Looking Across Disciplines to Share the Breadth of Innovation in Cancer Care
8/22/2023, American Journal of Managed Care
If one looked only at the progress in lung cancer over the last decade, there would be plenty to behold. Long-term efforts to promote smoking cessation and discoveries of druggable targets combined to push lung cancer mortality rates down 5% a year between 2015 and 2019, according to the annual data from the American Cancer Society.1 But the good news doesn’t stop there. Move to breast cancer, to chronic leukemia, to bladder cancer, and the wonders of innovation continue.
On July 25, AJMC brought its Institute for Value-Based Medicine (IVBM) series to Atlanta, Georgia, where innovation was on the agenda. Cochairs Ryan Haumschild, PharmD, MS, MBA, director of pharmacy, Emory Healthcare Winship Cancer Institute, and Jonathan Kaufman, MD, professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, presented an IVBM session where Winship faculty offered updates on innovation in 4 disease areas: non–small cell lung cancer, chronic lymphocytic leukemia (CLL), metastatic urothelial cancer, and hormone receptive-positive, HER2-negative (HR+/HER2–) breast cancer.
As the group would share later in a panel discussion, innovation can be costly. It can involve tradeoffs. Kaufman offered an example—switching to an induction therapy in multiple myeloma would cost six figures more up front, but it could yield deeper responses, which would mean less toxicity for the patients and less maintenance therapy later on. Each month that a patient doesn’t need lenalidomide maintenance represents savings of $15,000 to $20,000, he said. “We’re very thoughtful about that,” Kaufman said.
Haumschild said therapeutic advances aren’t the only area of innovation at Winship. Investments in technology and Epic implementation have occurred in the past year, and physical improvements are under way. “We have disease state working groups that have consolidated approaches to therapy to provide the best consistent outcomes for our treatments, and our patients,” he said.
Commitments to “a unique approach to our cancer patients with diversity, equity and inclusion considerations of social determinants of health [ensure] that at the end of the day, we’re making sure that our outcomes and value match our mission, which is to improve lives and provide hope,” he said.Ticiana Leal, MD: the Importance of Biomarker TestingIt’s well known that targeted therapy has demonstrated improved survival in clinical trials of patients with non–small cell lung cancer (NSCLC). The change of fortune for these patients has been so rapid, said Ticiana Leal, MD, that investigators are now seeing accelerated survival at a population level, along a time frame associated with approval of these therapies.2 Leal is an associate professor in the Department of Hematology and Medical Oncology and director of thoracic medical oncology at Winship Cancer Institute.
Leal shared Medicare data showing this good news at the start of her talk on the importance of using biomarkers to treat NSCLC. However, Leal noted, disparities remain between Hispanic and non-Hispanic populations.2 “So, a lot more needs to be done,” she said. Tools exist to help close the gaps, but they must be used for all patients; as she explained, it now makes sense to use tissue and plasma testing together.
“These advances in precision medicine, they’re really here to stay, and more specifically for lung adenocarcinoma,” Leal said. The genomic complexity of lung cancer and improved diagnostic testing mean that clinicians “are able to identify a growing number of druggable targets that are quickly being incorporated into clinical practice,” she said.
More than a dozen therapies and associated targets are now part of the clinical guidelines published by the National Comprehensive Cancer Network; these include tyrosine kinase inhibitors and antibody drug conjugates, in both frontline and second-line settings. The days of single-gene testing to match the right drug with the right patient are over, she said. “One of the greatest things [with the] selection of optimal therapy is the ability to do broad-based or comprehensive biomarker testing. And in my opinion, NGS [next-generation sequencing] is really the way to go.”
Are payers receptive to testing and to targeted therapies in general? During the question-and-answer session, Leal said some are easier to work with than others, and Emory’s pharmacy team excels at expediting approvals. “Payers are increasingly supportive of the cost effectiveness of targeted therapies,” she said.
Tissue, liquid, or both? For many years, Leal explained, tissue-based testing was “the gold standard” because tissue was needed to do a diagnostic biopsy. “If there’s insufficient tissue, then you go on to do a liquid biopsy,” she said.
But newer, complementary approaches may be optimal “because you’re doing tissue-based testing and liquid-based testing at the same time,” and this may be a better strategy for patients with lung cancer, she noted.
For some patients, “there’s the plasma first approach, which is when you do a diagnostic biopsy, and you really don’t have any tissue to perform the tissue-based testing and you’re unable to do another diagnostic biopsy for more tissue, [so] you use the NGS and liquid biopsy,” Leal said.
Leal explained that the caveat to this approach is that if the liquid biopsy does not reveal a biomarker, a surgical biopsy may be needed to rule out any biomarker.
“This is very complex,” she said. For all the advances in biomarker testing, the challenges of tissue acquisition—and finding accessible sites—can still delay treatment.
She shared results of a study comparing patients who received “piecemeal” testing, meaning 1 marker at a time, with those who had a liquid biopsy. Using the liquid test alongside the tissue tests identified more actionable markers, with 96% concordance between the tissue and liquid markers for an FDA-approved therapy.3
“And the turnaround time [for the liquid biopsy] was significantly lower than with tissue-based testing, 9 vs 15 days,” Leal said. “So we’re really improving the potential time to treatment initiation.”
Results of a separate, single institution study showed that adding liquid biopsy to tissue testing boosted the rate of identification of targetable mutations from 20% to 35%.4
Not enough testing. Results from the real-world MYLUNG study, presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that 17% of patients still did not have biomarker testing before starting treatment for NSCLC, and only 54% had NGS.5 Leal said this is alarming, given that results presented at the same meeting showed that the benefits of osimertinib (Tagrisso) for patients with newly diagnosed NSCLC with an EGFR mutation.6 She sees missed opportunities to cure patients in early-stage settings.
“We saw at ASCO 2023, at the plenary session, for the first time ever, [data showing] a significant improvement in survival in patients who receive a targeted therapy in the adjuvant setting,” she said. “And despite this, you’re seeing about 50% of patients receiving genotyping.”
Failing to test patients for PD-L1 status will be a major roadblock as chemoimmunotherapy becomes an important new adjuvant strategy, Leal said, “because only patients with PD-L1–positive disease are actually eligible for adjuvant immunotherapy in the adjuvant setting. So clearly, we still have a long way to go.”
Why are biomarker results not available before treatment? Leal pointed to results from MYLUNG that show patient and provider perceptions are the leading cause, at 54%. Other reasons are: issues with tissue retrieval, 25%; clinical deterioration, 10%; patient-provider knowledge about testing options, 12.5%; payer coverage, 8.3%. Leal said there are concerns that providers worry about the time needed to wait for biomarker results. And other data show that doing single-gene testing can limit the performance of NGS if done later, due to tissue inadequacy.5
“We’ve demonstrated in prior studies that go back to 2019 that the use of upfront NGS testing, vs single-gene testing, actually is cost effective,” Leal said. This approach results in less time to actionable test results and less likelihood that patients take therapy that will not work.
Disparities in testing. Leal presented data from Flatiron Health, which compared the likelihood of White vs Black patients to have NGS testing in general and before first-line therapy. Data for 23,488 patients were evaluated, and differences were seen in NGS rates for White patients vs Black patients before first-line therapy (36.6% vs 29.7%) and at any given time (54.7% vs 43.8%) in the nonsquamous NSCLC cohort. Disparities in NGS testing rates at any time were also seen among patients with colorectal cancer (White, 51.6%; Black, 41.8%), but no differences were seen in the breast cancer cohort.7
Testing is not only important to guide treatment, but data show it also can improve patients’ chances of gaining access to clinical trials, she said. “There is a significant need to improve biomarker testing in populations that are underrepresented, and specifically here in the Black population, but we’ve also seen this in the Hispanic population as well,” Leal said.
What are some solutions? Leal discussed reflex testing, which saves time by empowering the pathologist to begin NGS as soon as a diagnosis of NSCLC is clear from the biopsy. In addition to concurrent use of tissue and liquid biopsy, Leal called for better integration of biomarker results into the electronic health record.
Better multidisciplinary care and molecular tumor boards allow institutions to tap into regional strength, she said. Finally, patients and families should be educated about biomarkers.
“Whenever I see a patient and they get their biomarker results, I print it out. And I say these are your biomarkers, and I highlight what they need to know,” Leal said. Giving patients ownership by discussing their results in language they can understand helps them understand the importance of what is happening, “and how it impacts their care and survival,” she said.Jonathan Cohen, MD, MS: Tracing the Evolution in CLL TherapyChronic lymphocytic leukemia (CLL) might be the most common type of leukemia in this part of the world, but that doesn’t mean there’s one way to treat these patients, according to Jonathan B. Cohen, MD, MS, associate professor, Department of Hematology and Medical Oncology, and codirector of the Lymphoma Program at Winship Cancer Institute.Cohen, whose presentation focused on targeted therapies in CLL, started by noting that although many patients are in their 60s or 70s, “I do have some patients in their 30s. And for those patients, when you’re talking about a chronic disease, it’s a little bit of different perspective than someone who might be 75 or 80 [years of age],” he said.
CLL has its nuances, starting with the fact that one form of the disease, small lymphocytic lymphoma, behaves more like lymphoma, which Cohen said can be confusing for patients. The diseases are managed the same way, and most patients are asymptomatic at diagnosis—they tend to be referred to an oncologist after routine tests show an abnormal white cell count. Sometimes treatment is not necessary right away.
“Those are some of my most challenging clinic visits, because it’s often somebody who’s feeling well, where you’re really just trying to decide, does this person need treatment?” Cohen said.
Some of the original biomarkers in CLL are less useful today, Cohen said, although 2 discovered a generation ago remain part of a patient’s work-up: TP53 sequencing can reveal the presence of 17p deletion, which is an indicator of poor overall survival (OS), and IGHV mutation status is associated with better survival odds.
Patients may live with CLL for months, years, or decades; this is a consideration when deciding a treatment approach, Cohen said. As treatment has advanced from the chemotherapy options that were common a decade ago, a patient’s willingness and financial ability to take daily therapy indefinitely can drive decisions.
Ten to 15 years ago when Cohen treated patients newly diagnosed with CLL, the typical choices were a pair of chemotherapy-based combinations: bendamustine (Bendeka) plus rituximab (Rituxan; BR); or fludarabine, cyclophosphamide, and rituximab (FCR). Today, that’s all changed with the arrival of Bruton tyrosine kinase (BTK) inhibitors, which now have multiple options approved, as well as BCL-2 inhibitors, of which venetoclax (Venclexta) is approved and more are under development.
The chemotherapy combinations had tradeoffs. Although results of a randomized trial showed the FCR combination offered better progression-free survival, the 6-month regimen caused significant bone marrow suppression, and patients typically had to miss work through the entire treatment course. They were at high risk for infection, and “often patients can go months, if not years, without normal bone marrow function,” Cohen said. “It was a big ordeal.”Arrival of newer therapies. Then came the BTK inhibitors—first ibrutinib (Imbruvica), followed by zanubrutinib (Brukinsa) and acalabrutinib (Calquence), and now pirtobrutinib (Jaypirca), which thus far has FDA approval only in mantle cell lymphoma. Approval of ibrutinib in 2014 “significantly changed the way we thought about treating patients with CLL,” Cohen said.
Initially, BTK inhibitors were approved as second-line therapy. Ibrutinib was approved for frontline use in 2016, and second-generation BTK inhibitors zanubrutinib and acalabrutinib have since been approved for frontline use.
Cohen went through the pros and cons of BTK regimens vs a BCL-2 inhibitor. “The BTK inhibitors are given orally. They’re convenient; they’re dispensed from the specialty pharmacy, so they come to the patient’s house,” he said. Patients have no intensive monitoring at the start of therapy.
Venetoclax, the BCL-2 inhibitor, is also an oral therapy. But Cohen noted, “It is different in the front line. It’s only administered for 1 year, so it’s a time-limited therapy; it doesn’t have some of the cardiac or bleeding toxicities that are associated with the BTK inhibitors. And so, for patients who have a history of cardiac disease, often we may think about venetoclax.”
Adherence is also a consideration. For younger patients, the 1-year duration of venetoclax has appeal compared with BTK inhibitors, which are taken indefinitely. “Putting somebody on a therapy that you’re asking them to take for the next 15 years—that can be challenging, as you can imagine, to adhere to that.”
Although he did not characterize it as a cost-effectiveness analysis, Cohen said for patients looking at paying for a year of upfront therapy compared with therapy indefinitely, the venetoclax option “is a little cheaper for patients, and especially those patients with a larger co-pay. Often, they can make it work for a year,” he said.
Cohen went through results of studies that showed the survival advantage of BTK inhibitors over the chemotherapy combinations, including studies in which Emory participated that support the use of ibrutinib in untreated CLL.8,9
In second-generation therapy, the ELEVATE-TN trial (NCT05437250) compared acalabrutinib vs acalabrutinib plus the CD20 antibody obinutuzumab (Gazyva) vs obinutuzumab/chlorambucil (Leukeran).10 Cohen explained that this was part of a series of trials designed for patients who were older and had many comorbidities—typical of a real-world population—and who were not candidates for traditional therapy. (Of note, venetoclax is often used with obinutuzumab). He presented the data that showed the acalabrutinib arms produced much longer remissions than the chlorambucil arm.
He also shared results of a 2022 study comparing zanubrutinib vs the BR combination, which showed a 58% PFS advantage for zanubrutinib.11
“Again, this certainly indicates with all 3 of these that we are able to improve the remission duration; we’re able to keep people in remission longer, which obviously is a laudable goal,” Cohen said. “It does come at the expense of continuous therapy…. Fortunately, these tend to be very well-tolerated therapies.”
When using BTK inhibitors, patients are not observed at an infusion center, so it’s important that staff members are counseled about the types of adverse events (AEs) patients may experience.
“Atrial fibrillation is the most common type we see. It’s about 10% to 15% of patients,” he said. Patients must be warned to stop treatment temporarily if having minor surgery or a tooth removed, for example. Cardiac deaths are very rare, but they do occur. The grade 1 to 2 AEs, such as infections, fatigue, joint aches, or diarrhea, may not seem severe, but if these are happening every day, “It can certainly impact your life,” he said.
Despite all this, Cohen said, most patients do not experience toxicity. “They feel fine. I would say the majority of patients who come to see me in clinic are annoyed that we have to see them every 3 months,” he said.
In reviewing venetoclax, he presented data that show the majority of patients have not had disease progression 4 years after stopping therapy.12 It does have different toxicities, including tumor lysis syndrome. Even so, the time-limited duration means “this is certainly a very appealing approach for some patients,” he said.Questions, combinations, and sequencing. A big question today, Cohen said, is whether there’s still a role for chemotherapy in CLL. “I would say there may still be a role in a very few instances, perhaps for a young patient who doesn’t want to be on a longer-term course of therapy and who has low-risk disease. But I would say it’s been at least 3 years since I’ve started somebody on chemotherapy for CLL. And I would say there’s almost no role for chemotherapy in the relapsed setting,” he said.
Combining novel agents is an area of study. Cohen noted that although combining agents maximizes remission duration in multiple myeloma, “that is something that we haven’t necessarily seen in CLL.”
Adding more therapies without adding benefit would increase the cost impact, so right now, this is not the standard of care in CLL, he said. Sequencing—deciding which drug to give first, knowing that a relapse may come years later—is a consideration.
“We expect that most patients will ultimately relapse, despite the really fantastic results. We don’t know yet whether one does better than the other, or if the order matters,” Cohen said. “So really, right now, it’s primarily a matter of talking to patients about what’s important to them and taking into account comorbidities. And then we think about what’s next.”
Immunotherapies, he said, “are the next frontier for CLL,” Cohen noted. And other studies are asking the question of when therapy can stop, which may not be the same for every patient. In venetoclax, for example, “I wouldn’t be surprised in the next 5 to 10 years if we get to a place where we can identify some people who maybe stop after 6 months, some people go for a year, some people go 2 years, some people don’t stop,” he said.
Even if these practices aren’t in place today, he said, “Those are all things that are attainable.”Kevin Kalinsky, MD, MS: Genomic Assays Can Tell Us Which Patients With Breast Cancer Could Get Less TreatmentBeing treated for breast cancer is taxing enough without receiving more therapy than necessary. Thanks to the current generation of genomic assays —and a wave of research surrounding them—clinicians are gaining insights into how much therapy individual patients need when they are treated for early-stage, hormone receptor—positive, HER2-negative breast cancer (HR+/HER2–), according to Kevin Kalinsky, MD, MS, associate professor of medicine and the Louisa and Rand Glenn Family Chair in Breast Cancer Research. Kalinsky is the director of breast medical oncology and director of the Glenn Family Breast Center at Winship.
Use of genomic assays can determine “who needs chemotherapy or not, to de-escalation or even opting out of therapy,” Kalinsky said. This has value, he said, because some patients can just be treated with endocrine-based therapy and avoid chemotherapy.
He began with a review of the landmark TAILORx study (NCT00310180), funded by the National Cancer Institute (NCI), which brought clarity to the use of the Oncotype DX assay in deciding on adjuvant therapy in early-stage HR+/HER2– breast cancer.13 Just over 10,200 women took part in the study and 69% had midrange recurrence scores (11-25) where use of chemoendocrine therapy was not clear-cut. Results showed there was little difference between the chemoendocrine and endocrine-only groups but chemotherapy seemed to offer some benefit for women younger than 50 years with a recurrence score of 16 to 25.
But was it the chemotherapy or something else? The initial TAILORx study was presented in 2018 and now investigators have 13 years of follow-up data, and Kalinsky took a deep dive into questions that breast cancer researchers have been pondering ever since. Updated data presented in December at the San Antonio Breast Cancer Symposium found that the predictive value of the assay held across the different groups in the study.14
In this trial, the cutoff of aged 50 years acted as a surrogate for menopause, Kalinsky said. “There were some patients who did benefit in an exploratory analysis from the addition of chemotherapy, which [raises] the question, is that benefit that we’re seeing? Because this is really a premenopausal population.”
Is the benefit from the chemotherapy or “is it because these are all estrogen-driven breast cancers? Is it because we’re stopping their periods? Is this an expensive and unsophisticated way of just stopping patients periods, which is really what’s driving the benefit? That remains an ongoing question within our field,” Kalinsky said.
Kalinsky said TAILORx has shown that the recurrence score by itself cannot be viewed in isolation. “It’s the incorporation of clinical features like grade and tumor size and other pathologic features that really inform risk,” he said. An online tool that incorporates all these elements, RSClin, is now available.15
"We’re moving away from a one-size-fits-all approach. We’re offering precision medicine where we can say to patients, ‘Your risk is x and you don’t need chemotherapy based upon the biology of your tumor.’”
A later study, RxPONDER (NCT01272037), that examined women with node-positive cancer also upended old beliefs, he said. Decades ago, this feature would have always indicated chemotherapy. But when a study was done with the assay, postmenopausal women with recurrence scores of 0 to 25 did not have to have chemotherapy.16
“So this is saving tens of thousands of women—and men—unnecessary side effects and toxicities and all the things that are associated with giving chemotherapy,” Kalinsky said.
Once again, the premenopausal women in the study benefited from chemotherapy.
Other data from RxPONDER, which are still maturing, will show how ovarian function affects the brain’s ability to keep producing estrogen. Women with optimal ovarian suppression appear to fare better, but of course, the downsides are significant. “We’re putting patients into menopause and it’s not easy to tolerate,” he said. “It causes lots of side effects, including hot flashes, mood dysfunction, bone issues, and cardiac dysfunction.”
One facet that Kalinsky reported at the San Antonio meeting in December is that despite better medication adherence, Black and Hispanic women fared worse.17
Helping women avoid unnecessary chemotherapy has important quality-of-life implications, he said, because the cognitive effects are quite real, as seen in patient-reported data from RxPONDER.18 “This is something that patients complain about…‘chemo brain,’ ” he said. “The data support this.”
Kalinsky said he’s looking ahead to a national study coming soon that will randomly assign high-risk, node-negative, and node-positive patients to receive ovarian function suppression plus hormonal therapy, with or without chemotherapy. “This is the study that’s going to define, in a genomically defined population, whether or not we should be giving chemotherapy.”
Other assays, such as MammaPrint, are on the ASCO guidelines, he noted, but they are not all the same. Guidelines suggest sticking with 1 type of assay for a patient instead of switching back and forth.
He said the breast cancer field is seeing interest in circulating tumor DNA markers but “our colorectal colleagues are the ones who are furthest along in terms of escalation and de-escalation of therapy based upon circulating-tumor DNA. This is not quite ready for prime time in patients with breast cancer,” Kalinsky said.
“One of the issues that we face that others in this room likely face as well, is that if you check the test in a patient who has curable disease, and you have a positive assay, what do you do about it except for worry?”
Should a patient on an endocrine therapy switch to a different one or to a different drug class? Does that increase or decrease the rate of recurrence? “This is something that we don’t have the answer for yet. But there are a number of studies,” Kalinsky said. “There’s an NCI-sponsored study that should hopefully be opening with the year to address this question.”Jacqueline T. Brown, MD: ADCs, Drug Shortages, and the Effects on Patients With Bladder CancerAt an evening dedicated to innovation in cancer care, Emory University’s Jacqueline T. Brown, MD, an assistant professor at Winship Cancer Institute explained how her area of specialty—genitourinary malignancies—has become a poster child for the extremes of care delivery.
Her talk covered how the rise of this drug class and the approval of 2 antibody-drug conjugates (ADCs) have elevated the standard of care in the sixth most common cancer.
At the other end of the spectrum, Brown discussed how the shortages of cisplatin and carboplatin, 2 cornerstone chemotherapies, have led to tough decisions for doctors and patients alike—and brought issues of health equity into sharp focus.
The magic bullet. Brown started by discussing German scientist Paul Ehrlich, MD, whose work led to chemotherapy; he won the Nobel Prize in Physiology or Medicine in 1908. He conceived the idea of the magic bullet, an agent that would take out a pathogen without disturbing the cells around it.19
“We know that chemotherapy is not a magic bullet,” Brown said. “The toxicity from traditional chemotherapy is attributed to nonspecific drug exposure to these off-target tissues. And when I’m talking to patients and I’m explaining to them what they can expect from traditional chemotherapy, I say, ‘These are drugs that kill cells that divide quickly, and so that ends up resulting in toxicities like cytopenias, [gastrointestinal] upset, and hair and nail changes.’ ”
She continued, “So the Holy Grail would really be to create a drug that is able to kill malignant cells and leave normal cells unharmed. That’s the real magic bullet.”
ADCs come much closer to that concept, Brown explained, with a 3-part structure that features a monoclonal antibody specific to an antigen expressed on target tissue, specifically cell surfaces, but not on normal tissue. “And when the monoclonal antibody binds to that target, it then needs to be able to be internalized and transported within the cell,” she said.
The ADC structure features a covalent linker, either cleavable or noncleavable, which guarantees proper delivery of the cytotoxic payload at just the right time to avoid affecting nontarget tissues. The payload kills cancer cells and comes in 3 types: DNA damagers, tubulin-binding agents, and topoisomerase-1 inhibitors. In some cases, she explained, the payload can be taken up by nearby cells in what is called the bystander effect.
Brown presented diagrams of 14 ADCs approved starting in 2000 across multiple disease types, as well as types under development. She noted the pair approved in bladder cancer, enfortumab vedotin (Padcev; EV) and sacituzumab govitecan (Trodelvy; SG).20,21A deadly disease. “What is metastatic urothelial carcinoma?” Brown asked, “Why is this a disease that matters?”
Urothelial carcinoma can start anywhere in the urinary tract, she said, but 90% of cases start in the bladder, with 10% from the ureter, urethra, or renal pelvis. When cancer spreads beyond the bladder, there is a median survival of 2 years in clinical trials; Brown said in the real-world population survival is likely shorter.
A 2018 study shows that only 42% of patients ever receive first-line therapy.22 “That’s a pretty high attrition rate in a pretty aggressive disease. Of those, only 27% received standard of care, cisplatin chemotherapy,” she said, noting there were likely many reasons for this, from cisplatin ineligibility to preexisting neuropathy. Just 15% to 20% received second-line therapy and “a measly 6% received third-line therapy,” she said.
“This is an aggressive disease and this is a deadly disease,” Brown said. “The key to actually moving the needle on survival is not only having good drugs, but also moving them to early lines of therapy so that your patients actually have the opportunity to benefit from those drugs.”
Since Brown became an independent practicing oncologist in 2021, change has been swift in urothelial carcinoma. In 2016, platinum-based chemotherapy was the only option, but since that time targeted agents and now ADCs have been approved. In April 2023, FDA approved EV plus pembrolizumab (Keytruda) for the treatment of cisplatin-ineligible first-line metastatic urothelial carcinoma,23 based on the phase 1/2 EV-103 trial (NCT03288545).24
Brown elaborated on EV. “This is an antibody-drug conjugate targeted against nectin-4,” a surface marker involved in cell proliferation and migration, she said. “It’s expressed in multiple cancers, but maybe none as highly as urothelial cancer—it’s in 80% to 90% of bladder cancer cells. The payload in this drug is MMAE [monomethyl auristatin E], which is a very traditional microtubule inhibitor involved in multiple other drugs in this space.”
She reviewed data from the phase 3 EV-301 trial (NCT03474107) that led to the drug’s original approval. Median overall survival was 12.88 months for EV compared with 8.97 months for chemotherapy; response rate for EV was 40.6% vs 17.9% for chemotherapy in a heavily pretreated population.25
“I think a really key concept with antibody-drug conjugates is this idea that you can have 2 different types of toxicity,” Brown said. “You can have on-target toxicity because the antigen is expressed in nontumor tissue, and then you can also have off-target toxicity.”
If patients stay on the drug long enough, she said, they will experience peripheral neuropathy; approximately one-third of patients are affected. Other common adverse effects include gastrointestinal adverse effects and cytopenias.
Moving EV with pembrolizumab into first-line treatment for cisplatin-ineligible disease was practice changing, Brown said. In the trial, “the objective response rate in this population was 64.5%. [This] means, 64.5% of patients had shrinkage of their tumor by more than 30%. That’s something that would have been unheard of before. And when we compare it with cisplatin from what we know, we’re generally talking about 40% to 50%. That number was really amazing to everybody,” she said.
What’s more, there were confirmed complete and partial responses in patients whose disease did not express nectin-4, which Brown called “hypothesis generating.” Results from another phase 3 trial, EV-302 (NCT04223856), which enrolled cisplatin-eligible patients,26 will show whether this chemotherapy has been “dethroned as king in first-line urothelial carcinoma,” she said.
The phase 2 TROPHY-U-01 trial (NCT03547973) led to approval for SG in urothelial cancer,27 which targets TROP2. This drug is a topoisomerase-1 inhibitor with a payload of SN-38, which “causes DNA single strand breaks and ultimately death of the tumor cell,” Brown said.
In heavily pretreated patients, the response rate was 27%, and 77% had some tumor shrinkage, leading to accelerated approval in the third-line setting. Brown described toxicities for patients taking SG as “more straightforward” than those for patients taking EV. SG causes severe cytopenias, neutropenic fever, and diarrhea; granulocyte colony-stimulating factor therapy is often required.A new paradigm? The use of EV with pembrolizumab could represent “a new paradigm,” Brown said. She reviewed other combinations in the pipeline; another cohort of the TROPHY-U-01 study involves ADC with immunotherapy. The phase 2 DESTINY-PanTumor02 (NCT04482309), looked at the ADC trastuzumab deruxtecan (Enhertu) across multiple cancer types,28 including bladder cancer, with a 39% objective response overall. Its results were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. A phase 1b study will examine this ADC with the PD-1 inhibitor nivolumab (Opdivo) in metastatic urothelial cancer with HER2 expression. Disitamab vedotin plus toripalimab (Loqtorzi) in patients with treatment-naïve disease produced an ORR of 73% in a small phase 1/2 study (NCT05917158). “Again, unheard of numbers in urothelial carcinoma—so this is very encouraging,” she said.Although ADC combinations becoming the standard of care seems closer, it’s not yet here. And for now, if a patient is eligible for cisplatin, that’s still the standard—except that it has become difficult to find. “Most people in this room are probably relatively aware,” of the shortages, Brown said. “You can imagine the really dire impacts this has had on managing this disease across the country.”Brown shared the well-known details about the FDA needing to shut a factory in India that made most of the carboplatin for the US for quality control issues, which triggered the current supply chain nightmare. First carboplatin, then cisplatin ran short as patients taking carboplatin were switched to different drugs.
“ASCO issued guidelines on how to navigate these drug shortages,” Brown said. “In short, the main take-home messages from this are: Use other things whenever you can, and in palliative patients, if you can spread out the interval of treatment with these drugs, please do so.”
Brown said when she moved a patient’s carboplatin from every 3 weeks to every 4 weeks, the patient asked, “Are you rationing care?” She said that she told him, “I guess that I am,” in an effort to be honest.An uncomfortable conversation. Per ASCO guidelines for urothelial cancer, if cisplatin is not available, the alternative would be to use EV plus pembrolizumab or pembrolizumab alone, Brown said. And for cisplatin-eligible patients, Brown reminded the audience, the combination is not yet FDA approved, and pembrolizumab alone “would be considered substandard care in 2023. If you are eligible for chemo, you should get chemo.”
“Of course, the elephant in the room is the astronomical cost differences between these drugs,” she continued. “I believe in these drugs; I believe in the data that I just presented to you; I use them regularly. And I know the very real impact they have on our patients. But also remember that one of the pillars of medical ethics is justice. And namely, that is the equitable and fair distribution of our health resources.”
Brown continued, “I have colleagues across the country in various regions who have not been able to give the drugs I have on the screen to their patients, let alone our colleagues internationally, who may show up to a big meeting and be inspired by the data being presented, but it has really no impact on their Monday morning treatment because they just don’t have those drugs to give [patients]. And I think it’s our collective responsibility to create a health system that is sustainable.
“I often think of myself as part of the problem; I think about this with some frequency. And so I think we have to agree to continue this conversation, as uncomfortable as it may be,” she said.
Brown noted that the FDA recently addressed the shortage by allowing imports of cisplatin from China.29 But the question of when the next shortage will arise lingers, she said.
“I want to conclude with a couple thoughts,” Brown said. “One is which to remind you that antibody-drug conjugates have absolutely revolutionized the treatment of urothelial carcinoma. The needle for survival is moving in this disease. And it’s because of these drugs, period. But critical drug shortages have had really big impacts, requiring implementation and mitigation strategies, reliance on more expensive alternatives, and in some cases even rationing care.
“And lastly,” she said, “with great power comes great responsibility. But we have to remember that as technology advances, we have to control costs and avoid deepening inequities in access and outcomes.”
References1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA: Cancer J Clin. Published January 12, 2022. doi:10.3322/caac.217082. Howlader N, Forjaz G, Mooradian MJ, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640-649. doi:10.1056/NEJMoa19166233. Leighl NB, Page RD, Raymond VM, et al. Clinical utility of comprehensive cell-free DNA analysis to identify genomic biomarkers in patients with newly diagnosed metastatic non-small cell lung cancer. Clin Cancer Res. 2019;25(15):4691-4700. doi:10.1158/1078-0432.CCR-19-06244. Aggarwal C, Thompson JC, Black TA, et al. Clinical implications of plasma-based genotyping with the delivery of personalized therapy in metastatic non-small cell lung cancer. JAMA Oncol. 2019;5(2):173-180. doi:10.1001/jamaoncol.2018.43055. Evangelist MC, Butrynski JE, Paschold JC, et al. Contemporary biomarker testing rates in both early and advanced NSCLC: results from the MYLUNG pragmatic study. J Clin Oncol. 2023;41(suppl 16):9109. doi:10.1200/JCO.2023.41.16_suppl.91096. Tsuboi M, Herbst R, John T, et al; ADAURA Investigators. Overall survival with osimertinib in resected EGFR-mutated NSCLC. N Engl J Med 2023;389(2):137-147. doi:10.1056/NEJMoa23045947. Bruno DS, Hess LM, Li X, Su EW, Patel M. Disparities in biomarker testing and clinical trial enrollment among patients with lung, breast, or colorectal cancers in the United States. JCO Precis Oncol. 2022;6:e2100427. doi:10.1200/PO.21.004278. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib–rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443. doi:10.1056/NEJMoa18170739. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Blood. 2018;132(supp 1):6. doi:10.1182/blood-2018-99-11665310. Sharman JP, Egyed M, Jurczak W, et al. Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia. Leukemia. 2022;36(4):1171-1175. doi:10.1038/s41375-021-01485-x11. Tam CS, Brown JR, Kahl BS, et al. Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial. Lancet Oncol. 2022;23(8):1031-1043. doi:10.1016/S1470-2045(22)00293-512. Eichhorst B, Niemann CU, Kater AP, et al; GCLLSG, the HOVON and Nordic CLL Study Groups, the SAKK, the Israeli CLL Association, and Cancer Trials Ireland. First-line venetoclax combinations in chronic lymphocytic leukemia. N Engl J Med. 2023;388(19):1739-1754. doi:10.1056/NEJMoa221309313. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi:10.1056/NEJMoa180471014. Sparano JA, Gray RJ, Makower DF, et al. Trial assigning individualized options for treatment (TAILORx): an update including 12-year event rates. Presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX; Abstract GS1-05.15. Helwick C. Prognostic tool RSClin introduced for early breast cancer. ASCO Post. March 10, 2021. Accessed August 3, 2023. https://ascopost.com/issues/march-10-2021/prognostic-tool-rsclin-introduced-for-early-breast-cancer/16. Kalinsky K. Barlow WE, Gralow JR, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med. 2021;385(25):2336-2347. doi:10.1056/NEJMoa210887317. Study finds Black women have worst HR-positive, HER2-negative breast cancer outcomes of all racial and ethnic groups. News release. Winship Cancer Institute. December 6, 2022. Accessed August 3, 2023. https://bit.ly/3rTKj4618. Kang I, Forschmiedt J, Loch M, et al. Patient-reported cognitive impairment in women participating in the RxPONDER trial (SWOG S1007) by menopausal status. Presented at: San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS1-04.19. Paul Ehrlich. Science History Institute. Accessed August 4, 2023.https://bit.ly/3Opao2q20. FDA grants regular approval to enfortumab vedotin-ejfv for locally advanced or metastatic urothelial cancer. FDA. July 9, 2021. Accessed August 4, 2023. https://bit.ly/3QlzBgY21. FDA grants accelerated approval for sacituzumab govitecan in advanced urothelial cancer. FDA. April 13, 2021. Accessed August 4, 2023. https://bit.ly/3DJKSjO22. Galsky MD, Pal SK, Lin SW, et al. Real-world effectiveness of chemotherapy in elderly patients with metastatic bladder cancer in the United States. Bladder Cancer. 2018;4(2):227-238. doi:10.3233/BLC-17014923. FDA grants accelerated approval for enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. April 4, 2023. Accessed August 4, 2023. https://bit.ly/456fgjU24. O’Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. J Clin Oncol. Published online June 27, 2023. doi:10.1200/JCO.22.0288725. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384(12):1125-1135. doi:10.1056/NEJMoa203580726. Van Der Heijden MS, Gupta S, Galsky MD, et al. Study EV-302: a two-arm, open-label, randomized controlled phase 3 study of enfortumab vedotin in combination with pembrolizumab versus chemotherapy in previously untreated advanced urothelial carcinoma (aUC) (trial in progress). J Clin Oncol. 2022;40(suppl 6):TPS589. doi:10.1200/JCO.2022.40.6_suppl.TPS58927. Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase 2 open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021;39(22):2474-2485. doi:10.1200/JCO.20.0348928. Meric-Bernstam F, Makker V, Oaknin A. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41 (suppl 17):LBA3000. doi:10.1200/JCO.2023.41.17_suppl.LBA300029. FDA to allow import of oncology drug amid nationwide shortage. News release. American Hospital Association. June 2, 2023. Accessed August 4, 2023. https://bit.ly/3s5D 0Go