherapy-based regimens. The most common all-grade AEs were diarrhea (67.4%), nausea (45.3%). dermatitis acneiform (40%), rash (40%), and vomiting (37.9%). The most common grade 3 or higher AEs were anemia (10.5%), increased lipase levels (10.5%), diarrhea (9.5%), and nausea (8.4%).

Further, the most frequent serious AEs of grade 3 or higher were intestinal obstruction (14.7%), renal failure (7.4%), nausea (5.3%), and abdominal pain (4.2%). Investigators also noted that no meaningful changes in patient reported outcomes.

Eric Van Cutsem, MD, who reported the data at the conference noted that these results were “encouraging” and “support exploring the combination of encorafetinib plus cetuximab with chemotherapy in the first line setting.” Van Cutsem is the division head of clinical digestive oncology at University of Leuven and University Hospitals Gasthuisberg, Leuven, Belgium.

Investigators of the ongoing BREAKWATER study (NCT04607421) will evaluate the efficacy of encorafetinib plus cetuximab with or without FOLFOX or FOLFIRI vs the control of physician’s choice of either FOLFOX, FOLFIRI, FOLFOXFIRI, or CAPEOX with or without anti-VEGF therapy. Patients who received prior systemic therapy in the metastatic setting are not eligible for enrollment. The primary end points of the study are PFS for arm A vs control and arm B vs control by blinded independent central review. Key secondary end points are OS for arm A vs control and arm B vs control. Other end points include incidence of dose-limited toxicities, AEs, dose modifications and drug-drug interactions.

In April 2020, the combination of encorfenib and cetuximab was approved for the treatment of patients with metastatic CRC with a confirmed 

 V600E mutation who experienced disease progression after 1 or 2 prior lines of therapy based on results of the BEACON CRC trial (NCT02928224).4 Investigators of the trial examined outcomes of the doublet regimen as well as the triplet regimen of encorafenib, binimetinib, and cetuximab against the control of investigators’ choice of either cetuximab and irinotecan or cetuximab and FOLFIRI.

Although the triplet combination group outperformed the doublet therapy group against the control arm, respectively, the trial was not powered to compare the 2 experimental arms.

Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in 

. 2019;381(17):1632-1643. doi:10.1056/NEJMoa1908075

Van Cutsem E, Tabernero J, Taieb J, et al. ANCHOR CRC: results from a single-arm, phase 2 study of encorafenib, binimetinib plus cetuximab in previously untreated BRAF V600E–mutant metastatic colorectal cancer. 

. 2021;32(suppl 3):S222. doi:10.1016/j.annonc.2021.05.014

BRAF V600E-mutant colorectal cancer study of encorafenib taken with cetuximab plus or minus chemotherapy (BREAKWATER). ClinicalTrials.gov. Updated July 12, 2021. Accessed July 28, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04607421

Braftovi. Prescribing information. Array BioPharma Inc; 2020. Accessed July 28, 2021. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/210496s006lbl.pdf

This article was originally published on OncLive as 

“Triplet Combination Demonstrates Promise for Frontline Treatment of BRAF V600E–mutant CRC”

A combination of encorafenib (Braftovi), binimetinib (Mektovi), and cetuximab (Erbitux) in the first-line setting was tested for efficacy in patients with BRAF V600E–mutant CRC.

Triplet Chemotherapy Combination a Viable Option for Colorectal Cancer Mutation

In order to achieve health equity for patients with cancer, physicians must first understand the root cause of heath disparities, many of which may be invisible. Broadening conversations about health and equity, drawing attention to gaps in care, and prompting urgency on the issues that influence health care are crucial first steps to turn conversation into action.

“When we look at disparities, we often times look at them in the context of race and ethnicity, but looking at further at disparities—removing ethnicity and looking at income, economic status, or education&mdash;you’re going to see that cancer mortality rates are higher in poorer populations,” said Chasity M. Washington, MPH, CHES, during a presentation at the 

4th Annual School of Nursing Oncology virtual meeting

 hosted by Physicians’ Education Resource®, LLC (PER®). “We [need to ask]: What can we do outside of what we are doing in our clinics to help those [patients] break down some of those systemic racisms that have existed for those communities?”

Washington, director of the Center for Cancer Health Equity at The Ohio State University Comprehensive Cancer Center’s James Cancer Hospital and Solove Research Institute, said that a good place to start is by using the available data for good. These data include electronic medical records, cancer registries, and other resources that are available through the American Cancer Society and the Centers for Disease Control and Prevention.

“Use these data to see who is coming through your door, who is in your service area,” Washington said. “Because if your service area is 30% racial or ethnic minorities, but 10% of the patients coming through your door are racial or ethnic minorities, that is not a good thing; that is a disparity. Why are they not coming [to you]? They are [being diagnosed with] cancer, but where are they going? Are they going anywhere?”

A wide range of health risks and outcomes are affected by the patients’ environmental conditions, such as where they live and work, also known as social determinants of health. Five key determinants make up the framework and include economic stability, education, social and community context, health and health care, and neighborhood and built environment. “All [these determinants] play a role in the outcome of someone’s health regardless of race or ethnicity,” Washington said.

Patients with lower socioeconomic status have higher cancer death rates than those with higher socioeconomic status, regardless of race or ethnicity. Coupled with that, however, is the 2017 U.S. Census Bureau data that demonstrated 21% of blacks and 18% of Hispanics/Latinos live below the poverty line, compared with 9% of non-Hispanic whites

Factors playing into the higher cancer mortality rates include access to the continuum of care, education surrounding screening and risk factors, as well as health insurance coverage. For example, 42% of African American women are more likely to die from breast cancer than white women despite having similar incidence rates. The patients within this subgroup often receive a diagnosis at a later stage of disease and experience delays in treatment.

“Once you get the patient in the door, the equity issue is already there because they are coming with a later stage disease,” Washington said. “They got the diagnosis, but they delayed start of treatment because of a fear of other things or access issues. So, really trying to understand who you are serving and what are their barriers and what are the resources, not only within your hospital, but in the community.”

Engagement with patients once they are inside the clinic is another critical avenue to overcoming social determinants of health. “Clinical trials, biobanking, genetic testing, and counseling, all of these things are cutting edge and great for patients. But if you look at the data, people of color and [other] underserved marginalized individuals do not participate at the rate that they should,” Washington noted.

Implicit bias plays a role in the treatment decision-making process for patients with cancer. A 2016 study from Penner et al demonstrated that implicit racial bias was negatively associated with important aspects of conversations between non-black oncologists and black patients. The results included a significant negative association in communication (P < .01) and interaction length (P = .02). Further, patients who interacted with oncologists with higher implicit racial bias perceived their communication as less patient-centered (P = 0.01) and reported having greater difficulty remembering the contents of the conversation (P < .01), a key factor in determining courses of treatment.

“You may be presenting [a patient] with a clinical trial and that is sometimes one of the best options, but if you’re not spending enough time with [that patient] and are not spending enough time to address [the patient’s] questions, then they may be less likely to participate or enroll in that study,” Washington said.

Moving Beyond Equality to Equity and Justice

Fixing the system to offer equal access to health care, requires more than providing the tools to the community. It is a multistep process that includes customizing the tools to address inequality, as well as offering equal access to the tools and opportunities.

“You can give everybody the same tools and resources, but not everybody has the same barriers or the same access; [the tools] don’t always get everybody to that same destination, or if they get there, it’s going to take them a little longer or be a little more difficult,” Washington said.

This process begins by understanding the resources available to patients both in the hospital and the community. As the second highest level of influence on health outcomes, according to the social ecological model, community relies on collaboration between organizations and members of the community to address health disparities and their causes to enact change.

“Just because I live in the same city as you and I can get to the same hospital as you, my job may not let me get off during [clinic hours], or my insurance out-of-pocket expense may be more than yours and I might not be able to budget for that, or I may not have a vehicle to get there and [the hospital] is not on the bus line.” Washington said. “We have to look at those sorts of things and look for opportunities to remove those barriers.”

Adjusting clinic hours, providing assistance such as lay navigators or nurse navigators who can help patients enroll in Medicaid and Medicare, participating in state cancer plans, and using available resources from the American Cancer Society and other organizations are a few places to start, according to Washington. By taking the time to remove the barriers and provide more assistance to patients whose situation may require it, that is what elevates the access to care from equal to equitable.

Leadership at institutions are responsible for creating a culture of equity, according to Washington. “If it does not come from the top down, it is not going to happen,” she said.

Ways for institutions to be proactive about promoting equity includes offering implicit bias training for all members of staff, offering cross-culture training between physicians and nurses, interpreter training, and adding equity measures to the employee evaluation and institutional performance metrics.

1. Washington CM. Achieving cancer health equity for the oncology patient. Presented at: 4th Annual School of Nursing Oncology; July 31-August 1, 2020; virtual.

2. Yedjou CG, Sims JN, Miele L, et al. Health and racial disparity in breast cancer. Adv Exp Med Biol. 2019;1152:31-49. doi:10.1007/978-3-030-20301-6_3

3. Penner LA, Dovidio JF, Gonzalez R, et al. The effects of oncologist implicit racial bias in racially discordant oncology interactions. J Clin Oncol. 2016;34(24):2874-80. doi:10.1200/JCO.2015.66.3658

Get to the Root of Cancer Disparities

Patients with breast cancer who harbor multiple PIK3A-mutant tumors achieved a higher clinical benefit from PI3Kα inhibition compared with single mutant tumors according to response analysis data from the SANDPIPER trial.

“Double PIK3CA mutations are a novel and frequent genomic alteration in PIK3CA-mutant cancers,” said Neil Vasan, MD, PhD, medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York during a presentation that the AACR Virtual Annual Meeting II. “These findings confirm that [patients with] breast cancer [with] multiple mutant tumors achieve higher clinical benefit to PI3Kα inhibition compared to single mutant tumors. [The findings] support the rationale to test PI3Kα inhibitors in multiple PIK3CA mutant cancers.”

The phase 3 SANDPIPER trial (NCT02340221) examined the efficacy of taselisib (GDC-0032) plus fulvestrant versus placebo plus fulvestrant in 631 patients with advanced or metastatic ER-positive breast cancer who experienced disease recurrence or progression during or after aromatase inhibitor therapy. Using circulating tumor DNA to detect the presence of a PIK3CA mutation, investigators examined 508 patient samples using Foundation Medicine’s Foundation One Liquid test. Of those tested, 339 patients had PIK3CA mutations. Specifically, 19% (n = 66) of the 339 patients who harbored a PIK3CA mutation presented with 2 or more PIK3CA mutations while the remaining 81% (n = 273) had 1 PIK3CA mutation.

Response data demonstrated that patients with multiple PIK3CA mutations had increased tumor shrinkage on taselisib versus those with a single mutation. Single mutant patients in the taselisib arm (n = 193) had an overall response rate (ORR) of 18.1% versus 10.0% in those treated in the placebo arm (n = 80). The difference was not reported as being statistically significant. Patients with multiple mutations in taselisib arm (n = 43) achieved an ORR of 30.2% versus 8.7% in the placebo arm (n = 23), achieving statistical significance.

“This was not the primary end point of this trial but certainly this raises the hypothesis based on the best available clinical data that multiple PIK3CA mutations may predict for increased response to PI3K kinase inhibitors,” Vasan said.

“In this work, we have identified double mutations in cis as a novel, and relatively frequent, genomic alteration in PIK3CA, which translates into a clinically meaningful number of patients who may derive additional benefit from targeted therapy,” he added.

Activating mutations in PIK3CA are the most frequent oncogenic alterations in all cancers, including ER-positive breast cancer. Investigators sought to determine whether there was potential biological relevance and correlation with sensitivity to PI3Kα inhibitors in patients who harbored 1 or more PIK3CA mutations.1

A subgroup analysis of patients with double PIK3CA mutant tumors in the phase 3 SOLAR-1 trial (NCT02437318) served as the launching point for this analysis. SOLAR-1 investigated the efficacy of alpelisib (Piqray) in combination with fulvestrant in men and postmenopausal women with hormone receptor-positive/HER2-negative advanced breast cancer following progression on or after an endocrine-based regimen. Final results from the SOLAR-1 study showed that the alpelisib-containing regimen conferred a progression-free survival benefit in the cohort of patients with PIK3CA mutations. The agent was subsequently approved in combination with fulvestrant on May 24, 2019 for this PIK3CA-mutation harboring patient population.

Notably, patients with ER-positive breast cancer who had double mutations in PIK3CA were more likely to respond to the combination of the alpelisib with an aromatase inhibitor, Vasan said.

PIK3CA mutations are found in 10% to 15% of all PIK3CA-mutant cancers, including breast cancer, according to results from a genomic analysis of more than 70,000 patients with cancer conducted by Vasan and fellow investigators. In an additional clinical analysis, double PIK3CA-mutant tumors were found just as frequently in the primary setting as they were in the metastatic setting. This analysis of genomic alterations demonstrated that double mutations are not simply the function of therapeutic response or tumor heterogeneity, Vasan noted.

“Double PIK3CA-mutant tumors are more frequently found in hormone receptor—positive/HER2-negative receptor subtypes compared to other receptor subtypes in breast cancer,” he added.

Next steps included determining whether the presence of cis PIK3CA mutations—those existing on the same allele&mdash;may be a predictive biomarker for PI3Kα-inhibitor response. Using single molecule real time sequencing (SMRT-seq) of fresh breast tumor samples, investigators were able to determine that double PIK3CA mutations are in cis on the same allele. “This was the first use of SMRT-seq to phase multiple alterations in solid tumors,” Vasan said.

After examining the frequency of PIK3CA mutations, Vasan found that the most frequent hotspots are E542K, E545K, and H1047R, which collectively account for approximately 40% of PIK3CA mutations in patients. “Cis mutants activate PI3K signaling and growth more than single mutants through a combination of disrupter-binder mechanism, [as well as] increase response to PI3Kα-inhibitors compared to single mutants in breast cancer,” Vasan concluded.

1. Vasan N, Razavi P, Johnson JL, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Presented at: American Association for Cancer Research Virtual Annual Meeting II. June 22-24, 2020. Session VSYNGII. https://www.abstractsonline.com/pp8/#!/9045/presentation/11348

2. FDA approves alpelisib for metastatic breast cancer. FDA. Updated May 28, 2019. Accessed June 24, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-alpelisib-metastatic-breast-cancer

This article was originally published on OncLive as, "

Double PIK3CA Mutations in Breast Cancer Increase Sensitivity to PI3Kα Inhibition

PIK3A-Mutant Breast Cancer Shows Increased Sensitivity to PI3K&#945; Inhibition

Low-intensity surveillance may be comparable to high-intensity surveillance for cancer control in patients with high-risk non-muscle invasive bladder cancer (NMIBC). Results presented as part of the virtual science sessions of the 2020 American Urological Association (AUA) Annual Meeting demonstrated that patients who had low-intensity cystoscopy surveillance underwent fewer transurethral resections but did not experience an increased risk of progression or bladder cancer death compared with those who had high-intensity surveillance.

In an analysis of 1542 veterans diagnosed with high-risk NMIBC, patients who underwent low-intensity surveillance (33.7%; n = 520) were found to have almost 3-times fewer transurethral resections than those with high-intensity surveillance (37 vs 99 per 100 person-years, respectively; P <.001). Similarly, low-intensity surveillance patients underwent approximately 3-times fewer resections with cancer in the specimen (28 vs 77 per 100 person-years, P <.001), and 2-times fewer resections without cancer in the specimen (7.5 vs 16 per 100 person-years; P <.001).

"Low-intensity surveillance was associated with fewer transurethral resections or fewer times going into the bladder to remove or scrape these tumors and we found no increased risk in bladder cancer death whether [a patient] underwent low- or high-intensity cystoscopy surveillance of high-risk bladder cancer," said Michael E. Rezaee, MD, MPH, lead author and urology resident at Dartmouth-Hitchcock Medical Center in Lebanon, New Hampshire, during the virtual presentation.

Despite noting that low-intensity surveillance may be a reasonable option for high-risk muscle-invasive bladder cancer, Rezaee concluded that there is a need for "a trial to assess whether decreasing surveillance frequency in high-risk disease is actually safe."

Stratified results showed that among a subset of patients with a baseline diagnosis of Ta disease, low-intensity surveillance was associated with a decreased risk of progression to invasive disease (T1 or T2) or bladder cancer death (cumulative incidence, 19.3% vs 31.3% at 5 years; P = .002). Similarly, the patients with non-invasive disease who underwent fewer cystoscopies did not have an increased risk of death (5.7% vs 8.2% at 5 years; P = .24).

NMIBC accounts for 70% to 80% of new bladder cancer diagnoses and high-risk NMIBC lesions (high-grade Ta and T1 disease) have an 80% risk of recurrence 5 years following treatment and a 50% risk of progression.1,2 Patients who receive a diagnosis of high-risk NMIBC first undergo a transurethral resection or endoscopic scraping of their bladder tumor to remove the tumor from the bladder wall. Once the tumor has been removed patients then have to undergo a series of procedures where a cystoscope is inserted through the urethra and then into the bladder to examine if there is any evidence of the tumor coming back or any progression of the tumors.

The hypothesis-emerging findings provide rationale for clinical trial designs aimed at challenging the current, expert opinion standard of care. "According to AUA, the current recommendation of cystoscopy or looking at the bladder should happen every 3 to 4 months for the first 2 years after diagnosis of high-risk bladder cancer,"

 Rezaee said. "However, this recommendation is based on expert opinion and minimal scientific evidence, so there is not a lot of research supporting this AUA recommendation. For us this raised the question of whether this level of intensity or frequency of looking into the bladder is actually necessary for high-risk non-muscle invasive bladder cancer."

The retrospective cohort study reviewed the association of low-intensity surveillance cystoscopies (1 to 5 procedures) versus high-intensity cystoscopies (≥6 procedures) with frequency of transurethral resections, as well as risk of progression and bladder cancer death of 1542 patients from the Department of Veterans Affairs who received a diagnosis of high-risk NMIBC between 2005 and 2011 with follow-up care through 2014. Intensity was defined according to the number of procedures received over a 2-year surveillance window. The primary outcome was progression to fatal bladder cancer at 5 years.

Noting the limitations of the study, Rezaee said that despite the strength of the sample size, there were unmeasured patient and provider characteristics that could not be accounted for in the study despite rigorous analysis. "This is an observational study with both unobserved and unmeasured confounding [factors]. Therefore, it is really difficult for us to understand why some high-risk patients underwent low-intensity surveillance in the first place when they should have been undergoing high-intensity surveillance."

The surveillance window was 21.5 months to 24.0 months for 458 patients who underwent low-intensity surveillance (88.1%) compared to 365 patients who underwent high-intensity surveillance (35.7%; P <.001). A lower proportion of patients in the low-intensity cohort experienced a recurrence at 2 years (13.3%) versus those in the high-intensity cohort (64.1%). The median number of cystoscopies for patients who underwent low and high-intensity surveillance over at least 21.5 months was 4 and 7, respectively.

The Future of Surveillance and COVID-19 Data

The authors concluded that the study provides a strong rationale for a future randomized trial to assess whether low-intensity surveillance of patients with high-risk NMIBC is comparable to high-intensity surveillance in terms of cancer control and should not guide current clinical practice. "We cannot say that performing less surveillance for high-risk disease can be recommended at this time," Rezaee said. "This is not the study design nor the type of platform to make that recommendation."

The discussion turned to how the coronavirus disease 2019 (COVID-19) pandemic might potentially impact the field as the experience of having to delay cystoscopies could provide real-world evidence of what would happen if cystoscopies are performed less frequently than usual.

"I think there is a lot of impact from COVID-19 not even necessarily just relating to surveillance cystoscopy but urology surgeries and procedures in general," Rezaee said. "I would not be surprised to learn that there have been some delays especially for [patients] who have low-risk disease, but I think that could be some real-world data that could potentially be worth harvesting…The implications of that data wouldn't be known for a few years."

Senior author, Florian Schroeck, MD, MS, added, "We're always looking for natural experiments so that we can get rid of some of the confounding that is often in the data…COVID-19 is an opportunity for such a natural experiment, likely starting in March in 2020, there [potentially may be] a huge drop in the number of cystoscopies, there might be none for a period of time that is likely still ongoing and will hopefully end soon. I agree that moving forward there might be an opportunity to use that data to see how [it] applies to all of the cancer care that we are currently doing and see how much of an impact it has on cancer outcomes." Schroeck is an associate professor at The Dartmouth Institute for Health Policy and Clinical Practice.

1. Rezaee ME. The impact of low- vs. high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer. Presented at: American Urological Association 2020 Virtual Science Session; May 15, 2020.

2. Rezaee ME, Lynch KE, Li Z, et al. The impact of low- versus high-intensity surveillance cystoscopy on surgical care and cancer outcomes in patients with high-risk non-muscle-invasive bladder cancer (NMIBC). PLoS ONE. 15(3):e0230417. doi:10.1371/journal.pone.0230417

3. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol. 2016;196(4):1021-9. doi:10.1016/j.juro.2016.06.049

Low-Intensity Surveillance Demonstrates Utility in NMIBC

Low-intensity surveillance may be comparable to high-intensity surveillance for cancer control in patients with high-risk non-muscle invasive bladder cancer (NMIBC).

Low-Intensity Surveillance Is Beneficial for High-Risk NMIBC

The surge of treatment options for patients with ovarian cancer poses a daunting challenge as answers for optimal sequencing continue to elude clinicians. Bevacizumab (Avastin) continues to hold the most utility in this disease setting, but the addition of PARP inhibitors, and immunotherapy raises the question of how to best deliver efficient regimens to patients. The future looks to be defined by essential clinical trials.

“The problem relates to chaos in ovarian cancer management,” said Maurie Markman, MD during the virtual live webcast of the 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). “The questions that confront the clinicians the individuals designing clinical trials are profound and overwhelming.”

Markman, who is the president of Medicine & Science at Cancer Treatment Centers of America and clinical professor of medicine, Drexel University College of Medicine in Philadelphia, PA, discussed the how currently available treatments may hold untapped potential and how the design of clinical trials can help unlock the best outcomes for patients.

Navigating the Ovarian Cancer Treatment Landscape

Bevacizumab’s approval in 2014 kicked off the wave of new agents and indications in a stagnant treatment landscape. The initial approval was based on results from the phase 3 AURELIA study (NCT00976911) in 361 women with epithelial ovarian, primary peritoneal, or fallopian tube cancer in which bevacizumab plus chemotherapy decreased the risk of progression or death by 62% compared with chemotherapy alone. The median progression-free survival (PFS) was 6.8 months with bevacizumab versus 3.4 months with chemotherapy alone (HR, 0.38; P <.0001).2

“There had never been a phase 3 randomized trial in 50 years since cisplatin was developed showing an impact on an end point like PFS in platinum-resistant disease, the AURELIA trial was the first and remains the only positive trial with bevacizumab,” Markman said.

Next, bevacizumab was approved for platinum-resistant disease based on results of the AURELIA study and for recurrent platinum-sensitive disease based on results of the OCEANS (NCT00434642), and GOG-0213 (NCT00262847) studies, where it was combined with carboplatin/gemcitabine and carboplatin/paclitaxel, respectively.

In the OCEANS study, bevacizumab in combination with platinum-based chemotherapy increased the median PFS to 12.4 months versus 8.4 months with chemotherapy alone (HR, 0.46; 95% CI; 0.37-0.58; P <.0001) in patients with recurrent, platinum-sensitive disease.3

In June 2018, bevacizumab was approved in combination with carboplatin and paclitaxel, followed by bevacizumab as a single agent, for patients with stage III or IV disease following initial surgical resection. Efficacy was determined in the GOG-0218 study in which the use of initial and maintenance bevacizumab demonstrated a median PFS of 18.2 months compared with 12.0 months for chemotherapy alone (HR, 0.62; 95% CI, 0.52-0.75; P <.0001). In a third arm of the study, patients who received bevacizumab plus carboplatin and paclitaxel without the maintenance phase reached a median PFS of 12.8 months compared with 12.0 months chemotherapy alone, a difference that was not statistically significant.3

In final analysis none of the 3 treatment arms resulted in a statistically significant gain in OS after a median follow-up of 102.9 months. However, in patients who started with stage IV disease, the use of concurrent-plus-maintenance bevacizumab with chemotherapy was associated with a longer median OS of 42.8 months versus 32.6 months with chemotherapy alone (HR, 0.75; 95% CI, 0.59-0.95).4

“Data that demonstrates not only in ovarian cancer but other cancer types, the ability to give bevacizumab after bevacizumab continues to improve outcomes if you have a different backbone,” he added.

Three FDA-approved PARP inhibitors include olaparib (Lynparza), niraparib (Zejula), and rucaparib (Rubraca), which currently have 7 indications in ovarian cancer.5-7 Most recently on April 29, 2020, niraparib gained another indication with the approval of the agent for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response (PR) to first-line platinum-based chemotherapy, regardless of biomarker status.

While these approvals all mark progress, Markman noted that one of the controversies surrounding these 3 agents are their utility across real-world patient populations. “Is there a superior anti-PARP agent and does this differ based on specific clinical settings?” asked Markman.

Combinations for PARP inhibitors also extends beyond their utility and sequencing of one another, it also should be thought of for treatments such as bevacizumab, said Markman. “What is the role of adding an anti-PARP agent to bevacizumab in primary or second-line therapy, in specific molecular subtypes, like BRCA mutations or patients who are HRD positive, and is there greater clinical benefit associated with either combination versus sequential therapy?”

PARP inhibitors in combination with bevacizumab are in fact on the horizon as the FDA considers olaparib plus bevacizumab as frontline maintenance therapy for the treatment of patients with advanced ovarian cancer who are in complete or partial response to first-line platinum-based chemotherapy with bevacizumab. Of note, none of the other FDA-approved PARP inhibitors have received regulatory approval as frontline maintenance.

Data from the phase 3 PAOLA-1 trial (NCT02477644) showed a benefit with maintenance PARP inhibition in this setting. Patients were randomly assigned maintenance therapy with olaparib plus bevacizumab (n = 537) or placebo plus bevacizumab (n = 269). Olaparib or placebo were administered for up to 24 months and bevacizumab was administered for up to 15 months.8,9

The trial met its primary end point, showing that for the overall population, patients who received olaparib plus bevacizumab as maintenance therapy had a 5.5 longer median PFS and a 41% lower likelihood of relapse or death compared with patients who received placebo plus bevacizumab (22.1 vs 16.6 months; HR, 0.59; 95% CI, 0.49-0.72; P <.0001).

Further, patients harboring a BRCA1/2 mutation had an even greater PFS benefit of 37.2 months versus 21.7 months (HR, 0.31; 95% CI, 0.20-0.47), and patients who were HRD-positive also had a greater PFS benefit of 37.2 months versus 17.7 months (HR, 0.33; 95% CI, 0.25-0.45).

Markman also posed whether there is untapped potential of these agents that would come with optimal sequencing. “Is there a clinical utility associated with employing a PARP after PARP strategy and if there is, what difference does that specific combination or sequence make?” asked Markman.

In addition to testing for BRCA and HRD in patients, Markman transitioned to discussing the presence of mismatch repair deficiency (MMR) or microsatellite instability (MSI).

In a recent study, 582 patients with ovarian cancer were screened for MMR deficiency by immunohistochemistry. MMR deficiency/MSI was predominantly seen in endmetrioid cancers (8 of 35, 23%) signaling a higher prevalence of patients in this tumor subtype who may benefit from tailored treatments.10 “The question is should it be standard of care in that setting to do such testing and what line of therapy [should be used?” asked Markman.

The future of ovarian cancer management is in clinical trials. However, he stressed the need for pragmatic clinical trials designed to address simply address questions that are relevant to patients and their oncologists. “By quickly addressing multiple current clinical issues and controversies we can help oncologists optimally plan treatment for future patients,” he said.

Included in suggestions for how to best assess these patient populations were selecting end points that are meaningful to patients including efficacy, toxicity, and quality of life. Markman also added that trial design should strive to reflect real world populations by avoiding objectively unnecessary inclusion and exclusion criteria. Additionally, designs should address multiple current clinical issues and optimally plan treatments for future patients, while also allowing for and encouraging crossover.

“Hopefully these trials can be strongly supported by the FDA and receive the appropriate funding from agencies, payers, academic centers, patient advocacy groups, and pharmaceutical or biotech companies,” Markman concluded.

1. Markman M. Future directions: where are we headed. Presented at: 11th Annual International Symposium on Ovarian Cancer and Other Gynecologic Malignancies™ hosted by Physicians’ Education Resource®, LLC (PER®). May 2, 2020.

2. Bevacizumab solution in combination with paclitaxel. FDA website. Accessed May 2, 2020. bit.ly/33ZCsS9

4. Tewari KS, Burger RA, Enserro D, et al. Final overall survival of a randomized trial of bevacizumab for primary treatment of ovarian cancer. J Clin Oncol. 2019;37(26):2317-2328. doi:10.1200/JCO.19.01009

5. Lynparza. Prescribing information. AstraZeneca Pharmaceuticals LP; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/208558s006lbl.pdf

6. Zejula. Prescribing information. Tesaro, Inc; 2017. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2017/208447lbl.pdf

7. Rubraca. Prescribing information. Clovis Oncology, Inc; 2018. Accessed May 2, 2020. www.accessdata.fda.gov/drugsatfda_docs/label/2018/209115s003lbl.pdf

8. Lynparza (olaparib) regulatory submission granted priority review in US for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer. News release. Kenilworth, NJ. 9. AstraZeneca and Merck & Co, Inc. Published January 13, 2020. bit.ly/2Tl5GYS

10. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Eng J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

11. Fraune C, Rosebrock J, Simon R, et al. High homogeneity of MMR deficiency in ovarian cancer. Gynecol Oncol. 2020;156(3):669-675. doi:10.1016/j.ygyno.2019.12.031

Optimal Sequencing Remains a Hurdle in Ovarian Cancer Treatment

The future looks to be defined by essential clinical trials.

Sequencing Ovarian Cancer Treatments Remains Challenging

A broader set of clinical trial eligibility criteria proposed by the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research would nearly double the number of patients with advanced non-small cell lung cancer (aNSCLC) available for enrollment, according to findings presented at the 2019 ASCO Annual Meeting.

The study used enrollment criteria proposed in 2017 to consider 10,500 patients whose records were drawn from ASCO’s CancerLinQ Discovery database. They found that 98.5% of patients would be accepted for aNSCLC trials under the expanded criteria versus 52.3% under traditional criteria. This means that just 1.5% of the patients considered would be rejected for clinical trial participation.

The findings are significant due to the difficulty of accruing patients for clinical trials, investigators said in a release. They said that newer types of drugs have milder adverse event profiles, suggesting that the older standards are unnecessarily strict. In November last year, the National Cancer Institute (NCI) implemented revisions in its clinical trial protocol template to broaden eligibility for clinical trials, based largely on the suggested revisions by ASCO and Friends of Cancer Research. Investigators said more time is needed to determine whether these broader criteria are being widely adopted, but urge all clinical trial sponsors to adopt these criteria.

The expanded criteria employed in this retrospective, observational study allowed for the inclusion of patients with brain metastases, prior or concurrent cancer diagnoses, and creatinine clearance levels ≥30 mL/min compared to the traditionally accepted level of ≥60 mL/min. Patients with limited kidney function would also have been eligible for enrollment under the expanded criteria.

Results demonstrated that under traditional clinical trial enrollment criteria, 5005 patients (47.7%) of the 10,500-patient population would not have been eligible for trial enrollment, compared with only 154 patients (1.5%) who would have been excluded under the expanded criteria. No patients were excluded by brain metastases and prior or concurrent disease under the broadened criteria.

In a subanalysis, investigators concluded that expanded criteria would have permitted higher enrollment of the following: women (44% vs 40%), patients with stage IV disease diagnosis (60% vs 55%), patients who never smoked (16% vs 13%), and patients with nonsquamous types of lung cancer (47% vs 45%).1 The expanded eligibility would also raise the mean age of older patients (67.5 years vs 66.1 years) and increase the number of eligible patients ≥75 years (22.23% vs 16.09%).

Of the 10,500 patients, under traditional criteria 21.5% (2254) would have been excluded for recorded creatinine clearance >60 mL/min, 21.2% (2226) for brain metastases, and 14.4% (1509) for prior or concurrent malignancies.

ASCO’s CancerLinQ Discovery database collects and analyzes real-world data using electronic health record (EHR) data from practices across the United States.

In delivering the results, lead study author R. Donald Harvey, PharmD, BCOP, and director of the Winship Cancer Institute of Emory University’s Phase I Clinical Trials Section in Atlanta, Georgia, noted that traditional eligibility criteria for clinical trials placed unnecessary limitations on trial participants.

“It [is] increasingly difficult to conduct clinical trials necessary to demonstrate safety and efficacy of new therapies,” he said. “Changes to eligibility criteria are particularly important as we step further into the era of targeted therapies, including immunotherapies, that have different safety profiles than highly toxic chemotherapies.” The study authors noted that broader exclusion criteria should be based on compelling scientific rationale.

Harvey et al chose to conduct their study in NSCLC due to the population of more advanced patients and the higher existence of comorbidities, as well as the number of trials available to this patient population. Harvey noted that information about drug-specific and population-specific outcomes in NSCLC are needed so that eligibility criteria can be expanded safely, adding that investigators did not examine other criteria such as lowering the eligibility age, the HIV status of patients, and organ function.

The investigators are now developing other models to analyze differences between people who have undergone treatment for their disease and remained stable compared with those with concurrent brain metastases.

“It is important to point out that we looked at only 3 exclusion criteria of what are, oftentimes, dozens of criteria,” said ASCO Chief Medical Officer Richard L. Schilsky, MD, who serves as an author of the study. “There are still many other reasons patients could be excluded, but this study demonstrated the real value of very carefully thinking through what the inclusion and exclusion criteria are.”

Changes in clinical trial eligibility would not only expand the options available for the treatment of patients with cancer but also provide study data more reflective of real-world populations and lead to more equitable outcomes.

“Only about 3% of patients with cancer in the United States currently enroll in a clinical trial, and restrictive eligibility criteria established in an era before advances we have made in supportive care is one reason for this low number,” said ASCO expert David L. Graham, MD, physician administrator at Levine Cancer Institute in Charlotte, North Carolina. “This study makes the case for universal adoption of broader clinical trial eligibility criteria, such as those proposed by ASCO and Friends of Cancer Research, so that more patients with lung cancer and others have the opportunity to safely participate in potentially lifesaving research.”

Drug developers have expressed concerns about the expanded criteria. “The main concern that we’ve heard is that including a more heterogenous population runs the risk of obscuring the data they are looking for, [by] introducing more adverse events,” Harvey said. “We’ve also heard that the FDA is willing to work with companies to mitigate concerns.” Harvey noted that the goal of the broadened criteria is to make these drugs more applicable to treat patients that physicians are seeing in the clinic.

In 2017, ASCO and Friends of Cancer Research teamed up to draft revisions that affect potential clinical trial participants with preexisting conditions and recommended expanding eligibility to 5 categories of patient: those with brain metastases, prior and current malignancies, HIV and hepatitis infection, organ dysfunction, and those under the age of 18 years. The goal of their draft guidance was to improve trial accrual, ensure optimal patient access, and maximize information learned during trials.

“By expanding its clinical trial eligibility requirements, NCI is helping to ensure that participants in clinical trials better reflect the patients who will eventually receive cancer therapies once they’re applied in routine clinical care,” ASCO President Monica M. Bertagnolli, MD, FACS, said in a previous statement. “These requirements balance patient safety with the need to make sure that clinical trial results are generalizable to the broader patient population.”2

Harvey noted that the NCI's National Clinical Trials Network (NCTN) is updating templates for broadened eligibility and the ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) Study has already begun implementing these criteria. Additionally, in March 2019, the FDA issued 4 draft guidance documents concerning minimum age for pediatric patients, HIV status, organ dysfunction, and brain metastases for public comment.

1. Harvey RD, Rubinstein WS, Ison G, et al. Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: real-world analysis. J Clin Oncol. 2019; 37(suppl; abstract LBA108).

2. ASCO and Friends of Cancer Research applaud NCI’s expansion of clinical trial eligibility criteria [news release].; Alexandria, VA: American Society of Clinical Oncology; November 29, 2018. https://www.asco.org/advocacy-policy/asco-in-action/asco-and-friends-applaud-nci-expansion-clinical-trial-eligibility-criteria. Accessed June 2, 2019.

This article originally appeared on OncLive as, "

Broader Trial Criteria Would Almost Double Eligibility in Advanced NSCLC

Broader clinical trial criteria could nearly double the number of patients with advanced non-small cell lung cancer who are eligible to participate.

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