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Nothing about taking care of patients with cancer during the coronavirus disease 2019 (COVID-19) pandemic has been easy, but those practices that had already embraced transformation under the Oncology Care Model (OCM) are finding that its monthly payments and other features offer stability during an unprecedented health emergency.

That’s what Alexandra Chong, PhD, lead for the OCM within the Center for Medicare and Medicaid Innovation (CMMI), told the hundreds of online attendees at the 9th annual meeting of Patient-Centered Oncology Care®, presented virtually on September 25, 2020, by the American Journal of Managed Care®. The meeting engaged leaders from the payer, academic, and patient advocacy communities to discuss issues on patient-centered oncology care.

“We are living in a totally different world,” said event cochair Kashyap Patel, MD, CEO of Carolina Blood and Cancer Care Associates of Rock Hill, South Carolina, as he introduced Chong. “What we are learning is how COVID-19 impacts not just us as [to] what we do in the office, but how it impacts the rapid adaptation and changes from the payer perspective.”

Chong spent much of her talk walking attendees through the fine points of the OCM, which had been poised to transition toward Oncology Care First (OCF), a next-generation model built on a bundled-payment framework instead of fee for service (FFS).

As Chong explained, due to COVID-19, the OCM has been extended another year through 2022, and the CMMI has not yet fleshed out the details of OCF. OCM is an episode-based model, Chong said, that attaches 2 reimbursement elements to each practice’s commitment to reach certain financial and quality benchmarks while meeting practice standards that include having 24/7 access to medical records and developing care and survivorship plans with patient input. Although the number of practices in the OCM is 138, the number of physicians involved exceeds 7000, and the model now reaches 150,000 Medicare patients each year, or about a quarter of all FFS beneficiaries.

Practices in the OCM receive $168 per patient per month in Monthly Enhanced Oncology Services (MEOS) for delivering this higher-level care, as well as Performance- based Payments (PP), which come after each 6-month evaluation period ends.

As Chong explained, the work practices undertook to redesign their business for the high-touch requirements of the OCM was not easy—and it was a learning process for both sides.

But it’s paying dividends now. Practices that rely on administering expensive therapies—and having new patients walk through the door—have seen revenue plummet as people skip cancer screenings.

Those in the OCM have had some lifelines extended to them.

“We decided to retain the billing and keep up those MEOS payments, because we have heard across all of our practices, or majority of our practices, that a lot of the infrastructure that was put into place for the implementation of OCM has really helped our practices in terms of still achieving or still...focusing their care on their beneficia- ries,” Chong said.

To be sure, the OCM is not perfect, and Chong said the CMMI has heard the message from participating physicians that it must rethink reporting requirements and turn- around performance data in a time frame that lets practices fix problems quickly.

Because of COVID-19, the CMMI has made some data reporting requirements optional during the Public Health Emergency, including aggregate quality measure reporting and beneficiary-level clinical and staging data reporting.

“A majority of our practices still reported on these data, even though it was optional,” Chong noted.

Before COVID-19 hit, according to Chong, the OCM was gaining momentum as it headed into its final year. A third of the practices in the model had agreed to take on 2-sided risk or “some type of downside risk,” she said.

By embracing the tools that make the OCM work, Chong continued, “Participants have been able to not lose that momentum in providing the high-quality care that they had committed to giving their beneficiaries.”

Patel led a panel discussion on shifting from the OCM to the OCF, which featured Aaron Lyss, director of strategic payer relations, OneOncology; Terrill Jordan, president and CEO, Regional Cancer Care Associates; Mariam Alboustani, manager, Pharmacy Services, Blue Cross Blue Shield of Michigan; and Randall A. Oyer, MD, Lancaster Cancer Center/Penn Medicine.

Patel likened the OCM to an architect’s blueprint of how cancer care should work, one into which participants have put time and resources to build. He launched the panel discussion by asking what the OCF should look like when fully presented.

Jordan said the ground has shifted with COVID-19 and the CMMI must acknowledge that the population that comes through the door post pandemic will be different. “We will have to think about that, and challenge CMS/CMMI to take that into account appropriately,” he said.

The CMMI had a brief stakeholders’ meeting November 4, 2019, to discuss its OCF outline, Patel said, but there has been little information forthcoming since then. Oyer said the concerns among practices remain: physicians worry about improving outcomes, decreasing administrative burden, and maintaining revenue.

“We are also concerned about what our patients are facing, making access avail- able to people across our entire community, [and] providing quality outcomes and patient experience. And then we’re all concerned about our organizations—we work in these organizations.”

In terms of financial stability at the practice level, he said, it’s hard to deliver good care and be a community resource. Doing things the right way depends on having the resources to build a good team, Oyer said.

“One of the really good things that came out of OCM for us was that everybody on the team understood their value.”

Like Jordan, Oyer values transparency. “People see a line of sight between what they do in their daily practice and what results they want to accomplish.”

Lyss noted that achieving buy-in throughout an organization was important for success in the OCM and will be even more so in the OCF. The challenges ahead only become surmountable, he said, “through a culture throughout the organization that is committed to value and that is committed to evolve, adapting to change.”

Practice transformation “is going to take time. It’s going to be really hard; there are no shortcuts,” he continued.

Alboustani said her payer is working with practices on the data-sharing challenges
of the OCM, but that success in shifting to value-based care is not just about an indi- vidual model, it’s about recognizing that value-based care is not going away. “It’s not a phase. It’s probably going to become the norm down the line—and we all have to collaborate. We all have to work better in making this efficient for everyone—for the patient, for the plan, and for the provider.”

As practice transformation evolves, so must the concept of shared savings, Jordan said. Practices cannot keep squeezing savings out of the practice of oncology, and it’s a reason why some have left the OCM even as they embrace its transformation principles.

“The idea that you’re essentially judged against or measured against your own historic performance, I think is a real problem,” he said. “You should get measured against the market that you’re in. The variability in those markets is significant.”

Articles

Nothing about taking care of patients with cancer during the coronavirus disease 2019 pandemic has been easy, but those practices that had already embraced transformation under the Oncology Care Model are finding that its monthly payments and other features offer stability during an unprecedented health emergency.

Infrastructure of Oncology Care Model Helps Practice Through COVID-19

In the past year, 3 therapies have been introduced in the second and third line for patients with HER2-positive metastatic breast cancer. Although this represents a wealth of new options, experts say shaping treatment regimens for this patient population involves unpacking the nuances of clinical findings for these therapies and other available agents.

That was the goal of breast cancer specialists who participated in 

 video program, to discuss noteworthy data on efficacy and safety about fam-trastuzumab deruxtecan-nxki (Enhertu), neratinib (Nerlynx), and tucatinib (Tukysa) (

Trial Snapshots. Toxicity Profiles of HER2-Positive Metastatic Breast Cancer Agents

Trastuzumab deruxtecan was the first of the new therapies to enter the treatment paradigm, with an FDA accelerated approval in December 2019 based on findings from the DESTINY-Breast01 trial (NCT03248492). The objective response rate in 184 patients was 60.3% (95% CI, 52.9%-67.4%), comprised of a 4.3% complete response rate and a 56.0% partial response rate. Further, the median response duration was 14.8 months (95% CI, 13.8-16.9).

In February 2020, neratinib was approved in combination with capecitabine (Xeloda) based on data from the NALA trial (NCT01808573). The combination demonstrated median progression-free survival of 5.6 months (95% CI, 4.9-6.9) compared with 5.5 months (95% CI, 4.3-5.6) for patients treated with lapatinib (Tykerb) plus capecitabine, which translated to a hazard ratio of 0.76 (95% CI, 0.63-0.93; 

 = .0059). Median overall survival was 21 months and 18.7 months, respectively (HR, 0.88; 95% CI, 0.72- 1.07; 

Although the first 2 indications were for the third-line setting and beyond, the April 2020 approval of tucatinib in combination with trastuzumab (Herceptin) plus capecitabine was specified for patients who have received 1 or more prior anti–HER2-based regimens in the metastatic setting.

 Notably, this indication also includes patients with brain metastases, a population with a great unmet need. “Nearly 50% of patients with metastatic HER2-positive breast cancer will develop brain metastases,” said Sara A. Hurvitz, MD, who served as moderator of the program. “This is an area where we need more drugs like this.”

Hurvitz was joined by Aditya Bardia, MD, MPH; Claudine J. Isaacs, MD; and Sara M. Tolaney, MD, MPH, to review the latest data and ongoing investigations that can further carve out a role for these agents in a complex therapeutic landscape.

Trastuzumab Deruxtecan Offers Promise for Heavily Pretreated Patients

 For HER2-positive metastatic breast cancer, it’s been a real yawn lately, right? Only 3 FDA approvals in the past 7 months or so? It’s very exciting. We now have 7 FDA-approved drugs that target HER2 in the metastatic breast cancer setting.

Dr Bardia, if you could speak to the very exciting drug, trastuzumab deruxtecan. Can you tell us about the mechanism of action of this drug and the DESTINY Breast-01 results?

 Absolutely. Trastuzumab deruxtecan is a HER2-directed antibody-drug conjugate. It has several unique properties. The first is that it has a proprietary linker that allows for release of the drug potentially in the cancer cells. And also, this agent has a bystander effect, which allows the toxic payload to permeate outside of the cell membrane and affect the other cells in the microenvironment. The toxic payload with this agent is a topoisomerase 1 inhibitor, so it’s different from T-DM1 [ado-trastuzumab emtansine; Kadcyla], where the toxic payload is a [maytansine-derived toxin]. So in a number of ways, this drug is different than T-DM1 because of the bystander effect, as well as the toxic payload that it utilizes.

Investigators of DESTINY Breast-01 looked at the activity of trastuzumab deruxtecan in patients with metastatic HER2-positive breast cancer who were heavily pretreated. The median number of prior lines of therapy was 6. And [I have] never seen such an impressive waterfall plot. The data showed that the agent was incredibly active, with a very high response rate and deep responses in patients who were heavily pretreated.

The data were so compelling that the FDA provided accelerated approval to this agent for patients with metastatic disease. I think it’s an excellent option to have for our patients with metastatic disease. The challenge in the clinic is the sequencing of the various agents that we have and whether one should use 1 agent over the other.

 Yes, I agree. We don’t have data to guide our sequencing, and I think a lot of clinicians are using the presence or absence of brain metastases as sort of a litmus test of how to sequence tucatinib and trastuzumab deruxtecan. There are those who wonder whether we should be looking at trials to combine these 2 very active treatments. I think there are some [trials] that are being planned perhaps.

Dr Tolaney, can you take us through some of the important toxicities related to this therapy?

 In general, from a day-to-day basis, most people tolerate the drug pretty well. They do get some GI [gastrointestinal] toxicity; patients can have some nausea, some very low-grade, mild loose stool. It actually does lower your neutrophil count. We can sometimes see some neutropenia as well. I should mention it can also cause alopecia, and it is something to discuss with your patients too. 

A lot of attention was drawn to the risk of interstitial lung disease [ILD], and I think the reason this garnered some attention was the 4 deaths on the trial due to ILD. There was approximately a 13% rate of ILD overall.7 And actually, the majority of it was grade 1 and grade 2. But it is something I think we now are very cognizant of, given that it can be severe and can lead to complications. 

ILD has been a challenge because I think what we’d want to know is: what are the risk factors for developing this and can we re-expose patients to the drug? So far, what we know from the data is that the risk factors for higher rates of ILD [appear to be] more heavily pretreated patients, patients of Asian descent, and those who received higher dosing of drug—higher than the FDA-approved dosing—when it was studied in phase 1. 

And so I think we don’t yet have enough information about pulmonary function testing in these patients. Could we better predict who’s going to develop ILD if we had those tests at baseline to help us select patients? I think we’re going to learn more as time goes on. But for the time being, we have to be very cautious about this. So if a patient does develop, for example, asymptomatic ground-glass changes that [are seen] on CT, it is important to hold the drug and to monitor for resolution. And then if it resolves, the drug can be reintroduced with a dose reduction. But if the patient develops grade 2 ILD—they’re symptomatic— you do have to discontinue the drug and treat with steroids.

Given the outstanding efficacy from this drug with a progression-free survival of 16 months in someone with a median of 6 prior lines of therapy, I think we’re really eager to figure out which patients [with pulmonary toxicity] we could reinitiate the drug. I’m hoping we will learn more, but for now, those are the guidances.

 I think it becomes a little trickier in the COVID-19 [coronavirus disease 2019] era, where a patient can have cough and shortness of breath for an entirely nontoxicity-related reason. So all of us need to have this on our radar, certainly, when initiating any therapy that could cause a picture that mimics COVID-19. 

Dr Isaacs, could you speak about the data relating to the use of trastuzumab deruxtecan for HER2 low–expressing cancers? What are we seeing?

 We have early encouraging data suggesting trastuzumab deruxtecan has activity beyond what we would think of as a traditionally HER2- positive disease. In patients with low HER2 expression, [immunohistochemistry] IHC1+ or IHC2+, the tumors are not amplified by FISH [fluorescence in situ hybridization].

There is an ongoing phase 3 trial [DESTINY Breast-04; NCT03734029] to address the activity of this drug. And as Dr Bardia mentioned, there is an interesting bystander effect and some of the questions around why it may have this activity are based on that bystander effect. I think practically speaking, it’s an incredibly important trial for us to accrue to. In the clinic today, we probably all have some patients who have these tumors that are heterogeneous, for which we’ve done biopsies at various times, with HER2-positive expression in some but HER2 low in others. These are the patients for whom I really think about using this drug with the thought that I would have activity or have the potential for activity in the different clones of the tumor.

 I agree. And I think it’s a very exciting drug. I’m looking forward to seeing these data as well as the data for patients with HER2 low expression, especially triple negative, with HER1- positive and HER2-positive disease. My hope is that we’ll have some efficacy there.

 There are some very exciting data relating to tucatinib. Dr Isaacs, can you talk about the unique characteristics of this drug, the results of HER2CLIMB [NCT02614794], as well as some of the results relating to outcomes for patients with brain metastases reported at ASCO [2020 American Society of Clinical Oncology Virtual Scientific Program]?

 Tucatinib is a tyrosine kinase inhibitor [TKI], and the HER2CLIMB randomized trial was really focused on, I think, a really relevant patient population. For quite a while we’ve known what to do in the first-line setting and the second-line setting, but then it was sort of a free-for-all as for what to do in the third-line setting in patients who had progressed following trastuzumab- or pertuzumab [Perjeta]-based therapy based on CLEOPATRA [NCT00567190] data or in the adjuvant or neoadjuvant setting and then after T-DM1.

What was really nice about the design of HER2CLIMB was that all patients had to have received all 3 of those drugs previously. The trial also allowed us to do something very practical, which is to allow patients with brain metastases who did not require immediate local therapy to go on a systemic therapy to see if we could control the CNS [central nervous system] disease. This was really based on trials that suggested activity for this drug and activity for some of the other TKIs in this setting, for neratinib, for instance.

Investigators also required a baseline MRI, which picked up some patients who had asymptomatic brain metastases. We know that is a problematic issue for our patients who often have HER2-positive disease and CNS involvement. 

The trial design was for the treatment of patients with backbone therapy of either capecitabine/trastuzumab in a randomized placebo-controlled fashion with either tucatinib or with placebo. So the question was really, what does tucatinib add in this setting? 

Results showed a statistically significant benefit in terms of progression-free survival. But perhaps most importantly, there was also a significant survival benefit of 4.5 to 5 months or so with the addition of the tucatinib.

The percentage of patients who had brain metastases at baseline was very high, just under half the patients. And when investigators looked at the analysis, they found that the drug also had activity in that subset of patients who had brain metastases. And just to give a number on that, progression-free survival was 25% at 1 year [with tucatinib] versus 0% for patients treated with placebo. 

The presentation that Nancy U. Lin, MD, gave at ASCO focused on a related but separate question.

 And that was really specifically looking at the control in the CNS itself, not just control everywhere. CNS progression-free survival data for the patients who had brain metastases and brain metastases that were measurable showed a significant prolongation in CNS progression-free survival as well as an overall survival benefit. Further, [benefit was also seen] for patients who had brain metastases at presentation that were new, but the investigator felt that they did not require immediate local therapy. 

I think what these data show us is that we have very active agents that can help control CNS disease. These are very exciting findings.

 Tucatinib’s HER2 selectivity makes it a very unique drug. Dr Tolaney, can you take us through the toxicity of tucatinib?

 Tucatinib is a very potent TKI that is more focused against HER2 than some of the other TKIs. For example, neratinib is a pan-HER2 TKI, and lapatinib hits HER2 and HER1. The challenge with both lapatinib and neratinib has been the inhibition of EGFR, which has resulted in a lot of the toxicities that we’ve previously seen, such as rash or diarrhea. The advantage tucatinib has, from a toxicity profile, is that it is so selective against HER2 and really almost spares EGFR so that we are seeing much less in the way of GI toxicity. 

Interestingly, tucatinib was given with capecitabine, which does cause diarrhea and PPE [palmar-plantar erythrodysesthesia]. Those rates were just slightly higher in the tucatinib arm compared with the capecitabine/trastuzumab arm. We also do see some elevation of liver function. We can see liver enzymes go up, and sometimes we see a random kind of blip in the bilirubin that can happen. It’s not common, but you can sometimes see that happen with tucatinib and then it will come down. 

And so overall, I think it’s a pretty well-tolerated TKI compared with what we’re used to seeing with other TKIs.

Stacking the Deck in the Second Line and Beyond

 I think it was really interesting the FDA approved tucatinib in the second-line setting, so after patients had received a taxane and trastuzumab type of therapy. Are there any patients you would use this agent for in the second line?

 It’s clearly an active agent, and for me, this is attractive for 2 reasons. One is that it has activity in patients with brain metastases for whom traditionally, anti-HER2 therapies have not had so much activity. And second is the excellent safety. It gives patients an option to continue with a drug that is relatively well tolerated and good for brain metastases. 

One thing that was pretty interesting in the HER2CLIMB trial was that patients who developed brain metastases during the study and then received local therapy were allowed to continue on. Those patients who received tucatinib had a further delay in the development of additional brain metastases. So this would be an agent that I would be very comfortable using in the second-line setting, particularly in a patient who has a known history of brain metastases.

 I would say that we’re all very focused on brain metastases because that’s a huge area of unmet need. The overall activity regardless of brain metastases was also pretty phenomenal. 

On this niche topic of HER2-positive brain metastases, neratinib also had data relating to CNS outcomes from the NALA study.

 Neratinib has more toxicity due to the EGFR inhibition, but it is approved by the FDA in combination with capecitabine for HER2- positive metastatic breast cancer. Where do you see us using neratinib, if anywhere, in light of the very exciting tucatinib results?

 I think that you’re asking a really important question, one that we’re grappling with as well. There certainly are data that neratinib has CNS activity. There are data from the NALA study and also from some of the TBCRC [Translational Breast Cancer Research Consortium] trials that have looked and shown activity in the CNS for this agent. There may be individual patients for whom we would think about using it. 

We’re going to need to think about what’s next after tucatinib. And obviously, we have no data to tell us how these drugs will sequence with each other. But I think you’re raising a really important question. It is important to remember that we have options here, and there are going to be individual patients where we would choose one over the other. 

FDA approves fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive breast cancer. FDA. Updated December 20, 2019. Accessed October 25, 2020. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2-positive-breast-cancer

FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. Updated February 26, 2020. Accessed October 25, 2020. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-neratinib-metastatic-her2-positive-breast-cancer

FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed October 25, 2020. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer

Ennhertu. Prescribing information. Daiichi Sankyo Company Ltd; 2019. Accessed October 26, 2020. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf

Nerlynx. Prescribing information. Puma Biotechnology Inc; 2020. Accessed October 26, 2020. https://

www.accessdata.fda.gov/drugsatfda_docs/label/2020/208051s005s006lbl.pdf

Tukysa. Prescribing information. Seattle Genetics Inc; 2020. Accessed October 26, 2020. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213411s000lbl.pdf

Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. 

. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

Lin NU, Murthy RK, Anders CK, et al. Tucatinib versus placebo added to trastuzumab and capecitabine for patients with previously treated HER2+ metastatic breast cancer with brain metastases (HER2CLIMB). 

. 2020;38(suppl 15):1005. doi:10.1200/JCO.2020.38.15_suppl.1005

Awada AH, Brufsky AM, Saura C, et al. Impact of neratinib on development and progression of central nervous system (CNS) metastases in patients with HER2-positive metastatic breast cancer (MBC): findings from the NALA, NEfERT-T, and TBCRC 022 trials. 

. 2020;80(suppl 4):P2-20-01. doi:10.1158/1538-7445.SABCS19-P2-20-01

Breast cancer specialists discuss noteworthy data on efficacy and safety about fam-trastuzumab deruxtecan-nxki, neratinib, and tucatinib. 

Investigators Take Stock of New Landscape for Metastatic HER2-Positive Breast Cancer

Although metastatic urothelial carcinoma (mUC) remains generally incurable, management of bladder cancer has witnessed several multidisciplinary advances in the past few years (

). Cisplatin-based combination chemotherapy employing gemcitabine plus cisplatin; methotrexate, vinblastine, doxorubicin, cisplatin (MVAC) or dose-dense MVAC yields a median survival of 14 to 15 months and a 5-year overall survival (OS) of 5% to 15%, suggesting some potential cures.

Figure. Multidisciplinary Advances Have Expanded Treatment and Staging Options for mUC

Informed by tumor biology, the therapeutic landscape for mUC has been transformed with the advent of the PD-1/ PD-L1 inhibitors pembrolizumab (Keytruda), atezolizumab (Tecentriq), nivolumab (Opdivo), durvalumab (Imfinzi), and avelumab (Bavencio) for the treatment of patients with progressive disease who have previously received platinum-containing regimens.

In results from the KEYNOTE-045 trial (NCT02256436), pembrolizumab induced an impressive 2-year OS rate of 26.9% compared with 14.3% with taxane or vinflunine chemotherapy in the intention-to-treat (ITT) population regardless of PD-L1 expression.

 While the objective response rate (ORR) was higher with pembrolizumab (21.1% vs 11.0%), the most impressive aspect of outcomes may be the prolonged median duration of response greater than 2 years compared with just 4.4 months with chemotherapy. 

Pembrolizumab and atezolizumab are also approved as first-line therapy for platinum-ineligible patients and cisplatin-ineligible patients with high tumor PD-L1 expression, although phase 3 trials have not demonstrated improved survival with this approach.

 Indeed, findings from the phase 3 DANUBE trial (NCT02516241) did not demonstrate improved OS for durvalumab in patients with PD-L1–high tumors or for durvalumab plus tremelimumab versus gemcitabine-platinum in unselected patients.

Furthermore, the combination of PD-1/PD-L1 inhibitors with platinum-based chemotherapy in the KEYNOTE-361 and IMvigor130 trials for metastatic disease was not successful in improving survival.

 The combination of atezolizumab with gemcitabine-platinum in IMvigor130 (NCT02807636) demonstrated modestly improved progression-free survival (PFS; 8.2 vs 6.3 months; HR, 0.82; 95% CI 0.70-0.96; 1-sided 

 = .007). Similarly, investigators in KEYNOTE-361 (NCT02853305) did not observe an improvement in OS with the combination of either atezolizumab or pembrolizumab with gemcitabine-platinum. 

The ongoing CheckMate-901 trial (NCT03036098) is comparing the combination of ipilimumab (Yervoy) plus nivolumab versus gemcitabine-platinum with coprimary end points of survival in cisplatin-ineligible patients and patients with PD-L1–high expressing tumors. Moreover, this trial is devoting a large substudy to examining the impact of combining nivolumab with cisplatin-gemcitabine specifically in cisplatin-eligible patients.

More recently, the landmark JAVELIN Bladder 100 phase 3 trial (NCT02603432) demonstrated that first-line switch maintenance with avelumab in patients who demonstrated a response or stable disease on 4 to 6 cycles of platinum-based chemotherapy significantly improved survival compared with best supportive care (BSC) in the overall ITT population regardless of tumor PD-L1 expression (median OS 21.4 vs 14.3 months; HR, 0.69; 95% CI, 0.56-0.86; 1-sided 

Additionally, investigators reported prolonged OS in patients with PD–L1-positive tumors (HR, 0.56; 95% CI 0.40-0.79; 1-sided 

 = .0003). Avelumab plus BSC also extended PFS compared with BSC alone in the ITT population (HR, 0.62; 95% CI, 0.52-0.75) as well as the PD-L1–high population (HR, 0.56; 95% CI, 0.43-0.73). These data are considered practice-changing. 

Advances have occurred for the therapy of postplatinum patients with progressive metastatic disease, with FDA approvals of enfortumab vedotin-ejfv (Padcev), an antibody-drug conjugate (ADC), and the first targeted agent, erdafitinib (Balversa). In the phase 2 EV-201 trial (NCT03219333), investigators administered enfortumab vedotin, the first FDA-approved Nectin–4 targeting ADC, to 125 patients who previously received platinum-based chemotherapy and PD-1/PD-L1 inhibitors.

Enfortumab vedotin induced an ORR of 44% (95% CI, 35.1%-53.2%) including 12% complete responses (CRs).

 The median PFS and OS were 5.8 and 11.7 months, respectively. Investigators observed encouraging responses even in patients with liver metastases and those with no response to prior PD1/PD-L1 inhibitor therapy. In TROPHY-U01 (NCT03547973), the ADC sacituzumab govitecan, which targets trophoblast cell–surface antigen 2, showed preliminary promise in the same setting.

Erdafitinib, an oral FGFR inhibitor, is applicable to approximately 15% of post-platinum patients with activating genomic alterations in 

 and has provided advances in the salvage setting. In a phase 2 trial (N = 99) patients, ORR with erdafitinib was 40%. The median PFS was 5.5 months, and the median OS was 13.8 months.

 Ongoing phase 3 trials are attempting to validate the activity of the 2 agents. 

Targeted agents for HER2-driven tumors have shown preliminary promise, which has led to early trials evaluating potent HER2 inhibitors such as fam-trastuzumab deruxtecan-nxki (Enhertu).12 PARP inhibitors and epigenetic modifiers have been preliminarily disappointing in unselected or selected patients.

Moreover, combinations of active agents are undergoing evaluation. The combination of enfortumab vedotin plus pembrolizumab exhibited promising activity as first-line therapy for patients with cisplatin-ineligible advanced or metastatic UC.

 The ongoing phase 3 EV-302 trial (NCT04223856) is evaluating the novel combination of enfortumab vedotin plus pembrolizumab versus gemcitabine-platinum in the first-line setting. 

The combination of VEGF/FGFR inhibitors and PD-1/PD-L1 inhibitors has also shown preliminary promise. The phase 3 LEAP-011 trial (NCT03898180) is evaluating the combination of lenvatinib (Lenvima) and pembrolizumab as first-line therapy for cisplatin-ineligible mUC. The optimal sequencing of active agents needs investigation, although these efforts may have to rely on retrospective and real-world datasets. 

Unfortunately, applying atezolizumab to the adjuvant setting following radical cystectomy for high-risk muscle invasive disease did not improve outcomes in the phase 3 IMvigor010 trial (NCT02450331).

 Similar efforts to evaluate pembrolizumab and nivolumab in the adjuvant setting are ongoing. 

Interestingly, the phase 3 CheckMate 274 (NCT02632409) trial was reported in a news release to have met its co-primary end points of improving disease-free survival versus placebo in all randomized patients as well as in patients with tumor PD-L1 expression of 1% or higher. If these data prove practice-changing, the therapeutic landscape of first-line therapy of metastatic disease may be impacted for patients who relapse.

Neoadjuvant PD-1/ PD-L1 inhibitors alone for cisplatin-ineligible or cisplatin-refusing patients or combined with cisplatin-based chemotherapy preceding radical cystectomy have exhibited promising activity, and phase 3 trials are attempting to confirm a role for these approaches.

 The incorporation of PD-1/PD-L1 inhibitors in bladder-preserving trimodal chemoradiation approaches is being evaluated in ongoing phase 3 trials.

Therapy for non–muscle-invasive bladder cancer (NMIBC) has also enjoyed advances with the approval of systemic pembrolizumab for rigorously defined bacillus CalmetteGuérin (BCG)–unresponsive high-risk disease. Among 96 patients in the KEYNOTE-057 trial (NCT02625961) with high-risk BCG-unresponsive NMIBC with carcinoma in situ, the CR rate was 41% and the median duration of response was 16.2 months.

In April 2020, the FDA approved mitomycin gel (Jelmyto) as the first therapy indicated for low-grade upper tract UC based data from the pivotal phase 3 OLYMPUS trial (NCT02793128). Forty–one of 71 patients (58%) had CR. Of those patients, 19 (46%) had durable CR at 12 months.

 Moreover, other promising intraluminally delivered agents are emerging for high-risk BCG-unresponsive NMIBC including nadofaragene firadenovec (rAd-IFN/Syn3), a non-replicating adenovirus vector harboring the human 

 gene, and vicinium, a recombinant fusion protein of an anti-EpCAM antibody linked to a variant of 

Blue light cystoscopy has improved the sensitivity of detection of malignancy, although further studies are ongoing to evaluate efficacy and cost effectiveness to justify universal adoption.

 Multiparametric MRI and fluorodeoxyglucose positron emission tomography imaging may warrant further evaluation to enhance clinical staging of muscle-invasive disease.

Enhanced recovery after surgery (ERAS) protocols in the setting of radical cystectomy may improve the quality of life for patients.

 Robotic cystectomy was noninferior to open cystectomy for 2-year PFS and quality of life in the phase 3 RAZOR trial (NCT01157676).

Finally, the emergence of intensity-modulated radiation therapy and use of MRI to plan radiotherapy may improve the therapeutic index of radiotherapy for muscle-invasive bladder cancer.

Despite these advances in therapy, it is important to not lose sight that metastatic disease is generally incurable and that clinical trials should be considered a standard of care for all settings of the disease. The critically important first step that engenders advances is the understanding of tumor biology. Novel clinical prognostic factors have been presented in the setting of PD-L1 inhibitors following platinum-based chemotherapy.

The Cancer Genome Atlas program has shed light on the enormous heterogeneity of tumor biology, high mutation burden, and multiple potential driver alterations in subsets of patients.

 However, we must better understand the dynamic changes in tumor and microenvironment following therapy to develop insights into resistance and new therapeutic targets. Noninvasive molecular monitoring employing cell-free DNA profiling studies of plasma and urine may provide avenues to better understand mechanisms of resistance, new therapeutic targets, and minimal residual disease.

Precision medicine that leverages molecular information from multiple platforms may be necessary for optimal patient selection. In this context, DNA damage repair alterations and gene expression subtypes of tumor are a step in this direction and are associated with pathologic CR to neoadjuvant cisplatin-based chemotherapy.

 The combination of molecular and clinical factors may also warrant exploration to develop precision medicine.

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November 25, 2020 — Although metastatic urothelial carcinoma remains generally incurable, management of bladder cancer has witnessed several multidisciplinary advances in the past few years. 

Vol. 21/No. 22 | Oncology Live®

Infrastructure of Oncology Care Model Helps Practice Through COVID-19

Investigators Take Stock of New Landscape for Metastatic HER2-Positive Breast Cancer

New Strategies Enhance Care in mUC

TILs, the Ultimate in Personalized Immunotherapy, Move Closer to Market

Next-Generation Endocrine Therapy Moves Forward in Breast Cancer Trial

METex14+ NSCLC Armamentarium Welcomes First Targeted Therapy

Real-World Impact of Low-Grade AEs Needs a Closer Look