Nichole Tucker, MA, is the Web Editor for Targeted Oncology. Tucker received her Bachelor of Arts in Mass Communications from Virginia State University and her Master of Arts in Media & International Conflict from University College Dublin.
In an interview with Targeted Oncology following the announcement of sacituzumab govitecan accelerated FDA approval, Hope Rugo, MD, discussed the published data from the phase 1/2 basket trial and the relevance of having sacituzumab govitecan available for the treatment of patients with metastatic triple negative breast cancer.
The landscape for metastatic triple-negative breast cancer (mTNBC) offers limited treatment options, and even as new agents circulate as potential options, few clinical trials have provided long-term data on the efficacy of these available agents. One drug showing significant promise is sacituzumab govitecan-hziy (Trodelvy), which recently received accelerated approval by the FDA as treatment of patients with for adult patients with mTNBC who have received at least 2 prior therapies for metastatic disease.
“The real lesson for me and the excitement of this approval is that we are finally beginning to make progress for the treatment of our patients who have chemotherapy-resistant triple-negative breast cancer,” Hope S. Rugo, MD told Targeted Oncology.
In the phase 1/2 basket trial (NCT01631552), which supported the approval of sacituzumab govitecan in mTNBC, the drug demonstrated a response rate of 33% in the heavily pretreated patient population.
The next step for the development of the drug is to evaluate it in a phase 3 clinical trial with an active comparator. The phase 3 ASCENT trial (NCT02574455), an international, multi-center, open-label, randomized trial, launched to assess the efficacy and safety of sacituzumab govitecan against a treatment of physician’s choice.
In an interview with Targeted Oncology following the announcement of sacituzumab govitecan accelerated FDA approval, Rugo, professor, Department of Medicine (Hematology/Oncology); and Director, Breast Oncology and Clinical Trials Education at the University of California San Francisco, discussed the published data from the phase 1/2 basket trial and the relevance of having sacituzumab govitecan available for the treatment of patients with mTNBC.
TARGETED ONCOLOGY: As you know, the FDA just recently approved sacituzumab govitecan in mTNBC. What will it mean to have this drug available for use in the community setting?
Rugo: We're excited about the approval of sacituzumab govitecan. There are a number of reasons for this, but the most important one is that when patients have mTNBC, they have a remarkably small number of treatment options, and particularly, a small number of treatment options that are effective durable disease control.
The other part of this is the treatment that we give patients and the toxicity of the treatment. Having sacituzumab govitecan available for patients who had progressive disease after at least two lines of chemotherapy in the metastatic setting and you have triple-negative breast cancer is a tremendous advantage for patients in community or academic centers because the drug hasn’t been available to any of us. At least a third of the patients responded to sacituzumab govitecan who had extensive prior exposure to chemotherapy from metastatic breast cancer.
It’s also nice to know is more than half of the patients responded for at least six months,which is a big difference from some other chemotherapy agents that we can offer these patients.
As always, when we're treating patients who have bad metastatic cancer in a limited expected survival, having more treatment options makes a big difference. We don't know yet what the survival will be from sacituzumab govitecan compared to chemotherapy of physician’s choice. That will be presented at some point in the future from the results of the phase 3 ASCENT trial.
What we do know is that the approval leaves us with an additional treatment option that allows patients to start with immunotherapy first, if the patient has PD-L1-positive disease based on the Impassion130 results and it allows patients who had a recurrence to potentially derive benefit even a short time after their adjuvant chemotherapy.
Lastly, sacituzumab govitecan was overall well-tolerated. We don't see any major life-threatening toxicities or issues that would be difficult to manage in the outpatient setting. I think this is a win/win situation for patients, with the only downside being that many patients lose their hair with this particular antibody-drug conjugate.
TARGETED ONCOLOGY: The long-term efficacy data that is available around treatment options for mTNBC is limited. Can you discuss what outcome are generally like for these patients?
Rugo: The accelerated approval of sacituzumab govitecan was based on data from a phase 2 trial where 108 patients received sacituzumab govitecan. The drug is given on days 1 and 8 every 21 days, and there was no comparator, but we know that there are very limited treatment options as I mentioned in this situation. If you treat patients who have had more than two lines of prior chemotherapy in the metastatic setting, we already know that the outcome isn’t very good. The accelerated approval was based on having an additional treatment option that seemed to be a good option in terms of efficacy with tolerable toxicity.
In the patients who were treated about 33% of them had a complete or partial response to sacituzumab govitecan and as you would expect, most of the responses were partial responses. The medium duration was just under eight months, at about 7.7 months and that's encouraging.
I mentioned earlier that more than half the patients were responding at six or more months. If you looked at 12 or more months, it was almost 17% of the patients.
You can look at survival in that group of patients but that does not help you because you don't have a comparator as in the ASCENT trial which looked at progression-free survival as the primary end point, but we have not seen the data yet. I’m looking forward to seeing that as well as longer-term results that will help us understand the potential survival impact.
TARGETED ONCOLOGY: Can you discuss the toxicity profile of sacituzumab govitecan?
Rugo: The primary higher-grade toxicities are blood-related, and we have a much easier time managing blood toxicity than we do toxicities that occur outside of the hematopoietic system.
Neutropenia of grades 3/4 were seen in 43% of patients and anemia in only 12% and thrombocytopenia, which is hard for us to manage was a very uncommon toxicity occurring in less than 5%. That’s promising because if you don't have a lot of febrile neutropenia, you can manage the neutropenia fairly well by using growth factors. I have found in the patients that I’ve treated with sacituzumab, thatmost patients do require growth factors, but not all. It depends on the extent of prior treatment. I mentioned that alopecia is quite common in these patients, but not everybody loses all of their hair. It’s just something to warn patients about. We don't yet know if scalp cooling could help this.
Relative to gastrointestinal (GI) toxicities, the toxin that is attached to this antibody-drug conjugate is SN-38. This is a metabolite of irinotecan and we know the toxicity of irinotecan very well from our colleagues in the GI oncology arena. Interestingly, if you give SN-38 even at the high toxin per antibody level that’s seen with these newer antibody-drug conjugates, you don't see the toxicity that you see from giving naked irinotecan, where the body determines how much is metabolized to SN-38 and how rapidly it's cleared.
In this situation, grade 3/4 diarrhea and other GI toxicities were uncommon. Grade 3/4 diarrhea was seen in 9% of patients and mostly grade 3. You could manage this by telling patients in advance and giving them anti-diarrheal therapy. In patients that have treated, I haven't seen much of this. We need to educate patients carefully and make sure they all have Imodium at home. In addition, we give antiemetics as prevention, but the high-grade nausea is very rare, and was only seen in 6% of patients in this phase 2 study population. Low-grade nausea, and diarrhea were seen in more than 50%.
TARGETED ONCOLOGY: What is unique about the results seen in this trial that were recently published in the New England Journal of Medicine?
Rugo: What is unique is that we don't have a lot of trials that have done two different things. One is that it focused on patients who received a lot of prior chemotherapy with the registration-based pathway. That’s 2 to 4 prior lines of chemotherapy, which is a lot of chemotherapy for a patient population where the median survival after diagnosis of metastatic disease is about 18 to 19 months, based on the data from the Impassion130 trial. These patients are beat up, in terms of the treatment, and they have resistant disease and that makes this trial unique.
The other unique thing about this trial, I think is that it focused on triple-negative breast cancer. The prior trial that looked at heavily pretreated patients called the EMBRACE trial, which led to the approval ofthat left to the approval eribulin (Halaven), did not focus on any one subset of patients.
TARGETED ONCOLOGY: Like all clinical trials, there were some limitations in the basket study. Can you explain those limitations?
Rugo: The main limitation of this study is that it’s a single-arm study and therefore has no comparator.
You don't know how it compares to standard therapy and that limitation is being addressed in the phase 3 ASCENT trial that randomizes patients who have received at least two prior chemotherapy regimens for metastatic triple-negative breast cancer to receive either sacituzumab govitecan or treatment of physician choice. There is a menu of specific chemotherapy agents that patients can receive. There were no other significant limitations in the phase 2 trial.
A limitation of sacituzumab govitecan, in particular, is that we don't have a marker to know which patients might respond better. The antibody is to Trop-2 and Trop-2 is overexpressed quite commonly in triple-negative disease as well as in other subsets of breast cancer. So far, we don't have any data that has told us that we need to test for expression of Trop-2. As a result, we just treat everybody. We’re hopeful that some of the trials that are ongoing now and trial of the future will give us better information about this.
The ongoing TROPiCS-02 trial is evaluating sacituzumab govitecan in patients with metastatic hormone receptor-positive breast cancer and in this trial, we are looking at Trop-2 and I think it will be interesting to look at those data retrospectively.
There also is one other small limitation to mention and that's hypersensitivity. Any drugs that we give that have an antibody attached to it could potentially have hypersensitivity. Anaphylactic reactions are rare with this antibody-drug conjugate but some hypersensitivity reactions did occur. These reactions were higher grade and only 1% of patients that were treated in all different trials that were investigating sacituzumab govitecan. That’s a population of 408 patients in which only 6 patients had grade 3/4 hypersensitivity reactions, and it only led to permanent discontinuation in 3 patients.
We do recommend pre-infusion medications for patients for nausea and blood reactions. Physicians should have orders available to treat patients in case they have an infusion-related reaction, similar to what we do for paclitaxel. The rate is not any greater than what we see for taxane.
The last thing is that physicians may want to observe patients during the infusion and for 30 minutes after just to make sure they don't have one of these rare transfusion reactions. We have not seen it in a few patients who were treated with the drug.
TARGETED ONCOLOGY: Now that the drug is approved, there will likely be questions about how to manage patients while they’re on this drug. What advice can you give to community oncologists?
Rugo: I think this drug is a great option for patients. We should be able to prescribe it. It's important to get pre medications as I mentioned earlier, and it's important to be cautious about the day 8 blood counts.
If the neutrophils are not reasonable on day 8, oncologists should think about using prophylactic growth factors in the future. Sometimes when patients come in for cycle, even though their accounts were fine on day 1, they will have low neutrophils. Having a neutrophil count under 1.5 on day 1 should prompt consideration for growth factors to avoid more severe neutropenia complications with future cycles.
TARGETED ONCOLOGY: What is your overall outlook on the treatment landscape for mTNBC now that there’s a new treatment option is available?
Rugo: I think that progress in the field of triple-negative breast cancer has been long-awaited and slow to come. We're understanding the biology better now to some degree and we now have several new treatment options. They're improving our ability to treat patients and, most importantly, helping us to move agents that might offer a benefit for resistant disease to earlier in the phase of treatment. When we find something that works well and is reasonably well-tolerated, the first thing we want to do is move it into the early-stage setting and there are trials planned to open in the near future that will look at sacituzumab govitecan in patients who have early-stage triple-negative breast cancer upfront and in patients with poor response to standard neoadjuvant chemotherapy.
It’s important to treat most patients who have triple-negative breast cancer with neoadjuvant therapy because you want to be able to offer them rescue therapy with additional agents on clinical trials, or course, capecitabine outside of trials. We need to understand how immunotherapy is going to interact with these new agents as we’re waiting for disease-free survival data from the KEYNOTE-522 trial, which is looking at pembrolizumab (Keytruda) in the neoadjuvant setting.
Also, for patients who have BRCA mutations, we now have PARP inhibitors and we're waiting for the data from the Olympia trial that evaluated adjuvant olaparib.
The real lesson for me and the excitement of this approval is that we are finally beginning to make progress for the treatment of our patients who have chemotherapy-resistant triple-negative breast cancer.