Nichole Tucker

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 

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.

 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.

: 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?

: 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.

: 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?

: 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.

: Can you discuss the toxicity profile of sacituzumab govitecan?

: 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%.

: What is unique about the results seen in this trial that were recently published in the 

: 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.

: Like all clinical trials, there were some limitations in the basket study. Can you explain those limitations?

: 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.

: 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?

: 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.

: What is your overall outlook on the treatment landscape for mTNBC now that there’s a new treatment option is available?

: 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.

 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.

Articles

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.

Sacituzumab Govitecan Brings Long-Awaited Progress in the Treatment Landscape of mTNBC

A high percentage of pathologic complete responses (pCRs) were observed with atezolizumab (Tecentriq) in combination with carboplatin and nab-paclitaxel (Abraxane) chemotherapy as neoadjuvant treatment of patients with resectable non–small cell lung cancer (NSCLC), meeting the primary end point of a phase 2 study, which is the only known study of its kind.

“The results showed that a high proportion of patients had a complete pathological response or a major pathological response, even in the high-risk population of patients included in our study, in which more than 75% of patients presented with stage IIIA disease,” wrote the study authors, led by Catherine A. Shu, MD, of the Division of Hematology/Oncology, Department of Medicine, Herbert Irving Comprehensive Cancer Center at Columbia University.

 were from 30 evaluable patients with resectable NSCLC. After enrollment, one patient was found to have colon cancer and therefore was non-evaluable and replaced by another patient. In terms of cancer types, 57% of patients had adenocarcinoma (n = 17), 40% had squamous cell carcinoma (n = 12), and 3% had a large-cell neuroendocrine tumor (n = 1). Baseline screening showed that in 55% of patients (n = 16) had tumor PD-L1 expression of 1% or higher, and 27% of them (n = 8) had tumor PD-L1 expression of 50% or higher. AJCC 7th edition–defined stage IIIA disease was observed in 77% of patients (n = 23). Resection was carried out in 26 patients; however, 4 patients did not have a R0 resection due to unresectable disease in 3 and brain metastases in 1.

At a median follow up of 12.9 months (Interquartile range [IQR], 6.2-22.9) major pathological responses were observed in 57% (95% CI, 37%-75%) of 30 patients. In addition, pCRs were achieved in 33% of patients (95% CI, 17%-53%), and 6 of those patients were in the stage IIIA disease group. Of the responders in the study, 63% had a partial response as their best response per RECIST criteria. Stable disease was observed in 30% of those patients (n = 9), and progressive disease was observed in 7% of patients (n = 2).

An investigation of the potential correlation between PD-L1 expression and responses, no significant association was found (

 = .67). A significant association was observed between the achievement of major pathological response and RECIST criteria response categories (

 = .0022), which was noticed in a post hoc analysis. Objective responses regardless of PD-L1 expression were also observed through a post hoc analysis showing a median best percentage change in tumor size of –34% (range, –41 to –9) in patients with less than 1% PD-L1 expression and –40% (range, –52 to –21) in those with PD-L1 expression of 1% or higher (

Twenty-three patients received at least day 1 of treatment of all 4 cycles with atezolizumab in combination with carboplatin and nab-paclitaxel. Of those patients, 97% completed at least 3 cycles of combination therapy. Chemotherapy dose reductions were required in 67% of patients (n = 20). As a result of treatment-related toxicities, 17% of participants (n = 5) underwent surgery early. Ninety percent of patients developed thrombocytopenia or neutropenia, which led to missing at least one dose of nab-paclitaxel.

In the overall safety analysis, treatment-related adverse events (TRAEs) were seen in most patients. The most common any-grade TRAE was neutropenia, which was observed in 87% of patients (n = 26). Other common any-grade TRAEs included anemia (77%), thrombocytopenia (63%), fatigue (57%), alopecia (47%), and nausea (43%). Frequent grade 3/4 adverse events (AEs) included neutropenia (50%), alanine aminotransferase concentration increase (7%), aspartate aminotransferase concentration increase (7%), and thrombocytopenia (7%).

Arthralgia/myalgia, diarrhea, increased alanine aminotransferase concentrations, increased aspartate aminotransferase concentrations, hypothyroidism, and hyperglycemia were among possible immune-related events observed in the trial. Also, serious TRAEs occurred in 3% of patients and included grade 3 febrile neutropenia, grade 4 hyperglycemia, and grade 2 bronchopulmonary hemorrhage. No deaths occurred due to treatment. There were also no treatment-related surgical delays.

Other post hoc analyses looked into disease-free survival (DFS) according to pathological responses. Patients who did not have a major pathological response had a median DFS of 14.3 months (95% CI, 9.9 to not reached [NR]) versus 34.5 months (95% CI, 10.7-NR) in those who had a major pathological response (HR, 0.7; 95% CI, 0.1-4.3; 

 = .71). Among subjects with a pCR, the median DFS was 34.5 months but was not reached in those who did not have a pCR (HR, 0.4; 95% CI, 0.04-3.70; 

Responses were evaluated by tumor histology as well and showed that more patients had a major pathological response and pCR in the adenocarcinoma group (53% and 33%, respectively) than in the squamous cell carcinoma group (80% and 50%). According to molecular tumor tests, 15% of patients in the adenocarcinoma group had 

 mutations. These mutations did not impact responses.

“Pathological response as an early surrogate endpoint for survival is encouraging, and if validated as a biomarker, could shorten the time between trials and approval of therapy by pharmaceutical regulatory authorities, thereby allowing more patients faster access to better therapies,” wrote Shu et al about the implication of this research.

This was an open-label, multicenter, single-arm trial conducted at 2 sites in the United States. Patients who were enrolled had stage IB-IIIA NSCLC that was considered to be surgically resectable by a thoracic surgeon. All patients in the study had an ECOG performance status of 0 or 1, adequate organ function, adequate pulmonary function, and measurable disease, as was required per the study criteria.

Intravenous atezolizumab 1200 mg was administered on day 1 in combination withnab-paclitaxel (100 mg/m²) on days 1, 8, and 15, and carboplatin (area under the curve 5; 5 mg/mL per min) on day 1 of each 21-day cycle. This treatment continued for 4 cycles before patients were considered ready for surgery.

The trial’s primary end point was major pathological response, and the secondary end points were objective response, DFS, and overall survival.

“Our trial, together with ongoing randomized trials, provides more evidence on the risks and benefits of immunotherapy as a neoadjuvant treatment, and could help to answer questions regarding the optimal duration, best surrogate endpoint, and best predictive biomarkers for treatment,” the authors added.

Shu CA, Gainor JF, Awad MM, et al. Neoadjuvant atezolizumab and chemotherapy in patients with resectable non-small-cell lung cancer: an open-label, multicentre, single-arm, phase 2 trial. 

 Published online May 7, 2020. doi:10.1016/ S1470-2045(20)30140-6

"Our trial, together with ongoing randomized trials, provides more evidence on the risks and benefits of immunotherapy as a neoadjuvant treatment, and could help to answer questions regarding the optimal duration, best surrogate endpoint, and best predictive biomarkers for treatment."

Neoadjuvant Atezolizumab With Chemotherapy Feasible in Advanced NSCLC

Patients with chronic graft-versus-host-disease (GVHD) who received belumosudil (KD025) had clinically meaningful responses to treatment with belumosudil in the pivotal phase II ROCKstar (KD025-213) trial, according to top-line results announced by Kadmon Holdings, Inc.

Based on these primary analysis results, a New Drug Application is underway for submission to the FDA in the Real-Time oncology Review pilot program by the fourth quarter of 2020.

"Treatment with belumosudil has demonstrated compelling results for this major unmet medical need. Importantly, belumosudil has been very well tolerated, which allows trial participants to stay on therapy and achieve meaningful responses," said Madan Jagasia, MD, MS, MMHC, professor of Medicine, Vanderbilt University Medical Center. “These results demonstrate the potential of belumosudil to become a cornerstone of the cGVHD treatment paradigm if approved, as it delivers meaningful and sustained benefits to patients with this serious condition."

Belumosudil was administered on 2 different dosing schedules in the study, 200 mg once daily and 200 mg twice daily. The overall response rate (ORR) achieved with the once-daily dose was 73% (95% CI, 50%-83%; 

 <.0001). With the twice-daily dose of belumosudil, the ORR was 74% (95% CI, 62%-84%; 

 <.001). Treatment responses were observed across the various subgroups in the study.

In terms of durability, responses were maintained in 49% of patients for 20 weeks or more, at the time of the primary analysis. These data continue to mature, and the median duration of response has not yet been reached.

Overall, treatment with belumosudil was well-tolerated, and adverse events were consistent with prior reports. There were no occurrences of cytomegalovirus infection reactivation or drug-related cytopenias.

Results seen in the primary analysis are a slight improvement from the interim analysis results announced in February of 2020. At that time, the ORR was 64% (95% CI, 51%-75%, 

 <.0001) in patients who received the 200 mg once-daily dose of the drug and 67% (95% CI, 54%-78%; 

 <.0001) for the twice-daily group. The interim subgroup analysis showed responses across subgroups as well. In patients who had 4 or more organs affected by their disease, the ORR was 64%, in patients previously treated with ibrutinib (Imbruvica), the ORR was 62%, and in those who received prior ruxolitinib (Jakafi), the ORR was also 62%. Additionally, 3 patients achieved a complete response.

The open-label, randomized, multicenter ROCKstar trial accrued patients aged 12 years and older with chronic GVHD who have undergone allogeneic hematopoietic cell transplant, received 2 to 5 prior line of systemic therapy, who were receiving a stable dose of glucocorticoid therapy for 2 weeks prior to screening, a Karnofsky Performance Score of ≥ 60, and a weight of at least 40 kg. Patients with histological relapse of underlying cancer or post-transplant lymphoproliferative disease at screening, and those who were presently receiving ibrutinib (Imbruvica), were excluded from the study.

"The remarkable results achieved with belumosudil in this advanced patient population demonstrate its broad potential to offer meaningful clinical benefit to cGVHD patients," said Sanjay K. Aggarwal, MD, senior vice president, Clinical Development of Kadmon. "We look forward to sharing the full dataset from the ROCKstar study at an upcoming medical meeting.

Kadmon announces positive topline results of pivotal trial of belumosudil (kd025) in chronic graft-versus-host disease [news release]. New York, NY: Kadmon Holding, Inc; May 21, 2020. 

Kadmon announces expanded results of interim analysis of pivotal trial of kd025 in cgvhd [news release]. New York, NY: Kadmon Holding, Inc; February 23, 2020. 

"These results demonstrate the potential of belumosudil to become a cornerstone of the cGVHD treatment paradigm if approved, as it delivers meaningful and sustained benefits to patients with this serious condition."

Positive Responses With Belumosudil in GVHD Spark Pending FDA Submission

The addition of durvalumab (Imfinzi) to the only FDA-approved chemotherapy regimen of pemetrexed and cisplatin (Pem-Cis) improved overall survival (OS) in patients with malignant pleural mesothelioma, meeting the primary end point if the phase II PrE0505 study, announced PrECOG, LLC, in a press release.

“Durvalumab plus standard chemotherapy delivered a promising median overall survival rate for patients with previously untreated, inoperable malignant pleural mesothelioma,” said lead investigator Patrick Forde, MD, of Johns Hopkins University. “The data signal us to move forward with a phase three study.”

Data from PrE0505 will be highlighted during an oral presentation at the upcoming American Society of Oncology (ASCO) Virtual Annual Meeting, which will be held from May 29 to May 31.

The median OS in the durvalumab combination arm was 20.4 months compared with 12.2 months in the historical chemotherapy control arm (

 =.0014). At 12 months, the OS rate was 70.4%, and at 24 months, the OS rate was 44.2%.

At 6 months, the progression-free survival (PFS) was 69.1% with the addition of durvalumab. For 56.4% of patients (n = 31), the best response was a partial response, and 40% of participants (n = 22) had stable disease. There was 1 patient who progressed on treatment.

Durvalumab in combination with Pem-Cis was also well-tolerated in patients, and no new toxicities were observed. Most of the adverse events observed in the trial were grade 1 or 2 in severity.

In an exploratory analysis, tumor samples were examined for an association between PD-L1 expression and response, but no statistically significant associations were seen. The assessment did find a neoantigen-specific T-cell response in some patients.

PrE0505 is an interventional, non-randomized study ongoing at 15 clinical sites in the United States. The target enrollment of 55 patients has been reached. In the study, patients receive durvalumab at 1120 mg doses every 3 weeks for up to 6 cycles. Cisplatin is administered at 75 mg/m2 and pemetrexed is administered at 500 mg/ m2.

In some cases, cisplatin can be substituted with carboplatin in the event of toxicity. Patients have the option to switch to durvalumab until disease progression after completing 6 cycles of concurrent chemotherapy. Twelve months is the maximum duration allowed for treatment with durvalumab.

The secondary end points being explored in PrE0505 include safety and tolerability, PFS, and objective response rate.

To be eligible for the trial, patients are required to have histologically or cytologically confirmed malignant pleural mesothelioma, untestable disease, measurable disease with at least 1 lesion, and available archived tumor tissue samples. Fitness criteria included an ECOG performance status of 0 to 1 and adequate organ function.

Based on data from this study, the combination of durvalumab with Pem-Cis may advance to a phase III clinical trial.

“This is a remarkable result in mesothelioma, and warrants confirmation in a randomized phase three trial, which is already in the planning,” stated Peter J. O’Dwyer, MD, chief executive officer and chair, PrECOG, LLC.

Durvalumab added to standard chemotherapy improved overall survival in mesothelioma [new release]. Philadelphia, PA: PrECOG, LLC; May 20, 2020. 

"Durvalumab plus standard chemotherapy delivered a promising median overall survival rate for patients with previously untreated, inoperable malignant pleural mesothelioma."

Author | Nichole Tucker

Articles

Sacituzumab Govitecan Brings Long-Awaited Progress in the Treatment Landscape of mTNBC

Neoadjuvant Atezolizumab With Chemotherapy Feasible in Advanced NSCLC

Positive Responses With Belumosudil in GVHD Spark Pending FDA Submission

Durvalumab/Chemotherapy Combination Improves Survival in Mesothelioma