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Treatment decisions in the second-line setting for patients with HER2-positive metastatic breast cancer are not as cut-and-dried as deciding between which data have the best outcomes.

Nuances in patient populations, toxicity profiles, and sequencing considerations following disease progression in later lines of therapy are playing a larger role as new data mount. Adaptability will be key for oncologists in the coming years. been generated are going to move the sequence,” Gradishar said. “It’s going to be different 1 year from now, and 2 years from now. What we have learned with confidence is that things are going to change.” “What I am struck by is every time we go to the ASCO [American Society of Clinical Oncology Annual Meeting] or San Antonio [Breast Cancer Symposium], we compare the new data to the time when we started our careers....We fiddled with the handful of chemotherapy drugs we had and maybe the schedule. That was the big question at every meeting,” William J. Gradishar, MD, said. “Now we have new drugs, we understand more nuance or maybe we don’t understand, and we are trying to figure out how to use these drugs optimally, and that’s really exciting—to juxtapose those 2 time periods.” 

, breast cancer experts reviewed the clinical data that are reshaping approaches to metastatic HER2-positive breast cancer. The panelists illustrated how the treatment paradigm is likely to undergo waves of transformation for years to come given the surge of new agents demonstrating clinical benefit. “We haven’t learned a whole lot about sequencing because I think if anything all the data that have been generated are going to move the sequence,” Gradishar said. “It’s going to be different 1 year from now, and 2 years from now. What we have learned with confidence is that things are going to change.”

One area of unshakable stability is in the frontline setting for patients with HER2-positive metastatic disease. The phase 3 CLEOPATRA study (NCT00567190) provided the foundation for patients with previously untreated metastatic disease with the regimen of pertuzumab (Perjeta), trastuzumab (Herceptin), and docetaxel. “It’s been approximately a decade since the publication of CLEOPATRA—taxane, trastuzumab, and pertuzumab has been a mainstay of treatment,” Andrew D. Seidman, MD, said. Data published in 2020 demonstrated that at 99.9 months’ follow-up, the median overall survival (OS) for patients who received pertuzumab, trastuzumab, and docetaxel was 57.1 months (95% CI, 50.0-72.0) compared with 40.8 months (95% CI, 36.0-48.0) with placebo, trastuzumab, and docetaxel (HR, 0.69; 95% CI, 0.58-0.82). The 8-year OS rates were 37% (95% CI, 31%-42%) and 23% (95% CI, 19%-28%), respectively.

This is a great regimen; it’s our standard of care,” Tiffany A. Traina, MD, said, adding that paclitaxel is also a reasonable backbone for use in the combination. “Where I give some pause is in my patients who unfortunately had neoadjuvant or adjuvant taxane and have had a really short disease-free interval— less than 6 months, even less than a year,” she said. “Fortunately, we’re not seeing this as much as we used to, because of our impressive agents available in the early-stage setting. But this is where there is an opportunity for antibody-drug conjugates [ADCs] that we have for HER2-positive disease.” 

Following disease progression, the traditional approach to care was ado-trastuzumab emtansine (T-DM1; Kadcyla).

 Findings from the phase 3 EMILIA trial (NCT00829166) demonstrated that the ADC outperformed capecitabine and lapatinib (Tykerb) in patients with HER2positive, metastatic breast cancer who previously received trastuzumab and a taxane. However, after impressive data brought fam-trastuzumab deruxtecan-nxki (Enhertu) to the third and later lines of therapy, the natural next step was to test the agent’s efficacy against the long-standing standard of care in the second line.

“T-DM1 was the first drug to take that mantle,” Vijayakrishna Gadi, MD, PhD, said. “Recently, we’ve got these exciting data with the trastuzumab deruxtecan in that space, a randomized clinical trial comparing trastuzumab deruxtecan to T-DM1. If you recall, that had 22 zeros in the 

]. When was the last time we saw a drug approval trial with 22 zeros?” Investigators of DESTINY-Breast03 (NCT03529110) pitted T-DM1 head-to-head with trastuzumab deruxtecan among 524 randomly assigned patients. The 12-month progression-free survival rate was 75.8% with trastuzumab deruxtecan (n = 261) compared with 34.1% with T-DM1 (n = 263; HR, 0.28; 95% CI, 0.22-0.37; 

“There were superior PFS data, and a hint of an OS [advantage] already, although events are still occurring,” Gadi said, adding that safety data presented at the 2022 ASCO meeting showed that different analyses reflect another avenue for success with the newcomer.

“Depending on how you analyze the safety data, you could make the case that given the exposure time, individuals who are benefiting from a drug are going to be on it for longer,” Gadi said. “When you amortize the toxicity over that time frame, you can create ratios that suggest T-DM1 was more toxic in some scenarios and some cases.” The safety update had a cutoff date of September 7, 2021, and the median treatment durations for trastuzumab deruxtecan and T-DM1 were 16.1 months and 6.9 months, respectively.4 Interstitial lung disease (ILD), an adverse effect (AE) of special interest with trastuzumab deruxtecan, was included in the prespecified analysis of treatment-emergent AEs (TEAEs) with nausea, vomiting, fatigue, alopecia, and hematologic events. At the cutoff, 54.9% of patients who received trastuzumab deruxtecan on study (n = 257) discontinued treatment compared with 85.1% of patients who received T-DM1 on study (n = 261). The rates of TEAEs of any grade and grade 3 or higher were similar between the 2 treatment arms. TEAEs that led to treatment discontinuation were reported in 38 and 19 patients, respectively. Dose reductions due to TEAEs were also more prevalent in the trastuzumab deruxtecan arm (23% vs 13.8%, respectively).

The exposure-adjusted incidence rates (EAIRs) were measured to account for the differences in the treatment durations for the 2 agents. Using this analysis, the EAIRs per patient year were lower in the trastuzumab deruxtecan arm vs the T-DM1 arm except for TEAEs with drug discontinuation. These were primarily associated with ILD/pneumonitis in the trastuzumab deruxtecan (TABLE).

“We’re getting comfortable with trastuzumab deruxtecan and it’s now the preferred agent for a lot of patients in the second-line setting,” Gadi added. 

In offering a clinical scenario for discussion, Seidman said a patient presented with diffusing capacity of 73% from an undetermined source, possibly interstitial pneumonitis from a prior therapy, and asked whether a pulmonary test would be required before administering trastuzumab deruxtecan. “The problem is that we just don’t know who is going to develop ILD with trastuzumab deruxtecan,” Stephanie L. Graff, MD, said. “The updated safety data from DESTINY-Breast03 showed that 10.9% of patients developed ILD and the vast majority of that was grade 1 and grade 2. For those of you that don’t live and breathe the clinical trial AE profiles, grade 1 ILD means infiltrates, so no chest x-ray with no symptoms, which in a global pandemic of lung diseases is 10% grade 1 pneumonitis, it’s hard to put that into context. As the DESTINY-Breast portfolio has evolved, the rate of ILD has gotten better, certainly not worse, which is a testament to our learning curve as investigators, as a medical oncology community with the drug.” 

Pulmonary concerns were a common issue; the panel noted that as discussions in the community moved from the virtual environment to in-person gatherings, the real-world experiences of patients in the clinic came to light. “In the last year talking to physicians in the community, if they had a patient with lung metastases, one of the misconceptions we want to dispel is that you shouldn’t give [trastuzumab deruxtecan] but it’s the opposite,” Gradishar said. “When you have bulky visceral disease, those are the patients most likely to benefit.” Graff concurred, adding, “It’s a risk-benefit discussion with the patient on what you want to consider and try. I certainly would be monitoring those patients more carefully.” 

Beyond pulmonary concerns, the panel discussed brain metastases and how the emergence of newer agents looks to give the combination of tucatinib (Tukysa), trastuzumab, and capecitabine a challenge. The final HER2CLIMB trial (NCT026147942) OS analysis for example demonstrated that the combination improved outcomes compared with trastuzumab/capecitabine alone in patients with HER2-positive metastatic breast cancer who had stable or active brain metastases.

 At a median follow-up of 29.6 months, the addition of tucatinib resulted in a median OS of 21.6 months (95% CI, 18.1-28.5) vs 12.5 months (95% CI, 11.2-16.9) with trastuzumab and capecitabine alone in patients with active and stable brain metastases (n = 291; HR, 0.60; 95% CI, 0.44-0.81). 

Among patients with active brain metastases (n = 174), the tucatinib regimen resulted in a median OS of 21.4 months (95% CI, 18.1-28.9) vs 11.8 months (95% CI, 10.3-15.2) with trastuzumab and capecitabine alone (HR, 0.52; 95% CI, 0.360.77). Among those with stable brain metastases (n = 117), the median OS was 21.6 months (95% CI, 15.3-42.4) vs 16.4 months (95% CI, 10.6-21.6), in the experimental and control arms, respectively (HR, 0.70; 95% CI, 0.42-1.16). 

Those with stable and active brain metastases who received the addition of tucatinib experienced an improvement in median central nervous system (CNS)-PFS compared with trastuzumab/ capecitabine alone, at 9.9 months (95% CI, 8.4-11.7) and 4.2 months (95% CI, 3.6-5.7), respectively (HR, 0.39; 95% CI, 0.27-0.56).

“What was wonderful to see was that patients receiving the triplet had improved OS and that included the population with brain metastasis,” Traina said. “That benefit has been quite durable, so there are not only responses but improved PFS and improved OS for the overall study population as well as those patients with brain metastasis.” Moreover, the median CNS-PFS for those with active brain metastases was 9.6 months (95% CI, 7.6-11.1) vs 4.0 months (95% CI, 2.9-5.6) in the tucatinib and placebo arms, respectively (HR, 0.34; 95% CI, 0.22-0.54). Those with stable brain metastases experienced a median CNS-PFS of 13.9 months (95% CI, 9.7-24.9) with the tucatinib triplet vs 5.6 months (95% CI, 3.0–not evaluable) with trastuzumab/capecitabine (HR, 0.41; 95% CI, 0.19-0.85). Traina said these data raise questions concerning when local intervention with radiation is warranted if there is an opportunity to use a effective systemic therapy with blood-brain barrier penetration.

In a subgroup analysis of DESTINY-Breast03, investigators reported outcomes for patients with brain metastases. At a median follow-up of 15.9 months, the median PFS was 15.0 months (95% CI, 12.5-22.2) with trastuzumab deruxtecan vs 3.0 months (95% CI, 2.8-5.8) with T-DM1 (HR, 0.25; 95% CI, 0.13-0.45). The 12-month PFS rates were 72.0% (95% CI, 55.0%-83.5%) vs 20.9% (95% CI, 8.7%-36.6%), respectively. 

The confirmed ORR was 67.4% (95% CI, 51.5%80.9%) with trastuzumab deruxtecan vs 20.5% (95% CI, 9.3%-36.5%) with T-DM1. Among patients without brain metastases, the confirmed ORR was 82.1% (95% CI, 76.4%-87.0%) vs 36.6% (95% CI, 30.3%-43.3%), respectively. 

Notably, patients with brain metastases experienced a lower rate of progressive disease with trastuzumab deruxtecan vs T-DM1, at 48.8% vs 69.2%, respectively. 

Regarding intracranial responses, the complete response rate was 27.8% with trastuzumab deruxtecan vs 2.8% with T-DM1. The intracranial partial response rates were 36.1% vs 30.6%, respectively. Trastuzumab deruxtecan also led to a lower rate of intracranial progressive disease vs T-DM1, at 2.8% vs 22.2%, respectively.

Finally, primary outcome analysis of the phase 2 TUXEDO-1 trial (NCT04752059) also supported the use of trastuzumab deruxtecan for patients with brain metastases with an ORR via response assessment in neuro-oncology criteria of 73.3% (95% CI, 48.1%-89.1%).7 However, the data were only presented for 15 patients. Seidman noted that regardless of population size, this was an interesting signal of CNS efficacy. 

“We have a lot of options, but the question could be better posed: Do we have evidence that one sequence is better than another?” Gradishar said. “Therein lies the lack of the data. Patients are getting the CLEOPATRA regimen, they may have gotten trastuzumab deruxtecan as their second line, and then what comes next?” He added that the National Comprehensive Cancer Network guidelines are a good starting point for these treatment decisions but that not all supporting data have information for patients treated with some of the newer regimens.“

Tucatinib trial was evaluated in a randomized phase 3 trial with survival benefit, but it didn’t look at patients who had gotten trastuzumab deruxtecan before, but I would view that as a pretty strong piece of evidence that that would be a reasonable approach,” he said. “There are other options, of course. You could switch out chemotherapy or continue trastuzumab with a variety of agents. You could give neratinib [Nerlynx]. These would not be my first choices. I would use the HER2CLIMB regimen preferentially before then but the caveat is not every patient can tolerate it.” 

Approaches to brain metastases, as Gradishar pointed out, are not cut-and-dried and may require a multidisciplinary approach to care. 

In a case scenario, Seidman posed: “At the time of progression there is suspicion of CNS disease in a patient who has progressed on trastuzumab deruxtecan as her second-line regimen after having had CLEOPATRA therapy in the first line. On an MRI she had 2 subcentimeter lesions and it is not clear if they were causing her symptoms. You’re going to send her for stereotactic radiation. Are you going to try HER2CLIMB and see whether you get a CNS response in the asymptomatic oligometastatic patient? Are you going to give T-DM1?” 

Gadi noted that if there were disease control below the neck, he would retain the previous agent and target the CNS metastases with stereotactic radiosurgery. “If she is progressing below the neck and above the neck, that’s frightening because below the neck progression is strongly correlated with additional brain metastases,” he said. “Maybe target the CNS directly with stereotactic surgery and radiosurgery and then move on to the HER2CLIMB regimen for that patient—or, even better, if we have a clinical trial to explore some combinations in that setting, I might do both.” 

Graff noted that although the agents have a place, it is not fully transparent. “Approved therapies such as trastuzumab deruxtecan and tucatinib keep fighting to move earlier and earlier; I am lucky to practice in an environment where I have those agents on trials in those settings and we’re seeing patients stay on them longer.” Graff added that this raises the question about what to do with T-DM1. 

“If I am moving trastuzumab deruxtecan earlier in my portfolio of treatment, when am I putting T-DM1 back in the sequence? Because of the pattern of visceral metastasis and brain metastasis, is hard to know if patients with HER2-positive disease are going to get fifth, sixth, or seventh line of therapy especially after heavy pretreatment, and long durations of therapy with effective HER2 ADCs.” After these agents, Graff added, she would pick among neratinib, lapatinib, and margetuximab-cmkb (Margenza) as her next line of therapy. “The answer is somewhere in the data,” she said. “I am choosing based on the medications we are using in combination and the toxicity profile relative to the patient as well as their risk of AEs.” 

As for what’s next, Traina said, “I hopefully will be on a panel in a couple of years reporting out data from new agents, but it’s tough for the new agents that are being explored because they are designed to treat individuals who have previously seen drugs such as trastuzumab, trastuzumab deruxtecan, or tucatinib. It’s going to be a high bar to show benefit there.”

Swain SM, Miles D, Kim SB, et al; CLEOPATRA study group. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. 

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Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. 

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Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. 

. 2022;386(12):1143-1154. doi:10.1056/NEJMoa2115022

Hamilton EP, Bragaia VPH, Yeo W, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2-positive (HER2+) unresectable and/or metastatic breast cancer (mBC): safety follow-up of the randomized, phase 3 study DESTINY-Breast03. 

. 2022;40(suppl 16):1000. doi:10.1200/JCO.2022.40.16_suppl.1000

Curigliano G, Mueller V, Borges V, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with pretreated HER2+ metastatic breast cancer with and without brain metastases (HER2CLIMB): final overall survival analysis. 

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Hurvitz S, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd; DS-8201a) vs. trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): subgroup analyses from the randomized phase 3 study DESTINY-Breast03. 

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Articles

Treatment decisions in the second-line setting for patients with HER2-positive metastatic breast cancer are not as cut-and-dried as deciding between which data have the best outcomes. 

Experts Navigate the New World of HER2-Positive Metastatic Breast Cancer

The past decade has seen a change in the tide for patients with bladder cancer with the introduction of checkpoint blockade and molecular profiling. These advances have moved beyond the one-size-fits-most approaches of intravesical chemotherapy and BCG instillation, and investigators have ridden the waves of improvements for patients across histologies to address unmet needs in recurrent or residual disease and in cisplatin-ineligible patient populations.

Standard of care still dictates the necessity of maximal transurethral resection of bladder tumor to aid in pathology and staging of disease; however, investigators have also been exploring ways to get patients to therapy faster, rather than waiting and relying on results of tissue analyses.

“What’s challenging in the field right now is the pace of updates. Every 6 months or so, we’re seeing new, important data in urothelial carcinoma, specifically in the advanced setting, but even in the nonmetastatic setting, which changes the way we think of the disease and changes the way we should treat patients,” Pedro C. Barata, MD, MSc, said in an interview with 

. “A challenge that we need to overcome as a community is to make sure we are up to speed with these new data and the importance of novel therapies available for our patients.”

JAVELIN Bladder 100 Shakes Up the Standard of Care

Barata, a genitourinary medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, noted that practice-changing data arrived 2 years ago with the JAVELIN Bladder 100 trial (NCT02603432). Platinumbased chemotherapy is considered the standard of care in advanced disease and is associated with modest survival benefit, with up to 50% of patients experiencing objective response and up to 80% achieving disease control; however, most patients go on to develop treatment resistance.

Investigators sought to evaluate the effect of maintenance avelumab (Bavencio) in patients with locally advanced or metastatic urothelial cancer following completion of firstline chemotherapy. Patients enrolled on the study received 4 to 6 cycles of gemcitabine plus cisplatin or carboplatin, followed by avelumab (n = 350) or best supportive care (n = 350).

In the overall population, the median overall survival (OS) with avelumab was 23.8 months (95% CI, 19.9-28.8) vs 15.0 months (95% CI, 13.518.2) with best supportive care (BSC; HR, 0.76; 95% CI, 0.63-092; 

 = .0036). The survival benefit was more pronounced at 30.9 months at data cutoff in the PD-L1–positive cohort who received avelumab (n = 189) vs 18.5 months in the control arm (n = 169; HR, 0.69; 95% CI, 0.52-0.90; 

 The 30-month OS rates were 43.7% vs 33.5% in the overall population and 51.3% vs 38.5% in the PD-L1–positive populations with avelumab and BSC, respectively.

Chemotherapy remains the best treatment option for patients to date, but the results of JAVELIN Bladder 100 have integrated chemoimmunotherapy as a marker of success in the front line, signaling the added importance of testing, according to Guru P. Sonpavde, MD. “Determining PD-L1 status is cheap. It’s a lot cheaper than doing genomic profiling of the tumor [and] takes much less time. It’s very practical and a way to identify patients who may or may not benefit [from a PD-L1 inhibitor],” Sonpavde said in an interview with 

. He is the director of genitourinary oncology and the Christopher K. Glanz Chair for Bladder Cancer Research at the AdventHealth Cancer Institute in Orlando, Florida.

Sonpavde added that PD-L1 status, coupled with other factors, will play into treatment decision-making. “For example, a patient who has a very high, unfavorable neutrophil lymphocyte ratio—which is a poor prognostic factor—or a patient with reversible metastasis or low PD-L1 [status], these might not be the patients you want to start with the first-line PD-1 inhibitor,” he said. “This is something to think about it, especially when you have many options in these settings. Should you be giving an immune checkpoint inhibitor, or should you be giving other drugs, such as enfortumab vedotin-ejfv [Padcev], which is available in the second- and third-line settings? I think that this is a model that could be useful in the clinic when you have many options in front of you.”

As advances push chemoimmunotherapy into the front line, a domino effect has triggered changes in the second-line setting as well. However, for patients who are cisplatin ineligible, effective treatment options represent a significant unmet need.

“We’re moving checkpoint inhibitors into the front line with avelumab. That means that second-line therapy used to be checkpoint inhibitors, and now we’re getting other options upon progression,” Barata said, adding that the classic definition for treatment was whether patients were cisplatin eligible or ineligible. “The paradigm is really changing because it’s possible [to administer] checkpoint inhibitors much sooner than we started a few years ago and we can get antibody-drug conjugates that were really not an option for us just 3 or 4 years ago.”

Several trials have added data with strong clinical significance in the past year, highlighting the need to stay on top of presentations and published findings (

Standard criteria for patients who are cisplatin ineligible include those with poor renal function, grade 2 or greater hearing loss, poor ECOG performance status, cardiovascular disease, or peripheral neuropathy.

 The development of antibody-drug conjugates (ADCs) to fill this void in treatment for metastatic urothelial carcinoma led to enfortumab vedotin, which binds to the protein NECTIN4 and has a payload of monomethyl auristatin E.

The agent demonstrated activity as a single agent in the phase 2 EV-201 trial (NCT03219333) in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who had received prior PD-1/PD-L1 inhibitors. The FDA approved the agent based on the confirmed overall response rate (ORR) of 52% (95% CI, 40.8%-62.4%) among 125 patients. Subgroup analyses demonstrated responses in those with primary tumor sites in the upper tract (ORR, 61%), those with with liver metastasis (ORR, 48%), and those who did not respond to prior PD-1/PD-L1 inhibitors (ORR, 48%).

The agent also demonstrated synergy in combination with immunotherapy, specifically pembrolizumab (Keytruda) in cohort K of the phase 1/2 EV-103 trial (NCT03288545) in the first-line setting.

“Enfortumab vedotin and pembrolizumab as monotherapy have each shown antitumor activity with a survival benefit in pretreated patients with locally advanced or metastatic urothelial cancer,” Jonathan E. Rosenberg, MD, said in an interview with 

. “Enfortumab vedotin/pembrolizumab was previously evaluated in the EV-103 dose-escalation cohort A [n = 40], which showed encouraging safety and efficacy activity with a response rate of 73.3%.” Rosenberg is chief of the Genitourinary Oncology Service in the Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, and a professor of medicine at Weill Cornell Medical College in New York, New York.

“The OS in that cohort was an impressive 26.2 months, which is roughly at least double what you might expect with gemcitabine- and carboplatin-based regimens in historical data and probably, I suspect, better than the current treatment paradigm of chemotherapy followed by maintenance avelumab, although there have not been any randomized trials,” Rosenberg added.

A total of 149 patients were included in the study, with 76 treated with enfortumab vedotin plus pembrolizumab and 73 treated with enfortumab vedotin alone. The confirmed ORR for enfortumab vedotin plus pembrolizumab was 64.5%, and the median duration of response (DOR) was not reached. Confirmed ORR for enfortumab vedotin alone was 45.2%, with a median DOR of 13.2 months.

 The study was not powered to compare the arms in cohort K.

Regarding adverse events (AEs), 15.6% of patients receiving enfortumab vedotin plus pembrolizumab and 24.3% of patients receiving enfortumab vedotin alone stopped treatment due to an AE. The most common AEs seen in patients receiving enfortumab vedotin plus pembrolizumab included fatigue, peripheral sensory neuropathy, and alopecia. Three treatment-related AEs leading to death (3.9%) were seen in the combination group and 2 (2.7%) were seen in the monotherapy group.

 Rosenberg reported that skin reactions were more frequent with patients receiving enfortumab vedotin plus pembrolizumab, although none were serious.

Sonpavde noted, “What we’ve seen so far suggests that the enfortumab vedotin/pembrolizumab combination in the first line for cisplatin-ineligible patients is quite active. We believe that this could potentially have a practice impact.” He added that the EV-103 trial also evaluated a cohort of patients who received firstline atezolizumab (Tecentriq) or pembrolizumab, which might be an option in select patients.

Sacituzumab govitecan-hziy (Trodelvy) is another ADC with accelerated approval for the treatment of patients with metastatic urothelial carcinoma with disease progression on platinum-based chemotherapy and a checkpoint inhibitor.

 This population represents another group of patients who do not have durable treatment options following standard of care.

Data from the TROPHY-U-01 trial (NCT03547973) showed that the Trop-2–directed ADC had a confirmed ORR of 27.7% (31 of 113; 95% CI, 19.6%-36.9%), including a 5.4% complete response rate with a median DOR of 7.2 months. The median progression-free survival (PFS) with sacituzumab govitecan was 5.4 months (95% CI, 3.5-6.9), and the median OS was 10.5 months (95% CI, 8.2-12.3).

 Confirmatory data are being generated in the phase 3 TROPiCS-04 trial (NCT04527991).

Tyrosine kinase inhibitors (TKIs) may also influence the treatment landscape for patients who are cisplatin ineligible or experience disease progression on an immune checkpoint inhibitor, as demonstrated in findings from the multicenter, phase 1b COSMIC-021 trial (NCT03170960), in which participants received cabozantinib (Cabometyx) plus atezolizumab.

Three cohorts were evaluated: those who had received no prior therapy and were ineligible for cisplatin-based chemotherapy (n = 30), those who had received no prior therapy and were eligible for cisplatin-based chemotherapy (n = 30), and those who had received 1 prior immune checkpoint inhibitor and no prior VEGFR TKI therapy (n = 31).

The ORR was 20%, 30%, and 10%, respectively, with disease-control rates of 80%, 63%, and 61%, respectively. The median PFS and OS for each of the 3 cohorts were 5.6 and 14.3 months, 7.8 and 13.5 months, and 3.0 and 8.2 months, respectively. Investigators concluded that the combination demonstrated encouraging clinical activity in these cohorts.

Biomarkers Leave a Trail for Investigators

The rapid uptake of molecular testing is starting to signal even more nuances in the treatment of bladder cancer, with retroactive and prospective analyses revealing actionable targets in the space.

FGFR3 is an attractive therapeutic target in bladder cancer given the 10% to 30% prevalence of 

 aberrations (activating mutations or aberrant gene fusions) in these tumors and their preclinical sensitivity to FGFR-targeted therapy.

 aberrations lead to oncogenic signaling through the MAPK and PI3K pathways. Activating mutations in 

 occur in 10% to 20% of muscle-invasive bladder cancers.

The FGFR TKI erdafitinib (Balversa) was FDA approved for the treatment of adult patients with locally advanced or metastatic urothelial cancer with susceptible 

 genetic alterations who have progressed on platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

 The decision was based on data from the phase 2 BLC2001 trial (NCT02365597).

Longer-term data from BLC2001 published in 

 showed that at a median follow-up of 24.0 months (range, 22.7-26.6) with a median treatment duration of 5.4 months (range, 2.8-9.0), patients treated with the erdafitinib regimen achieved an objective response rate of 40% (95% CI, 30%-49%; n = 40/101). Further, 36% of the 40 responding patients experienced a partial response, and 4% achieved a complete response. Forty-one percent of responders had a best response of stable disease for at least 36 days, which translated to an overall disease control rate of 80% (95% CI, 72%-88%).

The median PFS with erdafitinib was 5.5 months (95% CI, 4.3-6.0), and the 12-month PFS rate was 21% (95% CI, 13%-29%). The median OS was 11.3 months (95% CI, 9.7-15.2), and the 12-month and 24-month OS rates were 49% (95% CI, 39%-59%) and 31% (95% CI, 22%-40%), respectively.

The most common treatment-emergent AEs of any grade included hyperphosphatemia (grade 1 or 2, 76%; grade 3, 2%), stomatitis (21% and 14%, respectively), diarrhea (50% and 4%), and dry mouth (45% and 1%).

The proportion of patients with central serous retinopathy, which is a known class effect of FGFR inhibitors and a treatment-emergent AE of special interest, was 27% and 85% of instances were grade 1 or 2. The median time to first onset of central serous retinopathy was 53 days (range, 32-100) for any grade and 94 days (range, 72-154) for grade 3 effects.

The absence of POU2F2 may be predictive of response to maintenance avelumab in patients with advanced or metastatic urothelial carcinoma, according to findings from an analysis of peripheral blood samples taken in the JAVELIN Bladder 100 trial.

 POU2F2, a transcription factor with known roles in B-cell maturation and participation in T-cell dependent humoral immunity, was strongly associated with the T-effector signature.

“In the peripheral blood, the chromatin signature was looked at in the peripheral blood cells, the white blood cells, and what was found was the lack of a signature, called the POU2F2, in peripheral blood, and this is derived from the chromatin signature within the nuclei of these white blood cells,” Sonpavde said. “The absence of the signature in peripheral blood correlated with increased gene expression, immune gene expression in tumor tissue, and correlated with better outcomes with maintenance avelumab.”

 expression in the tumor was linked to a survival benefit with maintenance avelumab. The benefit was highest in patients who had 

 expression and a tumor mutation burden above the median threshold of 7.66 nonsynonymous single- nucleotide variants per Mb (HR, 0.69; 95% CI, 0.51-0.93). Moreover, the absence of the POU2F2 loop in the blood samples was also associated with a better survival benefit with maintenance avelumab (HR, 0.62; 95% CI, 0.36-1.08).

The median survival probability for the 22 patients who received avelumab and did not have 

 expression but did have a low tumor mutation burden was 36.99 months vs 13.6 months for the 18 patients who only received BSC.

Another agent making a move in the treatment of patients with metastatic urothelial carcinoma is disitamab vedotin (RC48-ADC), a humanized anti-HER2 ADC.

 Under investigation in 2 studies, the agent is for patients with HER2-positive disease documented as immunohistochemistry (IHC) 2+ or 3+.

The 2 single-arm phase 2 studies (RC48-C005 [NCT03507166] and RC48-C009 [NCT03809013]) enrolled 107 patients with metastatic urothelial carcinoma, with 64.5% having received at least 2 lines of systemic chemotherapy. Patients received disitamab vedotin at 2 mg/kg intravenously every 2 weeks. The confirmed ORR with the ADC per blinded independent review committee was 50.5%.

In a subgroup analysis, the confirmed ORR was 52.1% for patients with liver metastasis (n = 48) and 55.6% for patients who had received prior PD-1/L1 treatment (n = 27). In terms of HER2 expression stratification, the confirmed ORR was 62.2% for those with HER2 IHC 2+ and fluorescence in situ hybridization (FISH)+ or with IHC 3+ (n = 45); 55.6% for HER2 IHC 2+ and FISHunknown status (n = 9); and 39.6% for HER2 IHC 2+ and FISH-negative status (n = 53). The disease control rate was 82.2%.

Pardo JC, de Porras VR, Plaja A, et al. Moving towards personalized medicine in muscle-invasive bladder cancer: where are we now and where are we going? 

. 2020;21(17):6271. doi:10.3390/ijms21176271

Tran L, Xio JF, Agarwal N, Duex JE, Theodorescu D. Advances in bladder cancer biology and therapy. 

. 2021;21(2):104-121. doi:10.1038/s41568-020-00313-1

Powles T, Park SH, Voog E, et al. Avelumab first-line (1L) maintenance for advanced urothelial carcinoma (UC): long-term follow-up results from the JAVELIN Bladder 100 trial. 

. 2022;40(suppl 6):487. doi:10.1200/JCO.2022.40.6_suppl.487

Balar AV, McGregor BA, Rosenberg JE, et al. EV-201 cohort 2: enfortumab vedotin in cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer who received prior PD-1/PD-L1 inhibitors. 

. 2021;39(suppl 6):394. doi:10.1200/JCO.2021.39.6_suppl.394

Rosenberg JE, Milowsky M, Ramamurthy C, et al. Study EV-103 cohort K: antitumor activity of enfortumab vedotin (EV) monotherapy or in combination with pembrolizumab (P) in previously untreated cisplatin-ineligible patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC). 

. 2022;33(suppl 7):S1441. doi:10.1016/j.annonc.2022.08.079

Tagawa ST, Balar AV, Petrylak DP, et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. 

. 2021;39(22):2472-2485. doi:10.1200/JCO.20.03489

Pal SK, Agarwal N, Singh P, et al. Cabozantinib (C) in combination with atezolizumab (A) in urothelial carcinoma (UC): results from cohorts 3, 4, 5 of the COSMIC-021 study. 

. 2022;40(suppl 16):4504. doi:10.1200/JCO.2022.40.16_suppl.4504

Balversa. Prescribing information. Janssen Pharmaceutical Companies; 2022. Accessed October 4, 2022. bit.ly/3CEVYa3

Siefker-Radtke AO, Necchi A, Park SH, et al; BLC2001 Study Group. Efficacy and safety of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma: long-term follow-up of a phase 2 study. 

.2022;23(2):248-258. doi:10.1016/S1470-2045(21)00660-4

Powles TB, Sridhar S, Bellmunt J, et al. Genomic biomarkers in peripheral blood (PB) from patients (pts) enrolled in the JAVELIN Bladder 100 trial of avelumab first-line (1L) maintenance in advanced urothelial carcinoma (aUC). 

. 2022;33(suppl 7):S1442. doi:10.1016/j.annonc.2022.08.080

Sheng X, He Z, Shi Y, et al. RC48-ADC for metastatic urothelial carcinoma with HER2-positive: combined analysis of RC48-C005 and RC48-C009 trials. 

. 2022;40(suppl 16):4520. doi:10.1200/JCO.2022.40.16_suppl.4520

The past decade has seen a change in the tide for patients with bladder cancer with the introduction of checkpoint blockade and molecular profiling. 

An Influx of Data Expands Options, Improves Treatment for Bladder Cancer

Frontline therapy for patients with advanced biliary tract cancers has remained unchallenged for decades, until investigators demonstrated that the addition of the immunotherapeutic agent durvalumab (Imfinzi) could prolong survival for this patient population. On September 2, 2022, the FDA approved durvalumab in combination with gemcitabine and cisplatin for patients with advanced biliary tract cancer.

The approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235), which randomly assigned patients to durvalumab (n = 341) or placebo (n = 344) in combination with standard-of-care gemcitabine plus cisplatin chemotherapy. The median overall survival (OS) was 12.8 months (95% CI, 11.1-14.0) vs 11.5 months (95% CI, 10.1-12.5) in the experimental and placebo arms, respectively (HR, 0.80; 95% CI, 0.66-0.97; 

 = .021). The estimated 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) and 10.4% (95% CI, 4.7%-18.8%), respectively.

The median progression-free survival was 7.2 months (95% CI, 6.7-7.4) in the durvalumab arm compared with 5.7 months (95% CI, 5.6-6.7) in the placebo arm (HR, 0.75; 95% CI, 0.63-0.89; 

 = .001). The incidence of grade 3/4 adverse events (AEs) was 75.7% and 77.8%, respectively.

“TOPAZ-1 is the first success of immunotherapy in biliary tract cancers. It opened the door of the study using immunotherapy agents in this field, which is quite an important message,” said principal investigator Do-Youn Oh, MD, PhD, of Seoul National University Hospital and Seoul National University College of Medicine in South Korea, in an interview with 

. “It is the first global phase 3 study to [show] improvement in the OS of patients compared with the current long-lasting, decades-lasting standard of care. At this time, we can say that we have a new standard of care first line [in] advanced biliary tract cancer, with the durvalumab plus gemcitabine and cisplatin combination.”

In our discussion, Oh highlighted the nuances of the TOPAZ-1 trial data that signal new pathways forward for investigative efforts in advanced biliary tract cancers.

What is the significance of the approval of durvalumab in combination with chemotherapy for patients with biliary tract cancer?

In advanced biliary tract cancer, there have been very limited treatment options, especially in the first line where we [have] only adopted gemcitabine and cisplatin globally for over a decade. Median OS [has been] less than 1 year.

With this approval of durvalumab, immunotherapy in combination with gemcitabine/cisplatin cytotoxic chemotherapy, the median OS has been improved. The beauty of immunotherapy is that [among the] responding patients their response [is] quite durable. In the TOPAZ-1 study [data], we observed [that] the 2-year survival rate of the patients is nearly 24%—a huge improvement of the OS in this field.

With this success, we can say, “Yes, biliary tract cancer is an immunotherapy-responsive tumor type.” This approval encourages the further study and further drug development using the very interesting, good immunotherapeutic agents in biliary tract cancer. I think TOPAZ-1 is just the start of the immunotherapy [for] biliary tract cancer.

Based on the success of the TOPAZ-1 trial, the NCCN [National Comprehensive Cancer Network] guidelines have already adopted the durvalumab, gemcitabine, and cisplatin regimen as a preferred regimen category 1 in first-line advanced biliary tract cancer.

In TOPAZ-1, the total sample size was 684, so a relatively smaller clinical trial compared with tumor types in other phase 3 trials targeting first-line [therapy]. We observed a durvalumab benefit regardless of clinical characteristics such as region, even though the Asian population get more benefit—the HR is better compared with [that of] non-Asian patients. The primary tumor location did not matter, and disease extent did not matter. And so far, PD-L1 expression [has] not mattered.

The benefit of durvalumab plus gemcitabine and cisplatin was observed regardless of the primary origin, including [patients with] intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer....There is some difference; for example, the HR for gallbladder cancer was higher compared with the other 2 tumor types in TOPAZ-1.

But now with [these data] we can say that the PD-L1 is not the biomarker for patient selection. Patients showed a benefit with durvalumab regardless of PD-L1 level at this time. We definitely need more studies on the biomarker selection and exploration of the role of PD-L1 for patient selection in larger clinical trials.

In the updated efficacy analysis, which has [6.5 months’] longer follow-up duration compared with the primary analysis, the median follow-up duration is...nearly 2 years, at 23 months. The HR for OS is 0.76 and in the original analysis, the HR was 0.80. With these data, we can say that the durvalumab benefit is shown consistently and is clinically meaningful in patients with biliary tract cancer compared with just [gemcitabine and cisplatin alone].

What should the toxicity findings signal for providers?

A very important finding from the TOPAZ-1 study is that adding durvalumab on top of [gemcitabine and cisplatin] had a safety profile that is quite good. In the placebo arm and the durvalumab arm, the frequency of all AEs, including serious AEs [and] those leading to study discontinuation, is all quite similar.

In the durvalumab arm the [incidence of] immune-related AEs was a bit high compared with the placebo arm, but grade 3/4 immune-related AEs were quite rare. And with longer follow-up data there were no new safety issues compared with the primary analysis safety data. [This regimen] can be easily and comfortably implemented in daily practice globally.

What is next for immunotherapy in biliary tract cancers?

At [Seoul National University Hospital and Seoul National University College of Medicine] we have many clinical trials targeting biliary tract cancer and new compounds in phase 1 studies, which includes a biliary tract cancer cohort. I am exploring the role of immunotherapy not only in the first-line setting, but also second-line or later-line setting, [as well as] in combination with other targeted agents, for example, antiangiogenics and other DNA damage response agents.

FDA approves durvalumab for locally advanced or metastatic biliary tract cancer. FDA. September 2, 2022. Accessed September 23, 2022. bit.ly/3LDKkyJ

Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. 

Do-Youn Oh, MD, PhD, highlights the nuances of the TOPAZ-1 trial data that signal new pathways forward for investigative efforts in advanced biliary tract cancers.

Durvalumab Plus Standard-of-Care Chemotherapy Shakes Up First-line Care in Advanced Biliary Tract Cancers

A landmark essay by the late eminent evolutionary biologist Stephen J. Gould, PhD, entitled “The Median Isn’t the Message” serves as an excellent opening for this commentary. Gould, after receiving a diagnosis of primary peritoneal mesothelioma, what he deemed an “incurable cancer” with a median life expectancy of 8 months, responded with noting the following: 

“[All] evolutionary biologists know that variation is nature’s only irreducible essence. Variation is the hard reality, not a set of imperfect measures for a central tendency. Means and medians are the abstractions. Therefore, I looked at the mesothelioma statistics quite differently— and not only because I am an optimist who tends to see the doughnut instead of the hole, but primarily because I know that variation itself is the reality. I had to place myself [amid] the variation….The [survival] distribution was, indeed, strongly right skewed, with a long tail (however small) that extended for several years above the [8]-month median. I saw no reason why I shouldn’t be in that small tail, and I breathed a very long sigh of relief. My technical knowledge had helped. I had read the graph correctly. I had asked the right question and found the answers. I had obtained, in all probability, that most precious of all possible gifts in the circumstances—substantial time.”

Gould survived for approximately 20 years following his diagnosis. This was likely related to an incomplete understanding of the natural history of the disease and possibly an unanticipated response to treatment. That is not the point to be highlighted here. Rather, what is noteworthy is the process whereby this patient employs both objective data and his personal beliefs to declare what he values. Further, it is reasonable to anticipate that, like Gould, other patients will carefully evaluate the risks vs benefits of various treatment options during their illness and the effect they will have on quality of life to generate a personal assessment of therapeutic value. 

In discussing commercially available anticancer drugs, the term therapeutic value is often applied.

 However, it is remarkable to contrast Gould’s eloquent and objectively scientific words with, in the opinion of this commentator, this misleading terminology. Consider, for example, a recent report examining drugs granted accelerated approval or conditional marketing authorization where the authors concluded that “a substantially lower proportion of cancer indications than noncancer indications were rated as having high therapeutic value.”

Considering the applied connotation of therapeutic value it is appropriate to acknowledge medical paternalism, a criticized and, I hope, discarded concept where the physician makes a highly personal treatment decision on behalf of the patient.

 Among the more painful historical examples of this in the oncology arena was the routine performance of a radical mastectomy for breast cancer immediately following histological diagnosis without first providing the patient an opportunity to discuss alternative therapeutic options with a care team. Today it appears the authority to determine the therapeutic value of a new drug or cancer treatment strategy is believed by some to not reside with the rightful decision-making party—the patient. Of further concern is the notion of labeling outcomes as meaningful or not. For example, some believe that phase 3 progression-free survival outcomes that are statistically significant serve as a “surrogate end point for a meaningful clinical outcome.”

Shouldn’t patients be permitted to decide what is meaningful to them as they make decisions during their illness? 

To be clear, this discussion and Gould’s words have nothing to do with the rapidly escalating costs of therapy or the disturbing effects of financial toxicity that patients with cancer and their families are experiencing.

 It is appropriate to challenge the unsustainable process for determining anticancer drug costs as well as the existing complex and often irrational methods of payment. Further, there is nothing inherently wrong with the academic and public policy exercise of attempting to conduct cost-vs-benefit analyses with, for example, differences in median time to disease progression or overall survival between study arms in a well-designed randomized trial to serve as an objective measure of benefit.

However, it must be recognized that this difference is nothing more than a population-based number and that subsequent analyses have little or possibly no relevance to the outcome of a specific patient, specifically in terms of the value that an individual assigns to a potential objective survival or toxicity severity result or to the actual observed experience. As so eloquently stated by Gould:

“This is a personal story of statistics, properly interpreted, as profoundly nurturant and life-giving. It declares holy war on the downgrading of intellect by telling a small story to illustrate the utility of dry, academic knowledge about science. Heart and head are focal points of one body, one personality.”

And if that is not sufficient to make the point, consider in conclusion the following from Gould, a scientist, academic, patient with cancer, and survivor:

“Attitude clearly matters in fighting cancer. We don’t know why (from my old-style materialistic perspective, I suspect that mental states feedback upon the immune system). But match people with the same cancer for age, class, health, and socio-economic status and, in general, those with positive attitudes, with a strong will and purpose for living, with commitment to struggle, and with an active response to aiding their own treatment and not just a passive acceptance of anything doctors say tend to live longer.”

Who exactly should be determining the therapeutic value of a treatment program? It is a very different question than one concerning an appropriate price and payment for a regimen. In the opinion of this commentator the answer is clear: the patient. 

Gould SJ. The median isn’t the message. Virtual Mentor. 2013;15(1):77-81. doi:10.1001/virtualmentor.2013.15.1.mnar1-1301 

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Ballreich J, Socal M, Bennett CL, et al. Medicare spending on drugs with accelerated approval. Ann Intern Med. 2022;175(7):938-944. doi:10.7326/M21-4442 

Shankaran V, Li L, Fedorenko C, et al. Risk of adverse financial events in patients with cancer: evidence from a novel linkage between cancer registry and credit reports. J Clin Oncol. 2022;40(8):884-891. doi:10.1200/ JCO.21.01636 

Dusetzina SB, Huskamp HA, Rothman RL, et al. Many Medicare beneficiaries do not fill high-price specialty drug prescriptions. Health Aff (Millwood). 2022;41(4):487-496. doi:10.1377/hlthaff.2021.01742

Oncology Live®

What is noteworthy is the process whereby this patient employs both objective data and his personal beliefs to declare what he values. 

Vol. 23/No. 20 | Oncology Live®

Experts Navigate the New World of HER2-Positive Metastatic Breast Cancer

An Influx of Data Expands Options, Improves Treatment for Bladder Cancer

Durvalumab Plus Standard-of-Care Chemotherapy Shakes Up First-line Care in Advanced Biliary Tract Cancers

Is Therapeutic Value a New Name for Medical Paternalism?