OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Data presented during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting in June and simultaneously published in the New England Journal of Medicine from the phase 3 DESTINY-Breast04 trial (NCT03734029) reshaped the treatment landscape for patients with metastatic HER2-low disease seemingly overnight.

 Updated National Comprehensive Cancer Center guidelines, FDA approval for fam-trastuzumab deruxtecan-nxki (Enhertu), and discussions surrounding immunohistochemistry results dominated the conversations in the months after the presentation.

“This year, the story at least thus far has been on the role of antibody-drug conjugates [ADCs] in the treatment of HER2-low metastatic breast cancer, where this therapeutic strategy has been shown to prolong progression-free survival [PFS] and overall survival [OS],” Joseph A. Sparano, MD, said.

, Sparano, chief of the Division of Hematology and Medical Oncology and deputy director of the Tisch Cancer Institute at Mount Sinai in New York, New York, highlighted practice-changing clinical trials, novel therapies, the evolving treatment landscape, and unmet needs in the field of breast cancer.

: What are some the top breast cancerspecific takeaways from 2022? 

Based on some of the major data we have seen this year, there is a lot of interest in the use of ADCs, particularly trastuzumab deruxtecan in HER2low, estrogen receptor [ER]-positive breast cancer and triple-negative breast cancer [TNBC] as well [as] sacituzumab govitecan-hziy [Trodelvy]. The use of PARP inhibitors in the adjuvant setting for patients who have early-stage breast cancer associated with germline BRCA1/2 mutations is an important new development in the [past] year that has had a big effect. 

[Additionally], we now have consistent evidence that the use of CDK4/6 inhibitors in metastatic breast cancer, particularly ribociclib [Kisqali], can not only improve PFS but now OS. There may now be some differences…emerging for the use of CDK4/6 inhibitors in the metastatic setting that will influence clinical practice. 

We also have first data from the [phase 3] monarchE trial [NCT03155997] demonstrating the role of abemaciclib [Verzenio] in high-risk adjuvant setting for patients with ER-positive, HER2-negative breast cancer. Palbociclib [Ibrance] has not been a successful therapeutic strategy in that same setting. We’re waiting to see the results of ribociclib from the ongoing [phase 3] NATALEE trial [NCT03701334], which will help round out the information that we have in this setting.

Another major advance has been the approval of pembrolizumab [Keytruda] for patients with both metastatic TNBC and in the neoadjuvant context where the use of this agent added to standard therapy has been shown to improve both PFS and OS in the metastatic setting in the subset of patients with a CPS [combined positive score] of at least 10. [Pembrolizumab] also improved the pathologic CR [complete response] rate and event-free survival [EFS] in 3 years in patients with localized disease irrespective of CPS. There have been a tremendous number of developments within the [past] year [for which] we need to hear the most recent updates.

As the landscape of clinically actionable mutations in breast cancer has expanded, how has your approach to determine who and what to test for changed for patients with early-stage disease and advanced disease? 

The only actionable somatic mutation that can drive therapy is the PIK3CA mutation in patients with ER-positive, HER2-negative breast cancer, which can occur in 30% to 40% of patients. If a patient’s tumor harbors a PIK3CA mutation, [we can expect] there is benefit from the use of the PIK3CA inhibitor such as alpelisib [Piqray] in terms of PFS. 

There are other, much less common mutations that may be acquired that are supporting the use of panel testing either of the tumor or based on ctDNA [circulating tumor DNA] to look not only for PIK3CA but also other potentially actionable alterations. They are less common, but when present could lead to a specific therapy that could provide benefit for individual patients.

What are some challenges for clinicians in determining patients at high risk of developing aggressive disease?

One of the challenges that we face for those patients who are high clinical risk and high genomic risk is trying to further stratify their risk. A substantial portion of those patients may be cured of their disease, even though they are  high risk. We need better tools [and] assays to identify those patients. Typically, we have relied on static biomarkers to help stratify risk and [then] integrate that information with clinical pathologic features. We are now beginning to move into a realm of using dynamic biomarkers sequentially over time rather than only at one time point. [These] may be useful in identifying which patients are at highest risk for recurrence. 

There is certainly a substantial body of literature showing that the presence of circulating tumor cells in the blood or ctDNA in the blood for patients in this context is associated with a higher risk of recurrence. What we have not figured out yet is how many of [these patients] have overt metastatic disease and what proportion of them [does] not. 

That is an area of investigation [in which] we should see substantial advances in the next few years. This has already made its way into the surveillance of colorectal cancer, but we are a bit behind in breast cancer in applying that technology.

What are some novel therapies you are looking forward to seeing integrated into practice?

Certainly, the CDK4/6 inhibitors in the early setting. We have evidence that the use of adjuvant abemaciclib can reduce the risk of recurrence in patients with high-risk, ER-positive, HER2negative breast cancer. There are some concerns about whether benefit in disease-free survival will be durable and will translate into an OS benef it. We need longer follow-up because patients with this subtype of breast cancer tend to be at continuous risk of recurrence. We also are waiting for information regarding the role of other CDK4/6 inhibitors in this context from the results of ongoing trials. 

[Regarding] ADCs, there has been striking activity in patients with metastatic breast cancer in the setting of ER-positive, HER2-negative breast cancer; TNBC; and HER2-positive breast cancer. The next challenge is going to be developing more effective ADCs [and] testing those that have been shown to be effective in the more advanced disease settings in the early disease settings. That is another area of investigation [for which] we will be seeing more clinical trials. 

There is also new information about the use of drugs such as olaparib [Lynparza], a PARP inhibitor, in the adjuvant setting that have been shown to reduce the risk of disease recurrence and improve OS in patients with germline BRCA mutations. That’s another important advance.

Finally, immune checkpoint inhibitors have been shown to have a proven role in prolonging OS in the metastatic triple-negative setting for patients who have a CPS of at least 10. [They have] also been shown to have a role in improving pathologic CR rate and EFS irrespective of CPS when added to neoadjuvant chemotherapy. Those are all major developments that have had a profound impact on the treatment of both earlystage and advanced breast cancer.

With the recent approval of trastuzumab deruxtecan for HER2-low breast cancer, what anticipated shifts do you see in terms of working with pathologists and selecting assays changing to guide treatment recommendations?

For institutions such as [Mount Sinai] where the level of HER2 expression is [done] by immunohistochemistry, it is routinely reported for those tumors that are HER2 low. There [is not] a big impact [at my institution]. 

For the institutions, centers, and laboratories where it is not reported, there needs to be a change in the reporting to adhere to the ASCO/ College of American Physicians guidelines in reporting by the level of protein expression because right now we have not demonstrated that drugs such as trastuzumab deruxtecan have activity in patients who have HER2-0 level of protein expression. There are some signals that there may be some activity in that context, but definitive evidence is lacking in that context. This clearly needs to be integrated into standard practice and reporting.

What are the unmet needs in terms of genetic testing at the community level? 

Germline testing for BRCA1/2 and other mutations has become an essential part of the care of women with early-stage breast cancer for a variety of reasons. The tests are widely available and inexpensive. They have a high degree of analytic validity [and] the results from these tests can have substantial clinical implications for the [surgical] management of the primary tumor, management of the contralateral breast [cancer], and possible screening for and prevention of other secondary cancers. 

In addition, we now know that women who have germline BRCA1/2 mutations can benefit from the use of adjuvant olaparib, with improvements demonstrated in disease-free OS for those who are at highest risk of recurrence. We need to make sure that every patient who could potentially benefit from that information has that information available.

You have had several studies published this year with a focus on identifying racial disparities among women with breast cancer. What have been some trends observed in conducting these analyses and what do you see as the first steps to closing the gaps? 

There are racial disparities in [clinical] outcomes [for patients with breast cancer] and there is a racial divide. The good news is that breast cancer mortality has been declining substantially; it has declined approximately 40% over the past 20 years. 

The bad news is that despite this declining mortality in both White women and Black women, there remains this persistent racial divide: Black women have worse outcomes. There are many reasons for that. Black women are more likely to present with TNBC, more advanced-stage disease, have more comorbidities, and may have less access to care. 

When you study clinical trial populations—that is, patients who were healthy enough to participate in clinical trials, have access to care, and get the best available therapy—you find that some of these disparities remain, not so much so in TNBC but for patients with ER-positive, HER2negative breast cancer. This disparity does not appear to be because of differences in adherence to endocrine therapy or chemotherapy or other factors. We need to do more work to better understand what are the factors that are driving those disparities.

Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2 low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2022. Accessed October 27, 2022. bit.ly/3bgJ070 

FDA approves fam-trastuzumab deruxtecan-nxki for HER2-low breast cancer. FDA. August 5, 2022. Accessed October 27, 2022. bit.ly/3zGfOPt

Articles

Joseph A. Sparano, MD, highlights practice-changing clinical trials, novel therapies, the evolving treatment landscape, and unmet needs in the field of breast cancer. 

Breast Cancer Advances in 2022 Showcase  a Shifting Landscape 

With patents expiring on some of the revolutionary agents in cancer treatment, the emergence of biosimilars as a lower-cost option has seen exponential growth. The interchangeable biological products have not only increased access to crucial cancer treatment agents but also saved the US health care system an estimated $7.9 billion in 2020.

Bevacizumab (Avastin), rituximab (Rituxan), and trastuzumab (Herceptin) are reference drugs with biosimilars approved in oncology, with a total of 12 approved biosimilars between the 3 (TABLE 1

 “Biosimilar products will continue to expand as more reference products lose patent protection,” Jeff Sharman, MD, said in an interview with 

 Sharman is director of research at Willamette Valley Cancer Institute in Eugene, Oregon, and medical director of hematology research for the US Oncology Network. “Most physicians have accepted biosimilar growth factors already, but more and more therapeutic antibodies will also have biosimilar competition in the coming years,” he said. 

Supportive care agents for cancer care have approved biosimilars as well. Filgrastim (Neupogen) has 3, pegfilgrastim (Neulasta) has 6, and epoetin alfa-epbx (Epogen) has 1.

The leukocyte growth factors filgrastim and pegfilgrastim have similar indications to hel preduce the chance of infection in certain types of cancers because of low white blood cell count brought on by treatments such as chemotherapy.

 The erythropoiesis-stimulating agent epoetin alfa manages anemia caused by chemotherapy and has an indication for reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery.

 In addition to oncology and supportive care, various areas of health care such as fertility and insulin have biosimilar development underway.

Sharman explained that despite the similarity between the products and their reference agents, “biosimilar approvals are based on very different data than innovator therapies. Innovator therapy approvals are based on the familiar clinical development pathways of dose-finding phase 1 studies, signal-finding phase 2 studies, and large, randomized phase 3 pivotal studies. Biosimilar approvals are based upon totality of the data, which comprises a multitude of preclinical studies including molecular similarity, biochemical similarity, and often a single confirmatory phase 3 study in a suitable population where a clinical outcome can be measured along with immunogenicity, pharmacokinetics, and other variables.”

Biologics made up 43% of US medicine spending in 2019 for an average of $211 billion. Biosimilars are estimated to cost 30% less than their reference brand biologics (TABLE 2).

 Bevacizumab, rituximab, and trastuzumab emerged in the market in 2019, and, with biosimilar competition, oncology spending growth declined from 16% in 2018 to 10% in 2020.

An analysis of real-world trends demonstrated that 8.2% of new prescriptions in 2020 for bevacizumab, rituximab, and trastuzumab were for their biosimilar products.9 “During the same period in 2020, when 5 trastuzumab biosimilars were available, 80.5% of patients initiating trastuzumab began treatment on a biosimilar, suggesting rapid uptake by providers. However, this differed by product,” Sharman said.

As part of the Patient Protection and Affordable Care Act, the Biologics Price Competition and Innovation Act was passed by Congress in 2010 to create a shortened licensure pathway for biosimilar drugs. The act’s primary goals were to encourage biosimilar competition and reduce spending costs for brand-name biologics. Furthermore, the Executive Order on Promoting Competition in the American Economy in 2021 highlighted increasing support for biosimilar and generic drugs in the market and encouraged the FDA and Federal Trade Commission to prohibit anticompetitive practices.

The national health care system in Europe has set a different pace of adoption for biosimilars compared with the United States. The estimated biosimilar share of volume achieved in the first 24 months after launch of a biosimilar was 30% in the United States compared with 50% to 60% in the European Union (EU). Starting prices in Europe were approximately 35% less compared with US prices, and reduction in price compared with the reference drug was 30% in the United States vs 70% to 80% in Europe. The speed of biosimilar adoption (the EU was 10 years ahead of the United States) can also be attributed to the patent landscape, which remains a barrier in the United States and impedes the release of biosimilars.

 “In many practices, use of biosimilar products [is] extensive, whereas in others, it has not been as broadly adopted,” Sharman said. 

Results from Cardinal Health surveys conducted from 2020 to 2021 showed that more than 90% of oncologists were comfortable prescribing a biosimilar with FDA approval. However, 5% of participating oncologists said clinical trial data were necessary for them to prescribe biosimilars.

Although data are a setback for biosimilar integration in practice, biosimilar integration in the market has other hurdles to surmount. Obstacles have arisen in part because of pharmacy benefit managers (PBMs), stakeholder incentives, Medicare Part D, hospitals in the 340B Drug Pricing Program, and policy makers. “Biosimilars have had variable uptake and often are driven by payer mandates,” Sharman said. 

Stakeholder incentives remain an issue in the American health care system, and PBMs hold a large amount of control when it comes to the pricing of agents. Although the official role of PBMs is to manage and control drug spending by negotiating with drug manufacturers and pharmacies, they often receive rebates based on the manufacturer’s list price; they can negotiate with the goal of giving more expensive drugs instead of biosimilars to receive a higher rebate.

 Because PBMs manage pharmacy benefits for large employers, health insurers, Medicare Part D drug plans, and other payers, they control a large scope of the health care system by encouraging more expensive drugs and increasing prices, determining which agents are used most often. 

Disproportionate share hospitals, hospitals in the 340B Drug Pricing Program, also prefer reference drugs because they can increase profits by raising drug prices after receiving the discounted price. The Affordable Care Act requires hospitals in the 340B Drug Pricing Program to publish their charges, showing that 1087 acute care hospitals in the 340B Drug Pricing Program increased costs of agents at a median rate of 3.8 times the hospital’s discounted acquisition cost. Additionally, approximately 25% to 46% of these hospitals only listed prices for reference agents, and almost none carried biosimilars.

Furthermore, as spending continues to increase for biologic drugs, Medicare reimbursement rules can hinder the adoption of biosimilars. Medicare pays providers for new outpatient agents based on wholesale acquisition cost plus 3%, but Medicare Part B reimburses providers when clinicians administer agents in a clinical setting or outpatient hospital based on average sales price plus 6%.

With this process, clinicians receive a greater reimbursement for the more expensive reference drugs. Medicare Part D covers patient-administered biologics that are distributed through pharmacies, but a lack of biosimilars coverage limits the amount beneficiaries could be saving; the plan formularies including biosimilars did not encourage their use.1 The Office of the Inspector General for the US Department of Health & Human Services recommended that the CMS encourage plans to increase access to biosimilars and push for their use after analyzing the Part D biosimilar use and spending trends from 2015 to 2019. They found that a decrease of 18% ($84 million) in spending could have resulted if biosimilars had been used as frequently as the most commonly used biologics.

“Insurance companies periodically mandate use of biosimilars or require an appeal if [a] branded product is to be used,” Sharman said. When biosimilars are used, companies can see large savings. Dean Foods recorded savings of 77% in 2019 after eliminating specialty drugs from their carrier and removing PBMs as part of their specialty drug savings program. The company spent $227,500 on 3 biologic drugs; after switching to 4 biosimilars, it spent $52,900.1 Additionally, the National Alliance of Healthcare Purchaser Coalitions reported that employers received incorrect safety and cost information about biosimilars from health plans, PBMs, benefits consultants, providers, and pharmacists.

Additionally, the National Alliance of Healthcare Purchaser Coalitions reported that employers received incorrect information about biosimilars such as false safety and cost information from health plans, PBMs, benefits consultants, providers, and pharmacists. 

The creation of more competition in the market and greater access to agents are benefits as well. With time, misconceptions about biosimilars may be mitigated and coverage has the potential to expand, with expectations for state legislatures to introduce new policies supporting biosimilars.

“If you believe that biosimilars are equivalent therapeutics, there should not be concern about differences in outcomes between different products,” Sharman said. “At that point, the discussion comes down more to economic considerations that may not be in the hands of the treating physician.”

Oncology Live®

With patents expiring on some of the revolutionary agents in cancer treatment, the emergence of biosimilars as a lower-cost option has seen exponential growth.

The State of Biosimilars: Obstacles and Barriers to Use in 2022 

For patients with colon cancer, traditional clinical and pathologic risk factors may soon take a backseat as stratification tactics for determining optimal candidates for adjuvant chemotherapy. Detection of minimal residual disease (MRD) has been evaluated more acutely in the past decade, with prognostic signals demonstrating that overtreatment may be avoided for patients who have no circulating tumor DNA (ctDNA) present following resection.

“Multiple studies have documented a role for MRD in colorectal cancer, rectal cancer, colon cancer, including stage II and III disease,” Peter Gibbs, MBBS, MD, FRACP, a medical oncologist at St Vincent’s Private Hospitals and a professor at the University of Melbourne in Australia, said in an interview with OncologyLive

. “Key data support [the hypothesis] that the detection of ctDNA after surgery is associated with a very high risk of recurrence and the absence of ctDNA is associated with a low risk of recurrence. The question is: How do we use that information to best treat our patients?”

Circulating cell-free DNA (cfDNA) refers to small DNA fragments found in a cellfree component of the whole blood.

 “In terms of biologic characteristics, the length of cell-free DNA strands suggest that DNA is released in the bloodstream through cell death,” Jeanne Tie, MD, said in a presentation during the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

 The exact mechanism of ctDNA remains to be clarified, noted Tie, the lower gastrointestinal medical oncology and trials lead at the Peter MacCallum Cancer Center and senior research fellow in the Personalized Oncology Division at the Walter and Eliza Hall Institute of Medical Research, in Melbourne, Australia.

“In healthy individuals, cfDNA is mainly derived from hematopoietic cells and is usually found at quite a low level,” Tie said. “In patients with cancer, a proportional fragment of DNA is derived from the tumor [referred to as] ctDNA. Intriguingly, tumor-derived DNA fragments appear to be smaller than normal cell-free or wild-type DNA fragment size. Therefore, apart from genomic and epigenetic changes that can be detected in ctDNA and that’s used to inform clinical practice, there’s now increasing interest in using fragment size to differentiate between ctDNA and cfDNA or to aid the accuracy of ctDNA testing in addition to genomic sequencing.”

High-risk of recurrence is determined by factors including staging (ie, T4 disease), lymph node involvement, presence of tumor deposits, all of which have been determined using retrospective analyses.

 Patients with stage III colon cancer have historically derived a greater benefit from adjuvant chemotherapy than those with stage II disease. With no definitive documentation of an overall survival (OS) benefit, predictive measures for mitigating postsurgical recurrence.

“There is a relatively low absolute survival benefit from adjuvant chemotherapy, despite the substantial adverse effects associated with this modality, which makes it imperative for us to identify which patients require adjuvant chemotherapy compared to the patients that can be monitored on surveillance,” Olatunji B. Alese, MD, FWACS, said in a presentation at the 2022 ASCO Annual Meeting on the future of ctDNA.

 Alese is an associate professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, director of gastrointestinal oncology, and associate medical director of the Ambulatory Infusion Center at Winship Cancer Institute of Emory University in Atlanta, Georgia. 

Pooled findings from 3 cohort studies showed that patients who had ctDNA detected in plasma samples collected 4 to 10 weeks postsurgery had worse 5-year recurrence-free survival (RFS) rates than those who did not (38.6% vs 85.5%; P < .001). Additionally, 5-year OS outcomes were poorer among those with MRD (64.6% vs 89.4%; P < .001). The studies enrolled a total of 485 patients with stage II or III colon cancer and ctDNA was detected in 12% of samples collected.

Among the 230 patients with stage II disease, 20 patients (8.7%) had detectable ctDNA after surgery. Nearly all (99%) of patients with stage III disease proceeded to adjuvant chemotherapy compared with 22.6% of patients with stage II disease. Investigators highlighted “that detectable ctDNA in patients with a low-risk pathology, such as low-risk stage II colon cancer or a rectal patient with a ypN0 disease, is associated with a far greater recurrence risk (57%) than the highest risk pathology with no detectable ctDNA.”

Findings from a study of patients with stage II colon cancer underscore the use of ctDNA as a marker for identifying patients with a very high risk of recurrence. Among 178 patients who were not treated with adjuvant chemotherapy, 7.9% (n = 14) had ctDNA detected after surgery. At a median follow-up of 27 months, 11 patients (79%) had disease recurrence. 164 patients with negative ctDNA (n = 164), 9.8 % had disease recurrence (HR, 18; 95% CI, 7.9-40; P < .001).

Observational data coupled with the practical advantages of liquid biopsy compared with tissue assays which are more relegated to only 1 tumor site, are more invasive, and do not afford the opportunity of serial testing, interest in the use of ctDNA has grown.

 “The beauty of ctDNA compared with tissue biopsy is we can do longitudinal multiple blood sample collections and analysis with pertinent key findings,” Alese said.

Tie noted that the clearance of ctDNA, which occurs primarily in the liver, is rapid with a half-life of approximately 2 hours

 “This a very attractive feature of ctDNA in terms of a dynamic tracking of tumor burden,” she said. “The half-life’s much shorter than [carcinoembryonic antigen] CEA, for example, with half-life of 7 days, and much more dynamic in terms of monitoring cancer response of resistance compared with a CT scan.”

A variety of factors influence whether ctDNA will be detected in the blood including time from surgery, disease status, tumor shedding patterns depending on tumor type, and the type of variant.

 In terms of detection rates, colorectal cancer has been reported as having higher frequency of detectable ctDNA per cases.

 With reported increases in ctDNA present following a traumatic event (ie, resection) the optimal testing window for ctDNA is 4 weeks postoperation.

Studies Underway to Bring ctDNA Into Practice

“Some factors to consider when you are requesting a ctDNA test include the targeted variants or regions examined by the assay, the type of variants covered or detected by the assay, the limit of detection for the different types of variant,” Tie said adding that more data are needed to appropriately declare ctDNA-guided treatment as a viable option in the clinic. 

Studies are underway to support this path forward including the DYNAMIC trial (ACTRN12615000381583).

 The 2 cohorts evaluated in the study were ctDNA-directed therapy (n = 294) or standard-therapy cohort (n = 147) (Figure).

Treatment decisions in the standard arm were based on clinical factors and those in the ctDNA-guided arm were able to elect whether to receive therapy or not based on results.

Overall, 15% of patients who were ctDNA negative received chemotherapy in the guided treatment arm compared with 28% in the standard-treatment group, (RR, 1.82; 95% CI, 1.252.65).

RFS rates were similar between arms: ctDNA-guided cohort had a 2-year RFS rate of 93.5% compared with 92.4% in the standard treatment group. The 3-year RFS rates were 91.7% and 92.4%, respectively (HR, 0.96; 95% CI, 0.51-1.82).

“ctDNA is a very useful marker in guiding adjuvant therapy,” Gibbs said, noting that even for patients who have negative or false negative results “who experience recurrence, the disease tended to be locoregional recurrence. Importantly, many of those patients can receive salvage therapy.”

In the study, which was conducted in Australia and New Zealand between 2015 and 2019, ctDNA analysis was completed for 99% of those in the guided arm (291 of 294). Two patients did not receive ctDNA-guided treatment. In this group, 45 patients were ctDNA-positive, with all except 1 receiving chemotherapy. Chemotherapy was not administered to those with ctDNA-negativity following surgery (n = 249), except for 1 patient. 

There was less chemotherapy used with the ctDNA-guided approach across all patient subgroups, except for those with less than 12 lymph node yield and those over the age of 70, who tended to receive less chemotherapy in the standard therapy arm. The biggest difference in chemotherapy use, favoring less in the ctDNA-guided group, was for patients with T4 tumors (RR, 2.57; 95% CI, 1.46-4.50), high-risk characteristics (RR, 2.14; 95% CI, 1.43-3.21), and poorly differentiated tumors (RR, 5.06; 95 CI, 1.02-25.10).

In the guided cohort, recurrence or death occurred in 6% of patients with ctDNA-negative status compared with 18% of the ctDNA-positive group. The estimated 3-year RFS rate was 92.5% in patients from the ctDNA-negative group who did not receive chemotherapy compared with 86.4% in patients with ctDNA positivity treated with chemotherapy (HR, 1.83; 95% CI, 0.79-4.27). Furthermore, there was a difference in RFS by type of chemotherapy used within the ctDNA-positive group, with a 3-year RFS rate of 92.6% for those receiving an oxaliplatin-based doublet compared with 76.0% for single-agent fluoropyrimidine therapy. 

A post hoc analysis of the data attempted to combine clinical characteristics with ctDNA status to further refine therapy selection. In patients with ctDNA negativity who did not receive chemotherapy, those with clinically low-risk characteristics had a 3-year RFS rate of 96.7% compared with 85.1% in those with highrisk features (HR, 3.04; 95% CI, 1.26-7.34). Those with T3 tumors with ctDNA-negative status had a 3-year RFS rate of 94.2% compared with 81.3% in those with T4 tumors (HR, 2.60; 95% CI, 1.01-6.71). 

In addition to avoiding chemotherapy in some patients, knowing patients were ctDNA-positive resulted in greater use of an oxaliplatin-based doublet chemotherapy. In the ctDNA-guided group, 62% of patients received an oxaliplatin-based doublet vs just 10% in the standard arm. A single-agent fluoropyrimidine therapy was used for 90% of those in the standard arm and for 38% of those in the ctDNA-guided group. 

Unanswered Questions in Postoperative Setting 

In an analysis of DYNAMIC presented at the European Society of Medical Oncology 2022 Annual Congress, investigators assessed postoperative dynamics of ctDNA and sites of recurrence to inform future studies.

“An interesting aspect of the study, which I wasn’t quite expecting was that we’re able to salvage a lot of the patients with a positive DNA result than in previous observational studies,” Gibbs said. “Other studies have shown in a patient with stage II colon cancer, if you could detect ctDNA after surgery there was close to 100% risk of recurrence. In DYNAMIC patients who received chemotherapy who were ctDNA positive, and received platinum-based chemotherapy, had a high RFS rates in excess of 80%. It suggests that we can salvage these patients that the detection of ctDNA may indicate that a patient is destined to have disease recurrence and the use of adjuvant therapy can prevent relapse in those in those patients.”

ctDNA clearance was achieved with adjuvant chemotherapy for 87% of patients with ctDNA positivity after surgery. This was also associated with favorable 2-year RFS rate of 97% with ctDNA clearance vs a 1-year RFS rate of 20% for patients without ctDNA clearance.

“In terms of future studies, what was interesting was the end-of-treatment, DNA analysis,” Gibbs said. “What we looked at was the patients that were positive after surgery, and then patients that had adjuvant chemotherapy, what happened to their circulating tumor DNA on treatment. What we could show is that if the patient’s DNA was clear, if it went from positive to negative, that was associated with a very good outcome. Whereas patients that were persistently positive with a DNA wasn’t cleared by the chemotherapy had a high risk of recurrence. It’s opening up a new frontier of research, which we’re calling second-line, adjuvant therapy, in which patients received standard adjuvant chemotherapy.”

Gibbs said that opportunities for future research include looking at ways to clear residual ctDNA and prevent the recurrence. “It’s a new frontier for adjuvant therapy research and fascinating that it has huge potential.” 

Alese echoed that sentiment stating, “For those who have access to these trials, I encourage you to enroll patients. Because I’m convinced that, as we finish enrollment and redo some of these trials, it’s likely to really change our practice. Using clearance of ctDNA as an end point for escalation/de-escalation of adjuvant chemotherapy, especially for those with highrisk disease, is an important area of research. And I’m even more excited about the possibility of using ctDNA as a surrogate for treatment response, which can arguably reduce the study duration and expedite the development of new therapies.”

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Tie J, Cohen JD, Lahouel K, et al. Adjuvant chemotherapy guided by circulating tumor DNA analysis in stage II colon cancer: the randomized DYNAMIC Trial. J Clin Oncol. 2022;40(suppl 17):LBA100. doi:10.1200/JCO.2022.40.17_suppl.LBA100 

Tie J, Cohen JD, Lahouel K, et al; DYNAMIC Investigators. Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. N Engl J Med. 2022;386(24):2261-2272. doi: 10.1056/ NEJMoa2200075 

Tie J, Cohen JD, Lahouel K, et al. Circulating tumour DNA (ctDNA) dynamics, CEA and sites of recurrence for the randomised DYNAMIC study: adjuvant chemotherapy (ACT) guided by ctDNA analysis in stage II colon cancer (CC). Ann Oncol. 2022;33(suppl 7):683. doi:10.1016/j.annonc.2022.07.456

For patients with colon cancer, traditional clinical and pathologic risk factors may soon take a backseat as stratification tactics for determining optimal candidates for adjuvant chemotherapy. 

MRD Detection Emerges as a Catalyst for Advances in Colon Cancer

The PI3K cell-signaling network has been an important therapeutic target in oncology research since its role in promoting multiple cancer types was first elucidated nearly 40 years ago.

Such efforts began to pay off in 2014 when idelalisib (Zydelig) became the first PI3K inhibitor to gain FDA approval, with indications in relapsed follicular lymphoma (FL), small lymphocytic lymphoma (SLL), and chronic lymphocytic leukemia (CLL). The FDA subsequently approved 4 additional PI3K inhibitors for oncology indications.

During the past year, however, the use of PI3K inhibitors in hematologic malignancies has come under scrutiny amid concerns about efficacy and safety.

 Since December 2021, pharmaceutical companies have voluntarily withdrawn indications for idelalisib in FL and SLL and for duvelisib (Copiktra) in FL; umbralisib (Ukoniq), which was approved in FL and marginal zone lymphoma (MZL), was completely withdrawn from the market.

Further, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in September 2022 against retaining indications for duvelisib for patients with relapsed or refractory (R/R) CLL or SLL after at least 2 prior therapies.

Meanwhile, copanlisib (Aliqopa) maintains its indication as monotherapy for the treatment of adults with relapsed FL after at least 2 prior therapies; however, Bayer has withdrawn a supplemental new drug application pending analysis for the combination of copanlisib plus rituximab (Rituxan) in patients with relapsed indolent non-Hodgkin lymphoma (iNHL).

Of note, questions about PI3K inhibitors in hematologic malignancies have not been raised about alpelisib (Piqray), which is approved in combination with fulvestrant (Faslodex) for patients with hormone receptor–positive,HER2-negative breast cancer harboring PIK3CA mutations.

 In April 2022, the FDA approved alpelisib under the trade name Vijoice for adult and pediatric patients with PIK3CA-related overgrowth spectrum, a set of rare genetic disorders caused by mutations in PIK3CA.

Investigators continue to explore PI3K inhibitors in hematologic settings. Additionally, the development of currently approved and emerging PI3K inhibitors continues in breast cancer and other solid tumors, according to a search of ClinicalTrials.gov (Table).

The FDA’s concerns about the class of PI3K inhibitors that have been approved for treating patients with hematologic malignancies involve 4 main issues: unfavorable trends in overall survival (OS) data, toxicity profiles, questions about inadequate dose optimization, and the use of single-arm trials.

Despite initial FDA approvals based on progression-free survival (PFS) or overall response rate (ORR), findings from 6 postmarketing randomized clinical trials have prompted concerns about the impact of these agents on OS, FDA officials said in briefing documents prepared for an ODAC meeting in April 2022.

 At that meeting, the ODAC panel voted 16 to 0 (with 1 abstention) to require randomized studies of future PI3K inhibitors in hematologic malignancies rather than basing approval decisions on the results of single-arm studies.

The postapproval studies that the FDA cited include 3 randomized trials—GS-US-312-0123 (NCT01980888), GS-US-313-0124 (NCT01732913), and GS-US-313-0125 (NCT01732926)— evaluating idelalisib-containing combinations vs placebo-controlled regimens for patients with CLL or iNHL.

In 312-0123, the HR for idelalisib plus bendamustine and rituximab vs bendamustine/ rituximab alone in patients with untreated CLL was 3.34 (95% CI, 1.08-10.39), and deaths in the 2 arms were 8% vs 3%, respectively. In 313-0124, the HR for idelalisib plus rituximab vs rituximab alone in patients with previously treated iNHL was 4.74 (95% CI, 0.6-37.12), and deaths were 5% and 1%, respectively. In 313-0125, the HR for idelalisib plus bendamustine and rituximab vs bendamustine/rituximab in patients with previously treated iNHL was 1.51 (95% CI, 0.713.23), and deaths were 8% vs 6%, respectively.

The trials were halted due to increased deaths or toxicities in March 2016.

The FDA initially granted an accelerated approval for idelalisib for R/R FL or SLL after 2 prior therapies and regular approval for relapsed CLL in 2014. Gilead Sciences, Inc voluntarily withdrew the FL and SLL indications in February 2022.

Meanwhile, idelalisib retains its indication in combination with rituximab in patients with relapsed CLL for whom rituximab alone would be considered appropriate therapy due to other comorbidities.

The combination showed an improvement in PFS, the primary end point, over placebo plus rituximab in study GS-US-312-0116 (NCT01539512), an earlier trial of idelalisib that supported the combination’s regular approval for CLL in 2014.

At the final analysis, the updated median PFS was 19.4 months (95% CI, 12.3-not reached) with idelalisib vs 6.5 months (95% CI, 4.0-7.3) in the control arm, which translated into an HR of 0.15 (95% CI, 0.09-0.24; P < .0001).

 The study was not designed to assess OS, but an exploratory analysis “indicated a potential survival benefit in the idelalisib-plus-rituximab arm,” with an HR of 0.34 (95% CI, 0.19-0.60; P = .0001), according to the FDA.

FDA officials also noted a pattern of declining benefit for other PI3K inhibitors. In September 2018, the FDA granted regular approval to duvelisib for patients with R/R CLL or SLL after at least 2 prior therapies and accelerated approval for adults with R/R FL after at least 2 prior systemic therapies. The indications were based on findings from the phase 3 DUO study (NCT02004522), in which adult patients were randomly assigned to treatment with duvelisib or ofatumumab (Arzerra). The trial recruited patients whose disease had relapsed after 1 prior therapy; most of the participants (312 of 319) had CLL.

The benefit-risk profile was deemed greater in patients with at least 2 prior therapies. Among these patients, the median PFS with duvelisib was 16.4 months compared with 9.1 months with ofatumumab (HR, 0.40; SE, 0.2). The ORR was 78% and 39% for the duvelisib and ofatumumab arms, respectively.

Findings for OS, a key secondary end point, were immature when the primary analysis was conducted. However, final 5-year data favored the control arm, FDA officials said in their briefing document. The HRs for the total study population were 1.09 (95% CI, 0.79-1.51) for the total study population and 1.06 (95% CI, 0.71, 1.58) for participants with 2 or more prior therapies. Deaths also were higher with duvelisib than ofatumumab among patients who had received 1 prior therapy (50.0% vs 44.0%, respectively) and among those with 2 or more therapies (55.8% vs 48.5%, respectively).

In response, Secura Bio, Inc, which is developing duvelisib, argued that the final OS results do not reflect negatively on the drug. Most patients on the ofatumumab arm crossed over to duvelisib, and none of the participants remained on either study drug at the 5-year mark, according to David Sidransky, MD, a clinical adviser to Secura Bio.

Sidransky is director of Head and Neck Cancer Research in the Department of OtolaryngologyHead and Neck Surgery at Johns Hopkins University in Baltimore, Maryland. 

Moreover, the OS findings were neutral at the interim and final analyses, Sidransky maintained. At 3 years, when most patients who were still on the study had received duvelisib, the OS rate was comparable at 59% with duvelisib and 60% with ofatumumab, he said.

The FDA has not announced a final decision on the CLL/SLL indication for duvelisib following the ODAC meeting. Meanwhile, Secura Bio voluntarily withdrew the indication for duvelisib in R/R FL in December 2021, which was based on findings from a single-arm trial (NCT02204982).

The treatment landscape for FL has changed since duvelisib gained accelerated approval more than 4 years ago, casting doubts on the merits of the logistics, cost, and timing of a confirmatory study, the company said.

At the same time, Secura Bio is continuing the development of duvelisib in hematologic malignancies, with ongoing phase 2 studies in R/R peripheral T-cell lymphoma, R/R CLL, iNHL, and other tumor types. The PRIMO trial (NCT03372057) evaluating duvelisib as a single agent in R/R peripheral T-cell lymphoma is fully enrolled.

In September 2017, the FDA granted an accelerated approval for copanlisib for treating adults with R/R FL who have received at least 2 prior therapies based on ORR data from the single-arm, phase 2 CHRONOS-1 trial (NCT01660451).

The FDA has raised concerns about findings from the phase 3 CHRONOS-3 trial (NCT02367040), in which patients with previously treated iNHL were randomly assigned to receive rituximab with or without copanlisib. 

The copanlisib combination demonstrated an improvement vs rituximab plus placebo in PFS, the primary end point, in the intention-to-treat (ITT) population with iNHL. The median PFS with the copanlisib regimen was 21.5 months (95% CI, 17.8-33.0) vs 13.8 months (95% CI, 10.2-17.5) with rituximab alone (HR, 0.52; 95% CI, 0.39-0.69). A PFS benefit also was seen in the subsets of patients with FL (HR, 0.58; 95% CI, 0.40-0.83) and MZL (HR, 0.48; 95% CI, 0.25-0.92).

However, an updated analysis of OS, an exploratory end point of the study, “raised concern for a potentially higher risk of death in the copanlisib-plus-rituximab arm,” the FDA said. With a data cutoff of August 2021, the HRs for OS were 0.87 (95% CI, 0.57-1.35) for the ITT population, 0.95 (95% CI, 0.52-1.74) for participants with FL, and 1.07 (95% CI, 0.38-3.00) for the MZL subgroup. The median OS was not estimable for any of the cohorts due to a low number of observed deaths. Death rates for the copanlisib combination were 18% for the ITT population, 16% for patients with FL, and 20% for participants with MZL compared with 21%, 18%, and 17%, respectively, with rituximab alone.

“While the wide confidence intervals of the OS HR and the survival percentage difference indicated estimate uncertainty, potential harm to patients in the copanlisib-plus-rituximab arm cannot be ruled out,” FDA officials said in the briefing document.

Bayer submitted a supplemental new drug application for the copanlisib combination in relapsed iNHL based on the CHRONOS-3 data in May 2021 but withdrew the application in December 2021.3 The company said existing and additional data would be analyzed and the potential for a resubmission would be assessed.

 The designated confirmatory trial for FL, CHRONOS-4 (NCT02626455), is ongoing. The phase 3 study, which is active but no longer recruiting participants, is testing standard chemoimmunotherapy with or without copanlisib in patients with R/R FL or MZL.

In February 2021, the FDA granted accelerated approvals for umbralisib for treating adults with R/R MZL who have received at least 1 anti–CD20based regimen and for patients with R/R FL after at 3 prior lines of systemic therapy based on ORR and duration-of-response rates in the single-arm phase 2/3 UNITY-NHL trial (NCT02793583).

A year later, however, the FDA issued a warning about the potential for an increased risk of death with umbralisib therapy after an initial review of data from the phase 3 UNITY-CLL trial (NCT02612311).

The study was evaluating the combination of umbralisib plus ublituximab, an anti-CD20 monoclonal antibody, compared with obinutuzumab (Gazyva), which also is directed at CD20, plus chlorambucil in patients with previously untreated and R/R CLL. 

Data from UNITY-CLL were submitted in March 2021 to support a supplemental new drug application for the combination in this population.

The findings showed that median PFS, the primary end point, was 31.9 months (95% CI, 28.235.8) with the umbralisib combination compared with 17.9 months (95% CI, 16.6-22.6) with the obinutuzumab regimen (HR, 0.546; 95% CI, 0.4130.720; P < .0001). 

Despite the PFS benefit, the interim OS outcomes favored the control arm (HR, 1.23), and patients who received the novel combination experienced more serious adverse events (AEs).

The possibility of a higher incidence of deaths due to the novel combination prompted the FDA to place multiple clinical trials involving the 2 drugs on hold.

 In April 2022, TG Therapeutics, Inc notif ied the agency that it would voluntarily withdraw the indications for FL and MZL.

Overall, the findings suggest that the toxicity profiles of PI3K inhibitors have a detrimental impact on OS in patients with CLL or iNHL, the FDA said. As monotherapies, the 4 PI3K inhibitors that the FDA analyzed have demonstrated rates of AEs of grade 3 or greater severity ranging from 51% to 85%, including infection (20%-27%) and neutropenia (17%-43%).

“The consistent findings of decrements in overall survival in 6 randomized trials in the setting of an advantage or potential advantage in PFS [are] unprecedented in oncology,” FDA officials stated in the April briefing document.

 “The overall survival information is early and represents a low number of events, yet we have the same pattern observed across multiple trials. Further, in each trial, there was a higher rate of death due to adverse events in the PI3K inhibitor arm, suggesting the potential detriment in overall survival may be due to toxicity.”

The toxicity profiles observed with PI3K inhibitors in hematological settings are associated with the agents’ distinct mechanisms of action, which vary according to the target isoform of PI3K. Each of the agents inhibits the PI3Kδ isoform, and duvelisib and copanlisib also inhibit PI3Kγ and PI3Kα, respectively.

 Copanlisib also has been described as a pan-PI3K inhibitor because it shows activity against all 4 PI3K isoforms.

Inhibitors of the δ and γ isoforms, which are preferentially expressed on leukocytes, are associated with infections and immune-mediated toxicities. “Infection may occur in part because of treatment-related cytopenias, but also because of the modulation of the immune system by the PI3 kinase inhibitor,” Nicholas C. Richardson, DO, MPH, said during an FDA webcast about PI3K inhibitors presented May 12, 2022.

 Richardson is a clinical team leader in the Division of Hematologic Malignancies II in the FDA’s Office of Oncologic Diseases.

He said infections include pneumonia, opportunistic infections such as Pneumocystis jirovecii, and cytomegalovirus reactivation. Immunerelated toxicities may result from a decrease in regulatory T-cell activity, causing damage to healthy tissue, with AEs such as hepatitis, pneumonitis, colitis, and rash. 

Inhibition of the α isoform may cause hyperglycemia and hypertension. “The α isoform is ubiquitously expressed and is essential to cellular growth and metabolism and glucose homeostasis,” Richardson said.

Moreover, the establishment of optimal doses across this class of agents also has been problematic, particularly because there is a narrow difference between an effective dose and toxic exposure, Richardson said. He said the relationships between exposure to the drug with safety and toxicity have not been sufficiently explored. The FDA is seeking to improve the evaluation and optimization of oncology drugs through its Project Optimus program.

The experience with PI3K inhibitors in hematology highlights the pitfalls of using data from single-arm trials for drug approvals, according to FDA officials. All the drugs under discussion gained indications for FL, SLL, and/or MZL based on ORR data from single-arm trials. In general, the limitations of single-arm trials include challenges in interpreting safety and efficacy data without comparator arms, questions about whether response rates will be predictive of clinical benefit, and difficulties interpreting the results of time-to-event end points such as PFS

Moving forward, the FDA will be looking for randomized clinical trial data in drug applications for PI3K inhibitors in hematologic malignancies, with OS as the preferred end point. The PI3K inhibitor journey also holds lessons for drug development in general, noted Yvette Kasamon, MD, during the webinar. Kasamon, who also is a clinical team leader in the Division of Hematologic Malignancies II in the FDA’s Office of Oncologic Diseases, said these lessons include the need for adequate justification for dosing levels, the limitations of single-arm trials, and the importance of OS as an end point.

The impact of the FDA’s stance on PI3K inhibitors is reverberating in the drug development f ield. In March 2022, the FDA informed the developers of the selective PI3Kδ inhibitor zandelisib that randomized data would be required for a new drug application, according to the drug’s developers, MEI Pharma, Inc and Kyowa Kirin Co, Ltd.

The drugmakers had planned to seek accelerated approval for zandelisib based on data from the single-arm phase 2 TIDAL study (NCT03768505) in patients with R/R FL or MZL after 2 or more prior therapies. The FDA’s position on the need for randomized data marks the first time the agency has declined to consider results of a single-arm study as a basis for accelerated approval, representatives of the companies said.

The supporting data are expected to eventually come from the ongoing phase 3 COASTAL study (NCT04745832) comparing zandelisib plus rituximab against standard-of-care chemotherapy plus rituximab in patients with R/R FL or MZL who have received more than 1 prior line of therapy including an anti-CD20 antibody in combination with chemotherapy or lenalidomide (Revlimid).

A month later, the ODAC panel formally endorsed the need for randomized data for this class of drugs to be considered for FDA approval for hematologic indications. That decision likely will hamper plans for several investigational PI3K inhibitors under development for hematologic cancers, market analysts say.

Investigators have been focusing on several strategies to boost the efficacy of PI3K inhibitors, with a focus on reducing toxicities, designing combination regimens, and overcoming resistance. 

Some experts believe that exploring new scheduling and dosing regimens would result in fewer toxicities and an improved therapeutic index.

In this vein, some studies of novel PI3K inhibitors have tested intermittent dosing, as opposed to continuous dosing at the maximum tolerated dose identified in phase 1 trials.

Although combining PI3K inhibitors with other targeted therapies has been challenging, there may be opportunities for rational combinations in patients with PIK3CA-mutant tumors.

In terms of resistance to PI3K inhibition, several mechanisms of intrinsic and acquired resistance have been described, such as reactivation of the PI3K pathway through feedback loops and activation of compensatory parallel signaling cascades.

 In a patient with PIK3CA-mutated breast cancer, for example, the inhibition of PI3K signaling led to recurrent PTEN loss, which in turn may limit the antiproliferative impact of PI3K-directed therapy.

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FDA withdrew its approval for the cancer medicine Ukoniq (umbralisib) due to safety concerns. FDA. Drug Safety Podcast. July 7, 2022. Accessed November 1, 2022. https://bit.ly/3FC651c 

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Piqray. Prescribing information. Novartis Pharmaceuticals Corporation; 2022. Accessed October 19, 2022. https://bit.ly/3TAXU8U

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OncLive® staff. ODAC unanimously votes to recommend randomized data for approval of PI3K inhibitors in hematologic cancers. OncLive®. April 21, 2022. Accessed October 19, 2022. https://bit.ly/3TzaxRV 

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The PI3K cell-signaling network has been an important therapeutic target in oncology research for nearly 40 years ago, but the use of PI3K inhibitors in hematologic malignancies has come under scrutiny amid concerns about efficacy and safety.

Vol. 23/No. 23 | Oncology Live®

Breast Cancer Advances in 2022 Showcase a Shifting Landscape

The State of Biosimilars: Obstacles and Barriers to Use in 2022

MRD Detection Emerges as a Catalyst for Advances in Colon Cancer

PI3K Inhibitors Face Challenges in Hematologic Malignancies

BRONx-CAN Program Aims to Deliver the Best Cancer Treatments Early

Tremelimumab Plus Durvalumab Receives Go-ahead for Treatment of HCC

Effective Communication on HPV Vaccination Benefits Is Needed