Editor's note: The TROPiCS-02 study looked at the efficacy and safety of the TROP-2 ADC drug sacituzumab govitecan monoclonal antibody (SG) for the posterior line therapy of HR+/HER2- advanced breast cancer. The results of the study's median PFS and OS data from the first interim analysis were disclosed at the 2022 ASCO Meeting. At this year's ESMO Meeting, Professor Hope S. Rugo from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, USA, reported the results of the second interim analysis of the TROPiCS-02 study OS. Invited by Oncology Frontier, Professor Hope S. Rugo gave a brief interpretation of the study findings.
Prof. Hope S. Rugo: Thanks for your interest in hearing about our data. I'm Hope S. Rugo, a professor of medicine and with focused in breast medical ecology at the University of California, San Francisco's Comprehensive Cancer Center.
Oncology Frontier:Could you introduce us to the research background of this study, such as the current status of HR+ advanced breast cancer treatment, why we choose a drug like SG, and what are its characteristics?
Prof. Hope S. Rugo: Hormone receptor positive/HER2 negative breast cancer makes up the most common subset of all breast cancer, the 2nd leading cause of cancer death and women worldwide. About 70% of breast cancers are hormone receptor positive/HER2 negative. Our current guidelines recommend sequential endocrine therapy in combination with targeted agents when available. However, for all patients, eventually resistance to endocrine therapy and their companion targeted agents develop. After that time, the guidelines recommend sequential single agent chemotherapy. However, this is limited by cumulative toxicity as well as decreasing efficacy as you go along from line to line of treatment. In addition, there are no specific guidelines about the appropriate sequencing of treatment that will optimize therapy for our patients.
In an initial umbrella trial, a phaseⅠB evaluated the novel trip to antibody drug conjugate in patients who had hormone receptor positive/HER2 negative, heavily pretreated disease. In this umbrella trial, phase ⅠB component, we saw a response rate of 30%. And this was quite durable with a very impressive progression-free survival as well. And that led to the development of a phase 3 trial to evaluate Sacituzumab Govitecan, just a little bit to answer your question about SG.
What is that? And what is the toxicity that's given with this novel trip to antibody drug conjugate? SG is the active metabolite of Irinotecan, a topoisomerase Ⅰ inhibitor. And we already had data suggest testing that Irinotecan, at lower doses, given weekly, could be quite effective as late line therapy for metastatic breast cancer. But it was a dose, to some degree, by toxicity over time with diarrhea. So, it made a lot of sense to give the active metabolite, metabolite of Irinotecan linked to this antibody to Trop-2. Trop-2 is expressed on about 80% of breast cancers and has been correlated with worse prognosis and faster progression of disease.
Oncology Frontier:Could you please tell us about the data updates of the TROPiCS-02 study at ESMO?
Prof. Hope S. Rugo: TROPiCS-02 is a phase Ⅲ trial that randomized patients, who had heavily pretreated tolerated receptor positive/HER2 negative metastatic breast cancer to receive either necessities. Sacituzumab Govitecan, which is given day one, in day eight, every three weeks, or treatment of physician choice, with the menu of chemotherapy agents. Patients who were eligible had received at least two, but not more than four lines of chemotherapy. In the metastatic setting, at least one line of endocrine therapy, and a taxane and CDK4 /6 inhibitor in any setting. So, this is unique in terms of chemotherapy trials. All the patients were required to have received a prior CDK 4/6 inhibitor.
Also, the patient population was a median of four years from initial diagnosis of metastatic disease until randomization on study. And more than 95% of patients had visceral disease. Again, a relatively unique, heavily pretreated patient population with visceral dominant disease. About 40% of patients had received CDK 4/6 inhibitors for more than a year, and many of these patients had been exposed to endocrine therapy for a very long time prior to starting their chemotherapy agent. 48% of patients received an eribulin as their chemotherapy of physician choice, and most of these patients had previously received capecitabine. In the trial, the primary end point was progression for survival by blinded, independent central review.
This data was presented at ASCO 2022, and was recently published in the Journal of Clinical Oncology. As a rapid communication, we showed that progression free survival was significantly longer in patients to receive SG with a hazard ratio 0.6, and the trial was powered for a hazard ratio 0.7. This was highly statistically significant. The media difference, however, was just months, which we attributed to the rapid fall off in a similar number of patients in both arms in the 1st two months of the trial, because these patients had very resistant cancer that didn't respond to any of the agents. However, after those two months, the curve separated and stayed separated.
So, we looked at landmark analogies at six, nine and twelve months, and showed at each of these time points that progression free survival, the number of patients alive and free of progression, was long greater in patients receiving SG versus chemotherapy of physician choice. In fact, at twelve months, three times as many patients were alive and free of progression.
At this presentation at ESMO 2022, we looked at this 2nd interim analysis for overall survival. At the 1st interim analysis, we showed a numeric improvement in overall survival, but it was not statistically significant. At this 2nd interim analysis, the medium follow-up is twelve and a half months, and wove increased the number of events by 100 events, so this is a big increase in the number of events. At this time, we showed a statistically significant improvement in overall survival, with immediate difference of 3.2 months going from 11.2 to 14.4 months. The hazard ratio is 0.79, which is corresponding to a 21% absolute improvement in overall survival.
So, this is very exciting, and because of the statistical hierarchical design, this allowed us to look at the statistics for overall response, other aspects of response, and the quality of life. We showed that overall response was significantly greater in patients receiving SG, as was clinical benefit rate and duration of response. In terms of patient reported outcomes, we showed that quality of life in global health status was took significantly longer time to deteriorate in patients receiving SG compared to those receiving TPC, and the same was true with the fatigue. More data on patient reported outcomes will be presented at ESMO 2022.
So, in summary, this data now shows that Sacituzumab Govitecan a patient population with limited treatment options and a poor prognosis improves both progression free and overall survival, with a significant difference in favor of Sacituzumab Govitecan. In an updated safety analysis, we showed no new safety signals with longer follow up, and the safety profile is similar to what's been reported in other studies, including the phase Ⅲa central in triple negative breast cancer. Neutropenia is the most common toxicity for SG, but this is well managed with growth factors. Those reductions were not required, and treatment delay when required. Interestingly, the discontinuation due to toxicity was not really any different for SG compared to treatment of physician choice. So, this is now a new and exciting treatment option for patients in this setting.
Oncology Frontier:In the TROPiCS-02 study, what is the safety performance of SG,what are the main adverse event profiles, and what are the implications for clinical prevention and management?
Prof. Hope S. Rugo: One of the things that's really important as we add new drugs to our treatment, and really, we’ve seen this tremendous and exciting advance with antibody drug conjugates. A much better way apparently to deliver chemotherapy than giving naked chemotherapy itself, is understanding toxicity and managing it proactively. And for SG, the most common toxicity is Neutropenia, and then the next most common toxicity is diarrhea. And in the studies, reported about 9 to 10% of patients at grade three diarrhea. So, these two toxicities are really important to understand and manage up front.
Interestingly, we do not see interstitial lung disease, and we have not seen decreases in cardiac function, so that's also very encouraging. You don't need to worry about that toxicity. In terms of the neutropenia and diarrhea, in my clinical experience, there appears to be more toxicity and patients who are heavily pretreated.
So, as we moved to the drug up earlier, e.g., in triple negative disease, we’ve seen a little less of this toxicity. Managing the neutropenia is very straightforward in patients who required prior growth factors for their last chemotherapy regimen. we use growth factors up front with the treatment with SG and then we give the growth factor after day one, day two or three, and after day eight, day nine or ten. And then we make sure that the neutral folk count is over a thousand when we start the next cycle. The trial actually required an ANC of 1500 at the start of each cycle. But in clinical practice, we really use a neutral folk count of a thousand in order to go onto the next cycle. This growth factor up front prophylaxis is very important for patients at high risk. But in patients who are at low risk, we wait until they become neutropenic, but then we do treat with growth factors.
And I think one really important point is, you know, up front management of diarrhea is very straightforward for oncologist. We give anti diarrheal agents, we delay treatment of patients at bad diarrhea. We help patients man manage the diarrhea in terms of their diet, and then we dose reduce for both neutropenia and diarrhea if that's not easily managed by the techniques that I just mentioned. But an important point is that a patient is neutropenic and they have bad diarrhea, it's very important to give growth factors, because what we know about drug induced diarrhea is that you can cause some inflammation of the lining of the bowel, and then, if you are neutropenic, that allows the bacteria to gain a foothold, so patients could become much more sick and but just by giving growth factors, you can prevent that completely in my experience, we also don't see mucositis or stomatitis that patients don't get mouth source from this drug. We don't see rash, for example, and we don't see neuropathy.
So overall, these are toxicities that oncologists are very used to managing and are quite straightforward in terms of our ability to provide supportive care.
Oncology Frontier:There are many innovative drugs such as PI3K, mTOR, AKT for HR+ MBC therapy. What impact do you think Trop-2 ADC drugs will have?
Prof. Hope S. Rugo: There are a lot of new targeted agents now available, but these targeted agents have had success only in combination with endocrine therapy. To date, the antibody drug conjugates are in the section of treatment that is chemotherapy. So, there's really no competition in CDK 4/6 inhibitors, AKT inhibitors, etc. At the present time, because we're giving these agents in combination with endocrine therapy and with sequential therapy, and then when we get onto chemotherapy, that's where we start thinking about where we're going to fit the antibody drug conjugates in, and how we're going to sequence anybody drug conjugates in various patient populations. There have been some studies looking at combining chemotherapy with, e.g., AKT inhibitors that are ongoing studies with AKT inhibitors and PI3K inhibitors as well, but we have yet to see positive data, and we don't really incorporate those agents into the chemotherapy part of treatment for our patients.