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Article

Evidence-Based Oncology
February 2023
Volume 29
Issue 2
Pages: SP101

New Century Health’s Andrew Hertler, MD, FACP: “You Have to Be Careful When You Look at Total Cost of Care”

Andrew Hertler, MD, FACP, is the chief medical officer for New Century Health, which works with payers and providers to improve pathway utilization and achieve cost savings. A board-certified oncologist, Hertler oversees New Century’s clinical quality and value-based strategy, utilization management, and thought leadership initiatives. He has volunteered on multiple committees of the American Society of Clinical Oncology (ASCO).
In this interview with Evidence-Based Oncology™ (EBO), Hertler discussed important developments with 3 therapies used in specific types of breast cancer: trastuzumab deruxtecan (Enhertu; AstraZeneca), pembrolizumab (Keytruda; Merck), and sacituzumab govitecan (Trodelvy; Gilead Sciences, Inc). Among the trials discussed was the DESTINY-Breast04 study (NCT03734029), presented at the ASCO Annual Meeting in June 2022, which found a 50% reduction in the risk of death or disease progression for patients with HER2-low metastatic breast cancer.1

This interview, which took place on January 18, 2023, has been edited and condensed for clarity.

EBO: The presentation of DESTINY-Breast04 brought a standing ovation at ASCO, along with predictions that trastuzumab deruxtecan would be adopted quickly as the new standard of care for patients who are now diagnosed with HER2-low breast cancer. Have the results changed practice as much as was predicted?

Hertler: That was a quite a moment at the ASCO meeting. You don’t see standing ovations, even at plenary presentations. My initial thought was, “This is going to change the face of oncology,” but not just because it’s a therapy with a very impressive improvement in overall survival. It added 5 or 6 months in overall survival; in the oncology world, that’s a massive increase—we look at results that add 1.5 to 2 months, and we do handstands. But it also defined a new disease category, this HER2-low category. And knowing this category was going to be a large number of patients, I thought at the time, “This is going to be a 3-fold increase of [trastuzumab deruxtecan] use.” I looked at our data for January to date compared with last year, when [trastuzumab deruxtecan] was added across some of our risk networks. In January 2022, we had 90 requests for it. We’re at 158 [requests] as of yesterday, so we’re going to come in at approximately 270 requests—it will be close to a 3-fold increase in utilization. That’s paradigm shifting.

I’m often critical of a lot of the accelerated approvals we see in oncology, because I don’t think they provide benefit. But my message to my own company and [to] the plans we work with was, get ready to spend a lot more on breast cancer next year, because these are not only changes, but they’re [also] very beneficial to patients. And you should actually be encouraged, because it’s good care.

EBO: One thing we’ve heard about trastuzumab deruxtecan from physicians who treat breast cancer is that this therapy is less toxic, which increases the ability of patients to stay on the therapy. Are you seeing that as well?

Hertler: [Patients] stay on the therapy, I think, because it works. I’m not as convinced it’s less toxic. This is a HER2-targeted therapy, and anything that targets HER2 has cardiotoxicity. People have looked at some of the disparities in health care and, particularly in the Black population, women stage by stage don’t do as well as those who are White. Increasingly, we see that part of that reason is cardiac deaths. It’s not cancer; it’s cardiac deaths.

One can hypothesize that perhaps there is [more] hypertension or high cholesterol in the years prior to the diagnosis. There is [also] less access to care, and [Black patients] may not have as well-controlled underlying cardiac disease. I worry about cardiac toxicity, and that [must] be monitored closely. [The therapy] has all the attendant usual chemotherapy complications. It may be a little better tolerated because it is a targeted therapy; it’s an antibody that carries a chemotherapy drug into the HER2 target. That may reduce the toxicity, but it’s still a chemotherapeutic agent….Approximately 65% of patients are still alive in 6 months and about 40% are still on it at a year. That’s a long duration when the average duration of regimens is around 4 months. My own suspicion is that [the therapy] may be a little less toxic, but those durations are because it’s working.

EBO: During the press briefing for DESTINY-Breast04, commenters said that although this was not needed for the trial, they could see a need for innovation in testing to better identify the population that is HER2 low, as this has not been a classification historically. Have there been developments in this area?

Hertler: Not yet, but I would agree with that. The way we grade HER2 is someone looks at a stain, sees how many bright spots there are, and gives it a 1+, 2+, or 3+. If it’s a 1+ or 2+ on the immunohistochemistry, then we can do actual testing for the gene copy number. If that’s positive at a 2+, we would call it HER2 positive. But if that’s negative, and it’s 1+ or 2+, that’s HER2 low. It’s essentially an eyeball test. I’ve also talked to pathologists, and I know it makes them a little nervous that it’s not a quantifiable test. How do you know what the difference [is] between a 0 and a 1+? We need better ways to define it.

The other problem is that there’s another new drug, [sacituzumab govitecan], that was used for triple-negative breast cancer, but [at press time the FDA had granted approval] to extend that from the from the triple-negative population to the HER2-negative, HR [hormone receptor]–positive population,2 which, again, is going to drive a massive increase in use. But then what do you do with the patients who are 1+ or 2+ on HER2 testng? Because for [sacituzumab govitecan], they’re technically HER2 negative, and you would treat them with [sacituzumab govitecan]. Sacituzumab govitecan doesn’t use that HER2-low classification. So, what do we want? How do we better define these [patients] pathologically? What’s the optimal treatment? Do we treat them with [sacituzumab govitecan] or with [trastuzumab deruxtecan]? Because they’re eligible for both. Or do we sequence them? If we do, in what order do we sequence them? I don’t know the answer to those questions. I can give you my biases, but they’re just biases.

EBO: The issue of sequencing seems to be a big question across so many cancers, because we have so many options now, which is great. But the order of when to give different therapies is the big challenge we are hearing about. You mentioned earlier that you said to health plans to get ready to spend more in breast cancer. What’s been the reaction of payers, or employer health plans? Have you encountered any resistance?

Hertler: No, I have not seen resistance, because we build up enough trust that when we say, “This is a good medication,” then it should be utilized. Clearly, there’s waste in oncology, and there are plenty of areas to attack for waste. But when there’s a good therapy, it needs to be endorsed and pursued. One of my arguments has always been to not just look at the drug costs, because the most expensive therapy of all is the one that doesn’t work. That means you’re going to use another therapy, and the patient is more likely to have complications and end up in the hospital. Just because the drug has a cost and you may spend more for a drug doesn’t necessarily mean it’s low value or that it’s going to drive up overall care costs. It’s more complicated than that.

Understand, yes, these are expensive drugs. I mean, 3 months of [sacituzumab govitecan] is $83,000 by Medicare allowable. That’s a lot of money for a single drug. But if it works, it’s not necessarily more expensive than using a cheaper drug that doesn’t work. The patient gets sicker and they end up in the hospital, so you have to be careful when you look at cost of care. That’s my line to many of our payer clients, that this is a good medicine. Ultimately, I believe in my heart of hearts that good care and high-quality treatment have got to lead to savings at some point down the road. I truly believe that.

EBO: Before we discuss more questions about sacituzumab govitecan, are there any more important patterns or predictions about care in HER2-low breast cancer that you wanted to share?

Hertler: You touched on defining this 1+, 2+ group; I do see some nervousness on the part of plans around this. If they’re savvy, some will ask, “How are you going to define this group?” That creates a nervousness that the barn door has been opened, that the test is not standardized. I think that will be worked out. I don’t know how soon or how fast, but I believe we will quantify this. [Trastuzumab deruxtecan] already has indications for HER2-bearing cancers. Non–small cell lung cancer is a little different, in that you’re targeting it to an actual mutation in the gene rather than copy number.3 Gastric cancer is another one.4 We may become better at finding out what HER2 positive really is and who shouldn’t be treated. From a management standpoint, that’s critical, because you want to get the therapy to the right [patients] who are really going to benefit from it. Yes, the drugs are expensive, so let’s do everything we can to make sure we’re identifying the patients who are going to clearly benefit. For those who won’t, let’s know who they are and find something else for them.

EBO: With sacituzumab govitecan, there have been significant developments in the past year, as well.5 How does this therapy fill voids that existed for patients with HER2-negative, [hormone receptor]–positive metastatic disease?

Hertler: This is a little harder to predict, because that’s an even larger group of patients than the group that’s eligible for [trastuzumab deruxtecan]. The group of patients who are ER [estrogen receptor] positive and HER2-negative is a large group of patients. I just ran our numbers when that data came out and said, “In theory, if everyone who fit [the criteria received] this—they won’t, of course—but if everyone who fell in that class received this therapy, all you have to do is be HER2-negative, ER-positive, or triple negative. That basically means a 5-fold increase in the number of patients eligible for the drug, potentially. That’s a huge bundle of patients. On the other hand, for HER2 negative, ER positive patients, we have a lot of therapies for adults already—that’s a very crowded space. Those patients can survive for many years, and that was before we had [sacituzumab govitecan].

The HER2-negative, ER-positive patients are very different from the triple-negative patients; historically, this is a patient population for whom we’ve had very little to offer. So although it’s a huge pool of eligible patients, the question is: Which direction will they go? Are patients going to jump to [sacituzumab govitecan] or are they going to continue to be treated initially with hormonal agents, or [in combination with] with CDK4/6 inhibitors? For some patients, PARP inhibitors are also possibilities. So although there’s a huge number of eligible patients, we’re not seeing [sacituzumab govitecan] take off quite the way [trastuzumab deruxtecan] has.

It will be interesting to see what happens. My own guess is that [sacituzumab govitecan] is going to come into play sometime after initial hormone therapy and hormone therapy with CDK4/6 inhibitors. When [patients] finally move off hormonal therapy, [they] will move to [sacituzumab govitecan] rather than the more conventional generic single-agent chemotherapy, which would have been the standard of care up until now. [They would] move to [paclitaxel] or single-agent therapy. We’ll see, but it’s going to be a much more competitive market in terms of options for those patients.

EBO: How would this compare with current options from a cost-effectiveness standpoint?

Hertler: That’s a good question. I haven’t seen any analysis, such as an ICER [incremental cost-effectiveness ratio], on this yet. When you look at $83,000 for 3 months, again, that may look like a lot. And it is, but it’s par for the course. For a new chemotherapy agent introduced in the market, we tend to look at what the market will bear, and markets bear $20,000 to $30,000 a month. Right now, that’s what the pricing tends to be. If you look at what the alternative would be in the settings where I think it would generally be used, it would be a single-agent drug such as paclitaxel. That’s essentially an $83,000 difference, because paclitaxel is very inexpensive. You know you’re going to spend a couple hundred dollars a month, so that’s a massive difference to make up. I was just trying to think what an ICER would likely be if one looks at the survival advantage, [and] my guess is that by looking at it the way ICER does, it’s going to be hard to show cost-effectiveness on this. But I have not seen an actual ICER, so there may be one done.

It’s going to be hard to show cost-effectiveness. It’s one of those instances where it’s a clinical advance, as in improved efficacy vs the alternatives. But what is the cost, and will the market bear it?

[As] much [as] I hate to say it, we pretty much ignore ICERs. I mean, society in general ignores those kinds of calculations, so I don’t think the fact that it’s expensive is necessarily going to impede it in the market. But at that cost differential, it’s going to be really hard to show cost-effectiveness. A year of the drug would cost more than $320,000. Even if you picked up a year of survival, that’s an ICER of over $300,000, which is generally not considered cost-effective.

EBO: Let’s talk about pembrolizumab, which is used to treat many different cancers. There have been more than 1 set of results reported in triple-negative breast cancer.6 Among the recent findings, what stands out for you to be of particular importance for payers?

Hertler: I would say the neoadjuvant use….Historically, [triple-negative breast cancer] is a very difficult cancer to treat. Not everyone with triple-negative breast cancer will develop metastatic disease; most patients with triple-negative breast cancer are going to get neoadjuvant therapy. That’s going to be a lot of up-front use and fewer alternatives. If you move into the metastatic setting, you’ve got [pembrolizumab] and [sacituzumab govitecan]. You’re not going to use [sacituzumab govitecan] in the neoadjuvant setting, so I think [pembrolizumab] is going to be utilized there. Its data were based largely on an increased rate of pathologic complete remission at the time of surgery after initial treatment.7 Now that raises an interesting question, which most people don’t talk about. We know that with conventional chemotherapy, if you have a pathologic complete remission, you have a greater overall survival, which translates into a survival advantage. What people don’t talk about is that if you weren’t going to get [this response] with chemotherapy, and you add [pembrolizumab] to the chemotherapy and get a pathologic complete response [CR] that you wouldn’t have gotten, does that translate into an overall survival advantage? We do not know that. [Also], could it be? Very few people talk about this, and I don’t know why. The fact that you don’t get a pathologic CR with conventional chemotherapy means you’re in a higher risk group, that you’re defining a group that’s more likely to relapse. And even though we moved that into a complete remission by administering some [pembrolizumab] doesn’t necessarily mean—but we’re assuming—that will translate into an overall survival advantage. We do not know that, but someday we will. At this point in time, we don’t know that, but it will be widely used because of poor prognosis of those patients, and it should. I’m just raising the [point] that we’ve got to be very careful about what a clinical trial says, as well as what this specific trial with pembrolizumab says. More pathologic CR [was seen], but was a pathologic CR in a patient treated with [pembrolizumab] the same as a pathologic CR obtained with chemotherapy alone? Because when you’re adding an additional therapy, maybe you’ve just defined a group of patients that are going to have a worse outcome no matter what you do. We will see.

EBO: Speaking of defining patients who will have different outcomes, there was a recent paper in JCO Oncology Practice that discusses recent progress with using biomarkers to predict which patients will have success with immunotherapy.8 How do you see the general landscape of biomarker use, particularly in terms of access to biomarker testing? We hear things are much better, but there are still reports of patients not having access.

Hertler: To me, that’s the key in managing these drugs. As I alluded to earlier in terms of defining ahead of time, who’s going to benefit and who’s not? You want the drugs to go to the patients who will benefit. You’d rather not give them to those who don’t benefit. We have trouble defining those up front, but I believe biomarkers/genomics are going to ultimately help us define these patient groups. And I tell this to payers when I am asked this question—I say quite frankly, “I think you’re being penny-wise [and] pound-foolish to not allow these tests.” A biomarker test can be $3000 to $4000 to determine who’s going to benefit from a drug that may cost $90,000 over 3 months. I would gladly spend $2000 to $3000 to find out [whether] that’s the drug we should use.

My message to payers is that they should be allowing and approving these biomarkers. I don’t even think they should be subject to prior authorization, to be honest. My message to physicians and providers is to pay attention to the biomarkers. I mean, you want to get the biomarkers, but if it said the drug is not likely to work, don’t use the drug. If you use the drug anyway, that’s going to fuel the fire about not allowing you to use the biomarkers to begin with.

EBO: That’s a really important point. Because pembrolizumab is such a well-studied drug and has been studied in so many different cancers, are there any global takeaways from all that we can apply in breast cancer? Or is our knowledge really specific, cancer by cancer?

Hertler: That whole class of drugs has changed oncology dramatically. I’m sure we will see additional checkpoint inhibitors, and we’re going to see drugs added to [pembrolizumab]. It’s interesting…that its role has been restricted to triple-negative breast cancer, and that’s still pretty much it. Interestingly, prostate cancer is another cancer that does not seem to get benefit from this class of drugs. Those 2 cancers make up a large proportion of the cancers we see in the United States. It’s interesting, and you wish you had better treatments for those diseases.

Some interesting news about [pembrolizumab] is that they’re working on a subcutaneously administered formulation of it. This is probably in part [because] their exclusivity runs out in a couple years, but in theory, the availability of a subcutaneously administered preparation would allow patients who had established tolerance to give it to themselves at home. We hear a lot about home-based chemotherapy and how patients clearly seem to want it. To me, that’s the really interesting thing about [pembrolizumab] in general and in breast cancer specifically, that this could allow some patients to self-administer therapy down the road. That would be a significant advancement. 

References
1. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
2. U.S. FDA approves Trodelvy in pretreated HR+/HER2- metastatic breast cancer. News release. Gilead. February 3, 2023. Accessed February 3, 2023. http://bit.ly/3X1WV2U
3. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki in HER2-mutant non-small cell lung cancer. News release. FDA. Updated August 16, 2022. Accessed January 25, 2023. http://bit.ly/3j1ebaO
4. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed January 25, 2023. http://bit.ly/3j3zU1E
5. New data for Trodelvy demonstrate clinical efficacy across Trop-2 expression levels in HR+/HER2- metastatic breast cancer. News release. Gilead Sciences, Inc. December 6, 2022. Accessed January 25, 2023. http://bit.ly/3JeorXE
6. Bagegni NA, Davis AA, Clifton KK, Ademuyiwa FO. Targeted treatment for high-risk early-stage triple-negative breast cancer: spotlight on pembrolizumab. Breast Cancer (Dove Med Press). 2022;14:113-123. doi:10.2147/BCTT.S293597
7. Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549
8. Jacob SL, Huppert LA, Rugo HS. Role of immunotherapy in breast cancer. JCO Oncol Pract. Published online January 6, 2023. doi:10.1200/OP.22.00483

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