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Hope S. Rugo, MD:
In this commentary, I discuss a case from my own practice to illustrate my thinking when considering first-line therapy with atezolizumab plus nab-paclitaxel, a new standard of care for patients with PD-L1–positive metastatic TNBC that was approved based on the phase III IMpassion 130 trial.
Case Study: Atezolizumab Plus nab-Paclitaxel in the Treatment of a Patient With Relapsed TNBC
Diagnosis and Treatment for Early-Stage TNBC
In February 2015, a 57-year-old woman presented in my clinic with a mass in her right breast. Imaging and a core biopsy led to a diagnosis of grade 3, ER/PgR-negative, and HER2-equivocal (IHC 2+) invasive ductal carcinoma. FISH testing showed no evidence of HER2 gene amplification, with a HER2 copy number of 2.1. A subsequent lumpectomy and sentinel lymph node biopsy showed a 2.1-cm grade 3 invasive ductal cancer, confirmed to be triple negative, and 1 negative sentinel node. She was then treated with adjuvant dose-dense doxorubicin/cyclophosphamide followed by paclitaxel and radiation therapy, which she tolerated very well.
Diagnosis and Treatment for Colon Adenocarcinoma Revealed Metastatic TNBC
In October 2018, a standard screening colonoscopy showed a small mass that was positive for a primary adenocarcinoma of the colon. A chest x-ray done in preparation for surgery was concerning for lung nodules, with a subsequent CT scan showing a 1.6-cm nodule in her lower left lung lobe along with bilateral mediastinal adenopathy (largest lymph node: subcarinal, 1.7 cm).
A resection of her sigmoid colon identified a 6-cm grade 2 carcinoma with invasion into the muscularis and pericolic tissue, along with 19 negative lymph nodes. PET/CT imaging following her recovery from surgery showed hypermetabolic mediastinal adenopathy. The largest lymph node was now 2.6 cm and the previously identified lung nodule was 1.3 cm with an SUV of 15. In addition, a 1.5-cm thyroid nodule picked up radiolabeled glucose on PET/CT.
In January 2019, a bronchoscopic core biopsy of a mediastinal lymph node revealed a high-grade carcinoma (GABA3 positive, ER/PgR negative, HER2 negative), which was consistent with metastatic TNBC. No colon adenocarcinoma was evident.
First-line Treatment for Metastatic TNBC
Her tumor biopsy was sent for biomarker testing. PD-L1 testing using the SP142 antibody assay was positive for PD-L1 in immune cells. Broad-based next-generation sequencing testing showed a low tumor mutational burden and stable microsatellites.
Because her tumor biopsy was PD-L1 positive, she was treated with weekly nab-paclitaxel (100 mg/m2; 3 weeks on, 1 week off) in combination with atezolizumab every 2 weeks. Her first follow-up PET/CT scan 4 months after starting treatment showed a significant reduction in the size of the lower left pulmonary nodule, now just 4 mm and no longer hypermetabolic, and complete resolution of her hypermetabolic mediastinal adenopathy. She continued on treatment and her next PET/CT scan showed no hypermetabolic foci to suggest metastatic disease. Continued follow-up of her colon cancer showed no anastomosis abnormalities; likewise, a colonoscopy showed no abnormalities.
In July 2019, her nab-paclitaxel dose was reduced to 80 mg/m2 due to fatigue and grade 2 peripheral neuropathy that was painful at night, particularly in her feet, despite the use of gabapentin. In September 2019, after 8 cycles of nab-paclitaxel, a PET/CT scan showed no residual or recurrent metastatic disease. She continued on atezolizumab alone every 2 weeks.
In October 2019, the patient reported multiple loose stools per day. With consideration of immune-related colitis in mind, I quickly referred her to gastroenterology where she underwent a colonoscopy. The colonoscopy showed no visual abnormalities, and several blind biopsies showed no evidence of inflammatory disease. I concluded that if she did have immune colitis, it was very mild. A dietary change to consume less high-fiber food resolved her diarrhea and she now has a baseline of 2-3 loose stools per day. Her weight is stable and she is able to eat well as long as she avoids certain foods.
A PET/CT scan in November 2019 again showed no evidence of residual or recurrent metastatic disease. She continues to do extremely well, with less fatigue and resolution of her peripheral neuropathy to grade 1. We plan to continue atezolizumab monotherapy for the foreseeable future. She would prefer not to have to come in every 2 weeks for her infusion but understands its importance to her ongoing care.
Considerations for PD-L1 Testing
The VENTANA PD-L1 SP142 IHC companion diagnostic assay was approved by the FDA to identify patients with PD-L1–positive tumors most likely to respond to treatment with atezolizumab plus nab-paclitaxel. Of importance, tumor PD-L1 positivity in this assay is based on PD-L1 expression in tumor-infiltrating immune cells (lymphocytes, macrophages, dendritic cells, granulocytes). For atezolizumab to be prescribed, the SP142 assay must show PD-L1 staining of any intensity in tumor-infiltrating cells covering ≥ 1% of tumor area.
That said, clinicians may be using alternate PD-L1 expression assays (eg, the PD-L1 IHC 22C3 pharmDx assay or the VENTANA PD-L1 SP263 assay) due to what they have available at their institution or, as is the case for the European Medicines Agency approval of atezolizumab for metastatic TNBC, because a specific PD-L1 assay is not specified. In a recent exploratory, post hoc analysis using samples from IMpassion130 to evaluate the performance of available PD-L1 IHC assays, it was shown that the 22C3 and SP263 assays are not concordant with the SP142 assay. Instead, they identify more patients with PD-L1–positive tumors than the SP142 assay, but with the population positive for PD-L1 by SP142 being nested within the PD-L1–positive populations by 22C3 and SP263. Thus, even though the 22C3 and SP263 assays are not clinically validated to select patients with metastatic TNBC for treatment with combination chemoimmunotherapy, I am confident they do capture those patients who will benefit with treatment with atezolizumab plus nab-paclitaxel, with the caveat that these assays will also identify additional patients as PD-L1 positive who will not benefit from this regimen.
Considerations for Patient Selection
Most patients with newly diagnosed metastatic TNBC and ≥ 1% PD-L1 tumor expression should be offered atezolizumab plus nab-paclitaxel, the new standard of care in this setting. Based on IMpassion130, this represents approximately 40% of the TNBC population.[4,5] However, there are some instances where this therapeutic decision presents a challenge.
First, we do not know if treatment with checkpoint inhibitor therapy will be effective in patients who relapse within 6 months of treatment for early-stage TNBC. I would still be inclined to try atezolizumab plus nab-paclitaxel in such a patient whose tumor tested positive for PD-L1 because their treatment options are very limited, and their prognosis is generally quite poor.
Second, for patients who have relapsed within a year of neoadjuvant or adjuvant treatment including a taxane for early-stage disease, we run into the issue of the indication for atezolizumab in the metastatic setting being in combination with nab-paclitaxel but it not being advisable to retreat this group of patients with a taxane. For insight on whether immune checkpoint inhibitors can be combined with other chemotherapy backbones as first-line therapy for relapsed TNBC, we eagerly await the presentation of results from the phase III KEYNOTE-355 study evaluating the addition of pembrolizumab to physician’s choice of chemotherapy, including nab-paclitaxel, paclitaxel, or the taxane-free regimen of gemcitabine/carboplatin, in patients who relapsed ≥ 6 months after completion of treatment for early-stage TNBC. I anticipate that data from this trial will soon give us confidence that atezolizumab in combination with alternate chemotherapy regimens such as gemcitabine/carboplatin will still achieve benefit in our patients. Combining atezolizumab with capecitabine, another option to avoid retreatment with a taxane, is also currently being investigated in the phase III IMpassion132 study.
Finally, because patients enrolled on IMpassion130 had not received previous therapy in the metastatic setting, it is unknown whether checkpoint inhibition would be effective in later-line settings.
Clinical Pearls for Optimal Integration of Immunotherapy Into the Treatment of Metastatic TNBC
Duration of Immune Checkpoint Inhibitor Therapy
The optimal duration of immune checkpoint inhibitor therapy is still being determined for metastatic TNBC. In studies of the PD-1 inhibitor pembrolizumab, treatment was stopped at 2 years. In IMpassion130, treatment was continued until disease progression.[4,5] For the case patient, we chose to continue treatment without stopping, at least for the time being. However, in the long run, I anticipate that immunotherapy will be similar to treatments for HER2-positive breast cancer where we stop treatment at some point—we just do not know when. My hope is that we will gain insights from our colleagues in other tumor settings where immune checkpoint inhibitor therapy has been in use for a much longer period of time.
Although immune-related AEs are relatively uncommon, clinicians must maintain a high level of suspicion for these toxicities and remember that they can affect any organ. For more information on management of immune-related AEs with immune checkpoint inhibition therapy in metastatic TNBC, please see the companion commentary by my colleague Sarah Donahue, MPH, NP, here.
Treatment After Progression on Atezolizumab
For patients with TNBC who progress on atezolizumab, there is a menu of chemotherapy options to pursue. However, considering that their expected survival following progression is so short and that we as clinicians want to offer the best possible option for our patients, I really encourage consideration of clinical trial participation for patients with metastatic TNBC who progress on chemoimmunotherapy.
Furthermore, we are hopeful about the prospect of the FDA approving some new agents as late-line therapy for metastatic TNBC. In fact, the antibody–drug conjugate sacituzumab govitecan recently was given accelerated approval by the FDA for adult patients with metastatic TNBC who have received at least 2 previous therapies for metastatic disease based on durable responses with good tolerability in a phase I/II trial.[9,10] A phase III study of sacituzumab govitecan vs physician’s choice of chemotherapy in relapsed/refractory TNBC is underway.
The antibody–drug conjugate trastuzumab deruxtecan (T-DXd), recently approved by the FDA for the treatment of HER2-positive metastatic breast cancer after at least 2 previous HER2-targeted regimens, is also being evaluated in patients with so-called HER2-low breast cancer (ie, IHC 1+ or 2+ with no FISH amplification), a group that can include patients with TNBC. The phase III DESTINY-Breast04 study is comparing T-DXd in patients with previously treated HER2-low unresectable or metastatic breast cancer, including a limited group of patients with metastatic TNBC. We will be looking with interest to see how the patients with TNBC respond.
My primary message to clinicians who treat patients with breast cancer is to consider clinical trials for all of your patients with metastatic TNBC. To date, atezolizumab plus nab-paclitaxel is the sole treatment for metastatic TNBC that can provide long-term disease stabilization and improved OS, but this is only in patients with PD-L1–positive disease and, at that, does not work perfectly well in all patients. Furthermore, this regimen has not been effective in patients with PD-L1–negative disease at all. Therefore, clinical trials are focused on finding ways, such as with combination or sequential therapy, to stimulate the immune response in these patients. Furthermore, because metastatic TNBC becomes increasingly unresponsive to immunotherapy as it progresses, it is important to enroll patients on these trials as early in the disease management process as possible, preferably in the first-line or second-line settings.
For more information on trials evaluating ways to reduce resistance to immunotherapy in the metastatic setting as well as on efforts to move immunotherapy into earlier settings for TNBC, please remember to come back to the CCO Web site and check here for additional companion commentaries covering these topics.