Investigators are optimistic about sacituzumab govitecan (IMMU-132), an antibody—drug conjugate that delivers the chemotherapy metabolite SN-38 to tumor cells expressing the TROP-2 receptor, for patients with relapsed/refractory triple-negative breast cancer (TNBC). The multicenter phase III ASCENT trial (NCT02574455) is currently recruiting patients previously treated with at least 2 systemic chemotherapy regimens.

The response rates for standard chemotherapy treatments are low in metastatic TNBC (mTNBC), and clinically there is an unmet need for better therapies, according to Aditya Bardia, MD, MPH, ASCENT’s lead author and director of Precision Medicine at the Center for Breast Cancer, Massachusetts General Hospital Cancer Center, Harvard Medical School, in Boston.

Sacituzumab govitecan combines SN-38, the active metabolite of irinotecan, with a humanized immunoglobulin G antibody targeted against TROP-2, a glycoprotein expressed on more than 90% of TNBC tumors. The conjugate can deliver a higher dose of SN-38 than can be achieved with irinotecan, according to Bardia.

Impressive phase II results, presented at the 2017 San Antonio Breast Cancer Symposium (SABCS), prompted the FDA in July 2018 to grant a priority review designation to a biologics license application for sacituzumab govitecan for mTNBC following at least 2 prior therapies for metastatic disease.

Sacituzumab govitecan elicited an objective response rate (ORR) of 34% in patients with heavily pretreated mTNBC. In the single-arm trial, the ORR was accompanied by stable disease for ≥6 months in 11% of patients, for an overall disease control rate of 45%. The median progression-free survival (PFS) with sacituzumab govitecan was 5.5 months (95% CI, 4.8-6.6) and the median overall survival (OS) was 12.7 months (95% CI, 10.8-13.6).

In the study presented by Bardia at SABCS, 57 patients had moderate (2+) to strong (3+) TROP-2 expression by immunohistochemistry and 5 had weak or absent staining for the marker. Data were not available for the remaining patients.

The study included 110 patients with a median age of 55 years (range, 31-81). Sacituzumab govitecan was administered at 10 mg/kg on days 1 and 8 of each 28-day cycle, which is the same dose being used in the phase III study. Patients had received a median of 14.5 doses of the medication (range, 1-88) and the median duration of treatment was 4.9 months (range, 0.2-32.1).

The patients’ ECOG performance status was 0 (30%) and 1 (70%), and the median time from metastatic diagnosis to treatment in the study was 1.5 years. Forty-one percent of patients were treated in the third-line setting and 59% were in the fourth line or greater. The most common prior therapies were taxanes (98%), anthracyclines (86%), cyclophosphamide (85%), and platinum agents (75%). Additionally, 17% of patients had received an immune checkpoint inhibitor. Most patients had visceral metastases (80%).

By blinded independent central review, the ORR was 31%, which confirmed findings seen in the local assessment, Bardia said. By local assessment, there were 3 complete responses (CRs) and 34 partial responses (PRs). There were 6 CRs and 28 PRs in the blinded review. A target lesion reduction was seen in approximately 74% of patients, suggesting that most patients experienced some type of response to the medication.

Sacituzumab govitecan is “like a smart bomb, because the drugs are delivered directly into the tumor. So, with this particular drug, when you attach it to an antibody straight to the tumor, you actually deliver 7-and-a-half times more drug than you’d normally be able to give. That’s the reason why we’ve seen such good results so far,” said Linda Vahdat, MD, chief of Medical Oncology and clinical director of Cancer Services at Norwalk Hospital, Connecticut, and a lead investigator in the trial. She also sees patients at Memorial Sloan Kettering Cancer Center in New York.

“We have worked with this drug for a long time,” said Vahdat. “I was [previously] with the Breast Center at Weill Cornell Medicine and we did all of the baseline work on this drug, not just in breast cancer. We were the first to identify that it was particularly active in TNBC and also in small cell lung cancer and bladder cancer.”

Figure. Ascent Phase III Study Testing Sacituzumab Govitecan in TNBC

In ASCENT, patients will be randomized to 10 mg/kg sacituzumab govitecan on days 1 and 8 of 21-day cycles versus treatment of physician’s choice: eribulin, capecitabine, gemcitabine, or vinorelbine (

 Projected enrollment is 488 from among 150 institutions in North America and Europe. Treatment will continue until progression, unacceptable toxicity, study withdrawal, or death. Follow-up is every 4 weeks during the first year and every 8 weeks thereafter. The primary outcome measure is PFS, and secondary measures are OS, ORR, and duration of response.

 “We ultimately want to see good shrinkage of the tumor,” said Vahdat. “TNBC involves big tumors that are aggressive, so we [also] want responses to be durable.”

Vahdat said that getting the word out about the study has been the biggest challenge in getting patients interested in participating. “The study actually has been very easy to accrue because [sacituzumab govitecan] is a very active drug and patients with TNBC tend to be good advocates for themselves,” she said. “They understand that it’s useful to them to have new drugs.”

Bardia A, Vahdat LT, Diamond J, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody—drug conjugate, as ≥3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer (mTNBC): efficacy results. Presented at: 2017 San Antonio Breast Cancer Symposium; San Antonio, Texas, December 5-9, 2017. Abstract GS1-07.

ASCENT: study of sacituzumab govitecan in refractory/relapsed triple-negative breast cancer (ASCENT). clinicaltrials.gov/ct2/show/NCT02574455?term=immu-132&rank=5. Updated August 8, 2018. Accessed November 15, 2018.

Articles

Investigators are optimistic about sacituzumab govitecan (IMMU-132), an antibody–drug conjugate that delivers the chemotherapy metabolite SN-38 to tumor cells expressing the TROP-2 receptor, for patients with relapsed/refractory TNBC. 

Novel Antibody-Drug Conjugate Enters Phase III Trial for Metastatic TNBC

Although long-term remissions are common in patients with hairy cell leukemia (HCL) who are treated with standard therapies, there remains an unmet need for novel agents that can eradicate the disease without excessive myelosuppression, according to Robert J. Kreitman, MD.

Kreitman and colleagues have spent more than decade investigating the potential of moxetumomab pasudotox-tdfk (Lumoxiti) in HCL. In September, the FDA approved the drug for treating adults with relapsed or refractory HCL who have received at least 2 prior systemic therapies.

 Please explain the mechanism of action of moxetumomab pasudotox.

, Kreitman discussed key attributes of moxetumomab pasudotox and its potential impact in HCL. He is a senior investigator in the Laboratory of Molecular Biology and head of the Clinical Immunotherapy Section at the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland.

 Moxetumomab pasudotox is an engineered protein drug—not a chemical&mdash; made up of a fragment of an antibody that binds to CD22 as well as a fragment of a toxin that’s made by 

 bacteria. This purifies chimeric protein because it’s made up of 2 parts. One part of the drug binds to the hairy cell and allows the drug to go inside the cancer cell, while the bacteria enters the hairy cell and kills it. It does that through the same mechanism that any bacteria uses to kill a cell, so it’s highly potent.

When we treat patients with HCL with this drug, we can get complete remissions in those who have not had good responses with chemotherapy and it’s because this is a different mechanism of killing.

What is the current prognosis for patients with HCL?

How do patients tolerate moxetumomab pasudotox?

The ultimate goal of the trial was to achieve complete remission with a resolution of normal blood counts, as blood counts are often low in patients with HCL at baseline. Patients who were minimal residual disease [MRD]—positive achieved complete remissions that lasted a median of 5.9 months, but investigators observed a significantly prolonged median duration of response for those who were MRD-negative by comparison.

While many patients with HCL experience a remission with current treatments, 30% to 40% will relapse 5 to 10 years after their first treatment. With subsequent treatments, durations of response diminish and toxicities accumulate, and few approved treatment options exist. Moxetumomab pasudotox represents a promising nonchemotherapeutic agent for HCL.

For patients with HCL, this is a very good drug. Patients need to be able to drink plenty of water and plenty of fluids to keep them feeling healthy during the time that they’re getting the drug, but most patients say that this drug is a walk in the park compared with chemotherapy or even rituximab [Rituxan], where there are significant infusion toxicities. We also can use very low doses of dexamethasone, a steroid, to treat fever, which sometimes arises in some patients.

Dexamethasone can also be used to treat nausea, which can occur in a minority of patients. So with those tools, it’s actually very easy to administer, and patients tolerate it very well. What they like most about it is that they have complete remission—they have no traces of HCL in most cases, and they can come back to see us very infrequently. We have some patients who come back only every 2 years to be examined and make sure they are still in complete remission, and they don’t need any treatment in the meantime.

The complete response rate during the trial was the most meaningful finding. There were 41% of patients who had a complete response rate, and 34% of those patients had MRD-negative complete remission, which means that we couldn’t find any traces of hairy cells using highly sensitive techniques.

Robert J. Kreitman, MD, discusses key attributes of moxetumomab pasudotox and its potential impact in hairy cell leukemia.

New Hairy Cell Leukemia Therapy Aims to Produce Complete Remissions

There is limited data on when and whether oncologists should change systemic therapy for patients with non—small cell lung cancer (NSCLC), but some studies provide useful guidance, Steven Vogl, MD, said at the 2018 New York Lung Cancers Symposium.

A key question is whether to continue a PD-1 inhibitor if a patient is doing well after 1 year, said Vogl, a medical oncologist with Montefiore Medical Center. “We all know there are some patients who get toxicity on PD-1 treatment, and we stop the PD-1 drug and they do okay.”

In CheckMate 153, Spigel et al examined the value of stopping treatment with a PD-1/PD-L1 inhibitor after 1 year as opposed to continuing for patients with advanced, previously treated NSCLC. The randomized trial found that patients who received continuous treatment with nivolumab (Opdivo) experienced superior progression-free survival (PFS) at 6 months (80% vs 69%) and 1 year (69% vs 40%). The hazard ratio was 0.42 (95% CI, 0.25-0.71).

Overall survival (OS) was also superior for the patients who continued treatment. At 1 year, OS was 88% for the continuous treatment cohort versus 81% for the treatment cessation group (HR, 0.63; 95% CI, 0.33-1.20).

More data would be desirable on whether to continue treatment in this setting, but based on CheckMate 153, the answer is, “Yes,” Vogl said. “There are a lot of things going on with these patients. You’re affecting the immune system; some people need the drug, and some don’t. Some patients’ immune systems are weakened, and they don’t have further options, and some of the tumors may have adapted to the immune liberation that we’ve induced with the PD-1 drug. Although there’s a lot we don’t know, what we do have is this study that outlines whether we stop or not,” Vogl said.

A related question is whether to continue targeted therapy without other therapy for asymptomatic slow progression, and the ASPIRATION trial sheds light on this issue, he said. The multicenter, phase II single-arm study enrolled 207 adults with stage IV EGFR-positive NSCLC and an ECOG performance status of 0 to 2. Patients received erlotinib (Tarceva) at 150 mg daily.

The study protocol suggested not continuing treatment post-progression for symptomatic extracranial progression, rapid progression, worsening performance status, or life-threatening complications. Those who continued were likely to have recurrent disease, new brain lesions, longer median time to progression, improved response, or longer time from best response to progression.

Among 93 patients who continued post-progression, the median continuation on erlotinib was 3.1 months. The median OS for those who continued was 33.6 months (95% CI, 27.3-34.3) versus 22.5 months (95% CI, 20.1-27.0) for those who did not continue. Sicker patients were more likely to stop, which partly explains the superior OS.

The findings from ASPIRATION do not provide a clear answer of whether to continue on TKI in the setting of asymptomatic slow progression, so the answer is, “Maybe,” Vogl said. “I would love to find out how these patients—the ones who lived 3 months longer&mdash;did in terms of symptoms. I would love to know how long the interval was between the first sign of progression and the time they progressed again. There’s some heterogeneity and there were some patients who might have gotten a year out of it…they’re the ones I would try this with.” Unfortunately, data on who those patients were not available, he noted.

Further questions from Vogl’s presentation addressed whether to continue TKI targeted therapy in conjunction with chemotherapy following progression on targeted therapy. Existing data suggest that further study of this question could be useful. The phase III IMPRESS trial tried the strategy of continuing EGFR TKI therapy at disease progression, randomizing patients to continue gefitinib (Iressa) plus platinum-based chemotherapy or chemotherapy alone. No synergy was noted between gefitinib beyond progression plus chemotherapy.

However, the phase III NEJ009 found “very impressive” advantages for the combination of gefitinib, carboplatin, and pemetrexed (GCP) compared with gefitinib monotherapy among patients with advanced 

-positive NSCLC. OS among patients treated with GCP was 52.2 months versus 38.8 months (HR, 0.695; 

 = .013). The ORR was 84.0% vs 67.4% in the combination group as opposed to the monotherapy group.

“This raises important questions about whether chemotherapy should accompany TKIs in the first line or any line. These require study,” according to Vogl.

Spigel D, McLeod M, Hussein M, et al. Randomized results of fixed-duration (1-yr) vs continuous nivolumab in patients (pts) with advanced non-small cell lung cancer (NSCLC). 

. 2017;28(suppl_5). doi: 10.1093/annonc/mdx380.002.

Park K, Yu C, Kim S, et al. First-Line Erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation—positive non–small-cell lung cancer: the ASPIRATION study. 

. 2016;2(3):305-312. doi: 10.1001/jamaoncol.2015.4921

Nakamura A, Inoue A, Morita S, et al. Phase III study comparing gefitinib monotherapy (G) to combination therapy with gefitinib, carboplatin, and pemetrexed (GCP) for untreated patients (pts) with advanced non-small cell lung cancer (NSCLC) with EGFR mutations (NEJ009). 

There is limited data on when and whether oncologists should change systemic therapy for patients with non–small cell lung cancer, but some studies provide useful guidance.

Vince Calio

Articles

Novel Antibody-Drug Conjugate Enters Phase III Trial for Metastatic TNBC

New Hairy Cell Leukemia Therapy Aims to Produce Complete Remissions

More Data Needed on Changing Systemic Therapy in NSCLC