Hope S. Rugo, MD

 The real clinical pearls we need in this situation is to be sure to measure for PD-L1–positivity. Think about checkpoint inhibitors in the metastatic setting. Carefully choose the chemotherapy based on the patient’s own history of response to chemotherapy agents. Use nab-paclitaxel preferentially rather than paclitaxel if you’re using a taxane. Monitor carefully for immune toxicity. Treat early and educate our patients about these toxicities, because you can get almost any patient through toxicity if you recognize it early and treat early. It’s clear that if you don’t, the toxicities can become life-threatening. With the use of checkpoint inhibitors, we’ve seen real improvements in our patients with triple-negative breast cancer.

The future is trying to move these treatments earlier. There are exciting data from the early-stage setting we talked about, but also looking at new ways to give checkpoint inhibitors in the metastatic setting. Giving induction with checkpoint inhibitors or chemotherapy to try to jump-start the immune response. Using different targeted agents with immune checkpoint inhibitors, antibody-drug conjugates, or radiation therapy are all areas that are being tested. I mentioned PARP inhibitors earlier. It’s certainly an exciting time, when we have immune therapies that are effective in our patients with triple-negative breast cancer. But this only affects about 40% of patients in the metastatic setting who are at least a year from their recurrence, and about 38% of patients who are 6 months or farther out. We need better solutions for our patients with the most highly resistant disease and for those patients with PD-L1–negative disease.

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Hope Rugo, MD, provides insights on best practices for managing metastatic TNBC in community settings.

Clinical Pearls for Treating Patients With Metastatic TNBC

 One of the important things to consider when we’re thinking about using immunotherapy in patients with metastatic triple-negative breast cancer, or potentially in the not-too-distant future in the neoadjuvant setting for patients with curable triple-negative breast cancer, is what downsides we see from using checkpoint inhibitors. If you improve survival, or in the early stage setting, you improve event-free survival for a bad cancer, you’re pretty excited to use the drug. But you want to balance this against the knowledge of immune toxicities.

I was just talking to a patient in the neoadjuvant setting who developed hyperthyroidism. I was talking to her about the fact that she would likely develop hypothyroidism and be on thyroid replacement for life. And although we had talked about this in the consenting process for the clinical trial she’s on, she was overwhelmed by the idea that she might take a pill for the rest of her life. Of course, I explained to her that she would need to take hormone therapy for many years as well. She has locally advanced pleomorphic high-grade invasive lobular cancer, so she’s going to be on hormone therapy anyway. And she would be having ovarian suppression, and then she felt a little better.

This is a big issue for patients, and it’s important for them to know. The most common immune-related toxicities that we see are rash. Rash is the most common toxicity in which we use steroids not to treat the immune-related event. The next most common toxicities include abnormalities of the thyroid. We often will see a hyperthyroidism—really a thyroiditis—that then quickly burns out and the patient becomes hypothyroid. I haven’t had to personally treat the hyperthyroid phase, except for occasionally a beta-blocker for tachycardia. You do need to monitor these events, because patients can get very sick from undetected hyper- and hypothyroidism.

The other immune-related toxicity that’s a little more common than very rare is adrenal insufficiency. We tend to see this more in patients in the early stage setting than metastatic, but I have several patients in the metastatic setting who presented with dizziness and hyponatremia and were found to have adrenal insufficiency. Adrenal insufficiency can be primary or secondary. It can be the fact that your adrenal gland is not producing cortisol, or you can have hypophysitis, where your hypothalamus is not making ACTH [adrenocorticotropic hormone]. Those tests should be obtained with a Cortrosyn stimulation test when you suspect that a patient has adrenal insufficiency.

First, just getting a cortisol level and showing that it’s 0 is your first indicator. But then you want to work it up and, in addition, get a brain MRI. Those patients then need to be on cortisol replacement for the rest of their lives. I suggest that they also put a medical alert bracelet on, because if they have any kind of acute event, they can go into crisis if you don’t give them stress dose steroids. This is something that’s very important to educate patients about. It’s uncommon, like all the immune toxicities, but it’s more common than diabetes, which is extremely uncommon as an endocrine toxicity.

We’re more familiar with the other toxicities we see. Colitis and hepatitis are more common than pneumonitis or renal toxicity. Those are most of the toxicities we see. We’ve actually seen toxicities at the brain where people develop encephalitis, but that’s incredibly uncommon. We monitor these by the TSH [thyroid-stimulating hormone] laboratory studies and asking the patients how they’re doing in their symptoms, because adrenal insufficiency is hard to find. And then being sure that even when I have patients on maintenance, that you’re really following these symptoms and their regular laboratories and investigating symptoms carefully. Don’t think the diarrhea or liver enzymes are because of chemotherapy. You want to be thinking first that it’s because of the immunotherapy. Have a low threshold for using steroids when patients have significant toxicities. For some of the immune toxicities, we can actually continue or rechallenge with immunotherapy.

For example, when a rash resolves to grade 1 or better, I’ve rechallenged patients successfully with checkpoint inhibitors. Although I have 1 patient who had the rash return and couldn’t be on the checkpoint inhibitor. If a patient has hypothyroidism or hyperthyroidism, we continue the checkpoint inhibitor. We also do that if a patient has adrenal insufficiency. For hepatitis, colitis, pneumonitis, etc, you have to hold the checkpoint inhibitor. I haven’t rechallenged most patients. I have 1 patient who has very resistant pleomorphic lobular cancer and had very long disease control on pembrolizumab. That patient has rechallenged a few times. Another patient had colitis and eventually got colitis again, so it can be difficult. Only a small number of patients will be able to continue if they have recurrent episodes of immune toxicity.

The frequency is similar to other tumor types. Mostly what we see is the same. It’s just that if you can combine different immune agents, immune agonists, you clearly see more immune toxicity, and we don’t do that yet in breast cancer as standard of care. In my experience with using checkpoint inhibitors in patients with triple-negative breast cancer, it’s been very similar to what we just discussed. I have some patients who’ve had very long disease control. I have 1 patient who received single-agent checkpoint inhibitor and seems to be cured of her metastatic triple-negative breast cancer to lung. She’s more than 5 years out now and is almost 1 year off her checkpoint inhibitor due to recurrent colitis. So we do see those rare patients. But in most of my patients, the disease eventually does progress again. Can we rescue patients back by re-treating with the checkpoint inhibitor if you stopped it? That’s a good question. Based on other disease states, I would retreat if you stopped the checkpoint inhibitor and give chemotherapy again to try to jump-start the immune response.

An expert explains the different types of immune-related adverse effects associated with the use of immune checkpoint inhibitors.

Immune-Related Adverse Effects of ICI Therapies in Metastatic TNBC

 When you choose the chemotherapy regimen, you really have to understand how the patient has responded in the neoadjuvant and adjuvant settings. In the patient we have today, she relapsed quite a long time after her most recent taxane therapy, which was given in the neoadjuvant setting. Nab-paclitaxel is an excellent chemotherapy choice in that situation. For patients who have relapsed at 6 months from their taxane exposure, gemcitabine and carboplatin would be our chemotherapy choice. Because of the data from IMpassion131 that we just discussed, a patient who is going to receive a taxane should probably receive nab-paclitaxel. Our best data are with nab-paclitaxel, so I don’t see any reason why you would select paclitaxel as a chemotherapy partner for a checkpoint inhibitor.

What if our patient had the same situation, but her tumor tested positive for a germline mutation in 

? Would we change our approach? We’ve talked about this a lot. The 1 thing that would change based on data presented at the 2021 ASCO [American Society of Clinical Oncology] Annual Meeting is that this patient would have received the PARP inhibitor, olaparib, as her adjuvant therapy. The question about what we do with capecitabine remains to be answered, but the data from the OlympiA trial showed a remarkable improvement in invasive disease-free survival and a distant disease-free survival, although that number included new primary tumors, which we know to be higher in patients with 

 mutations. There’s even a numeric difference that’s not statistically significant in overall survival, so these data are practice-changing.

If she presents with metastatic disease but hasn’t seen a PARP inhibitor, we know she has disease that was sensitive to carboplatin in the neoadjuvant setting even without a pCR [pathologic complete response]. We would take the exact same approach that I’ve defined here for the patient who didn’t have a 

 mutation. The reason is because we’ve seen such a remarkable survival benefit in IMpassion130. Even though this was complicated statistically, it’s still a big numeric survival difference. We’d still use the same nab-paclitaxel, atezolizumab approach.

When would we use the PARP inhibitor? We generally give a PARP inhibitor in the second-line setting, but a fascinating idea that’s now being studied in the KEYLYNK-009 trial with pembrolizumab is the concept that you could use a checkpoint inhibitor in the maintenance phase combined with a PARP inhibitor. We know that PARP inhibitors can potentially enhance the immune activation of the tumor via the cGAS–STING [stimulator of interferon genes] pathway and interferon. For this reason, there are ongoing studies looking at combinations of checkpoint inhibitors and PARP inhibitors in metastatic disease. What better way to try to improve the duration of disease control than to take patients who’ve had a good response to, for example, chemotherapy and a checkpoint inhibitor, continue the checkpoint inhibitor, discontinue the chemotherapy, and add the PARP inhibitor, which we know to be safe. We don’t have any data to encourage this as standard clinical practice at this time, but it’s an intriguing question. And certainly, maintenance PARP inhibition has been very successful in ovarian cancer.

Right now, that would only be a question in patients who have germline 

. The KEYLYNK-009 trial is studying this in all-comers in looking at HRD [homologous recombination repair deficiency] as well as germline mutations.

Dr Hope Rugo discusses the importance of testing for germline BRCA1/2 mutations in patients with triple-negative breast cancer.

Germline BRCA1/2 Mutations in Metastatic TNBC

 Both atezolizumab and pembrolizumab have accelerated approval from the FDA based on the data from the 2 trials we just discussed. When we try to decide which chemotherapy and checkpoint inhibitor we should use, we base the clinical trials on our decision-making process. First, all women with metastatic triple-negative breast cancer should have testing for PD-L1 as soon as possible after their diagnosis. This testing can be done on any tumor sample that’s available. If it’s not feasible to obtain a metastatic tumor biopsy, send the archival sample from their early stage diagnosis.

If you can get a biopsy, it’s important, because you want to retest those markers. You always want to be sure you’ve confirmed that the tumor is triple-negative and something wasn’t missed on the testing of the early-stage disease. At that point, you have tumor tissue that can be sent for PD-L1 testing. If 1 test for PD-L1 is negative, there isn’t an overall guideline approach. But because there isn’t a complete overlap and this is such an important decision for our patients, it’s reasonable to send the other test to be sure the patient’s tumor is really negative for PD-L1 by all tests available.

There also has been some discussion about which organ you should get the tumor from. That seems a little beyond what we can do in clinical practice. You’re not going to biopsy the lung rather than the liver because there’s a higher rate of PD-L1 positivity in the lung. It’s true that the lung may be more likely to be positive than the liver, and that might motivate you if you find a negative test to go back and check the archival breast tumor sample to see if some of the cells might be PD-L1 positive, but you’re just not finding them in the liver. We don’t know the implications of discordant testing to response to checkpoint inhibitors. If patients relapsed after 12 months, I would use the IMpassion130 data with nab-paclitaxel and atezolizumab.

Data from IMpassion131 that was presented at ESMO [European Society for Medical Oncology] Virtual Congress in 2020. This trial looked at a similar population to IMpassion130, with a slightly different randomization, with an intent-to-treat population and then a plan to look at the PD-L1–positive population. Patients received paclitaxel rather than nab-paclitaxel, and for that reason, they received steroids. There was absolutely no difference in the PD-L1–positive population for progression-free survival [PFS] or overall survival. In fact, the cohort of patients who had PD-L1–positive disease and received atezolizumab and paclitaxel had a slightly numerically worse survival than the control population, although this was in no way statistically significant.

What’s intriguing about this is that the median overall survival for the control population was 28 months. We haven’t seen that in any other study. It’s longer than we’ve seen. What you take from that study is that there’s some variable that we don’t understand that by chance picked a patient population that had very chemotherapy-sensitive disease in IMpassion131. Hopefully, additional correlative studies might help to elucidate what population that represented. It certainly could be steroids with atezolizumab, although steroids were used in KEYNOTE-355 with paclitaxel and gemcitabine and carboplatin, and a PFS benefit was seen. We are waiting for overall survival data from KEYNOTE-355, but crossover to checkpoint inhibitors in some countries because of the accelerated approval of atezolizumab may complicate this analysis.

Hope Rugo, MD, continues to discuss key clinical trials affecting metastatic triple-negative breast cancer, including IMpassion131.

IMpassion130 and KEYNOTE-355 Trials in Patients With Metastatic TNBC: Part 2

 This patient actually meets the criteria for IMpassion130 perfectly. Patients who were eligible for IMpassion130 had to be at least 1 year out from their treatment given in the curative setting. This patient is 13 months out. The reason why that criterion was used for patients who were enrolled in IMpassion130 is that we chose to use a taxane backbone of chemotherapy. We wanted to make sure patients did not have disease that was inherently resistant to up-front taxane therapy. We chose nab-paclitaxel as the chemotherapy partner to avoid using steroids as a premedication, potentially abrogating the immune effect. IMpassion130 randomized patients like this 1 regardless of PD-L1 status but stratified by PD-L1 status to receive nab-paclitaxel and placebo or nab-paclitaxel and the checkpoint inhibitor, atezolizumab. Nab-paclitaxel was given in a 3 weeks on, 1 week off schedule, which made the scheduling with atezolizumab and coordination complicated but doable for patients.

The patient by PD-L1 testing is clearly eligible based on the IMpassion130 trial. What did the trial show? We talked about this a little already. We saw a statistically significant improvement in progression-free survival [PFS] with the addition of atezolizumab in the patient cohort who had tumors positive for PD-L1 defined as having SP142 staining in tumor of 1% or greater. A fairly small number of patients had liver biopsies that determined their eligibility in IMpassion130. It didn’t matter whether the tumor that determined eligibility by SP142 positivity was obtained from an early stage or late-stage lesion. Interestingly, most tumors were obtained a median of 60 days before treatment started, and most of these were de novo metastatic lesions or metastatic tumor biopsies after an early stage diagnosis.

IMpassion130 also looked at the intent-to-treat population in patients who had PD-L1–negative disease and showed that there was not a benefit in the PD-L1–negative subpopulation. We also looked at data recently published by Leisha Emens on whether it made a difference how intense the SP142 staining was. It didn’t make a difference. Patients responded to treatment with an improved PFS and OS [overall survival] regardless of whether there was intense or minimal SP142 positivity for PD-L1. Additionally, having 

 mutation didn’t make a difference. PD-L1 positivity was the best predictor of response to atezolizumab; better than tumor infiltrating lymphocytes or CD8 positivity.

This patient is an excellent candidate for the treatment. Treatments are particularly appealing for triple-negative breast cancer in any setting if we can improve survival, our gold standard. That’s a great option for this patient and was the treatment she received. What if the patient had relapsed earlier, like less than 12 months after completing her adjuvant treatment? In that case, if she was disease-positive for PD-L1 using the 22C3 antibody and CPS [combined positive score], a scoring system, with a score of at least 10, she would have been eligible for pembrolizumab and chemotherapy as her first-line treatment based on data from the KEYNOTE-355 trial. In that trial, patients were eligible if they had recurred at least 6 months out from their last treatment with curative intent. The chemotherapy options include gemcitabine and carboplatin, which about half the patients received, and paclitaxel or nab-paclitaxel. More patients received nab-paclitaxel than paclitaxel. As I mentioned, progression-free survival was improved by a little more than 4 months in patients who had PD-L1–positive disease defined as this score of 10 or greater. Patients benefited regardless of the chemotherapy backbone, although it appeared that patients had a better improvement in their outcome if they received a taxane, compared with gemcitabine and carboplatin, and if they had de novo metastatic disease. And this is just an indicator of resistance. Similar data have been seen in IMpassion130. Patients who were farther out from their last taxane or hadn’t received a taxane at all seemed to have a better outcome with the steady treatment.

An expert in breast oncology discusses the IMpassion130 and KEYNOTE-355 clinical trials.

IMpassion130 and KEYNOTE-355 Trials in Patients With Metastatic TNBC: Part 1

 Our goal in looking at all new treatments for triple-negative disease is to improve survival and outcome for patients with metastatic breast cancer but also to move these therapies into the early stage setting as quickly as possible to try to prevent metastatic disease. This is the goal of many of the clinical trials that are going on. We’ve already seen a press release suggesting that adding the immunotherapeutic agent pembrolizumab to neoadjuvant chemotherapy might improve event-free survival from the KEYNOTE-522 trial. We also see that the addition of atezolizumab to nab-paclitaxel, anthracycline-based neoadjuvant regimen improves pathologic complete response. We are making progress in the early stage setting despite this unfortunate situation for this patient.

The patient presents with visceral disease in her lung and liver, and she has moderate symptoms. What’s her prognosis? The median survival overall for patients who present with metastatic triple-negative breast cancer is quite unfortunate. There are subtypes of triple-negative breast cancer that have more indolent course triple-negative cancers that express the androgen receptor. For example, rare subtypes, such as apocrine triple-negative breast cancer, may have a much longer median overall survival. But for the classic highly proliferative visceral-dominant triple-negative breast cancer, median survival is quite short.

However, we now have new regimens that are available to treat these cancers. For patients who have metastatic triple-negative breast cancer, the first test we should be obtaining is PD-L1 testing. We have 2 tests that we can do, including the SP142 assay used for this patient. If SP142 is negative, we generally will test the tumor with CPS [combined positive score] using the 22C3 antibody. Although these tests both have about a 38% to 42% positive rate in metastatic triple-negative breast cancer, the results do not completely overlap, so it’s possible that you would find a patient whose tumor was positive with 1 test and not the other. Both tests make the patient eligible to receive an immune checkpoint inhibitor. That’s very important, because using the immune checkpoint inhibitor, atezolizumab, has improved median overall survival by 7.5 months in the final analysis of the IMpassion130 trial. The addition of pembrolizumab to chemotherapy in the first-line setting in patients with PD-L1–positive disease has improved progression-free survival by a little over 4 months. Overall survival data have not yet been presented.

Dr Rugo educates on early stage treatment options and molecular testing guidelines for patients with metastatic triple-negative breast cancer.

Hope S. Rugo, MD | Authors

Articles

Clinical Pearls for Treating Patients With Metastatic TNBC

Immune-Related Adverse Effects of ICI Therapies in Metastatic TNBC

Germline BRCA1/2 Mutations in Metastatic TNBC

IMpassion130 and KEYNOTE-355 Trials in Patients With Metastatic TNBC: Part 2

IMpassion130 and KEYNOTE-355 Trials in Patients With Metastatic TNBC: Part 1

Early Stage Options for Patients With Metastatic TNBC