|Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer
Bardia A et al., J Clin Oncol. 2017 Jul 1;35(19):2141-2148.
PubMed ID: 28291390
TNBC treatment is challenging due to the aggressive nature of the disease and limited therapies compared to other breast cancer subtypes. Trop-2 is an oncogenic glycoprotein found to be overexpressed in malignancies including breast cancer and is a potential target for novel therapy.
Sacituzumab govitecan is an antibody-drug conjugate consisting of SN-38 which is 100 to 1,000x more potent than its prodrug, irinotecan. In a phase 1 trial, sacituzumab govitecan demonstrated clinical activity in unselected patients with solid malignancies including breast cancer. This prompted further investigation, the results of which are summarized below for the mTNBC cohort.
- Patients: histologically confirmed mTNBC refractory or relapsed to at least one prior line of therapy, ECOG 0-1, stable brain mets
- Study design: phase 1/II basket design, single-arm trial
- sacituzumab govitecan 10 mg/kg IV day 1 and 8 q21 day cycle
- Primary: Safety
- Secondary: ORR, DOR, TTP, PFS, OS
- 69 patients enrolled (68 females, 1 male)
- Baseline patient characteristics: median age 56 yrs., 83% white, 67% ECOG 1, 36% stage 2 at initial diagnosis, median number of prior therapies: 5, 97% prior taxane, 91% prior cyclophosphamide, 84% prior anthracycline, 4 patients with prior anti PD-1/anti PD-L1 inhibitor, 62% lymph node mets, 51% lung mets
Table 1: Efficacy Outcomes
- 3 patients out of 4 who received prior immune checkpoint inhibitor achieved PR
Table 2: Tumor response by BRCA1 status (n=43)
- Safety (only device-related adverse events)
- Grade ≥3 adverse events: 41%
- Most common grade ≥3 adverse events: neutropenia (39%), leukopenia (16%) anemia (14%), diarrhea (13%)
- 3 patients discontinued treatment due to toxicity
- 35% had dose reductions mainly due to neutropenia
- No treatment-related deaths were reported
- No neutralizing antibodies were observed for SN-38 drug and antibody
- Trop-2 Staining
- 48 patients had archival tumor samples of which 42 (88%) had moderate (2+) to strong (3+) staining; majority expressed Trop-2 in >50% tumor cells
- Responders had moderate to strong Trop-2 staining while weak or non-responders had SD as best response.
- Patients with moderate to strong Trop-2 staining had a trend towards better PFS compared to weak or Trop-2 negative staining (7.1 mos. vs. 3.1 mos.; p=0.019)
- In this small study of heavily pretreated mTNBC patients, sacituzumab govitecan provided rapid and durable clinical responses and prolonged survival at a median follow-up of 16.6 mos.
- Tumor responses occurred early at a median of 1.6 mos. and were noted in at least 30%. OS was extended to 16.6 mos. and is comparable with standard 2nd line treatment in mTNBC.
- Hematologic toxicity was commonly observed with sacituzumab govitecan, particularly neutropenia, which resulted in dose reduction in a third of the study population. Febrile neutropenia was reported in 7% and most adverse events were well tolerated. The incidence of high grade diarrhea was significantly less than that reported in trials on irinotecan. Neutralizing antibodies were not detected during the study and no treatment-related fatalities occurred.
- Three patients who previously received immune checkpoint inhibitor achieved PR with sacituzumab govitecan. This finding suggests continued response to treatment with sacituzumab govitecan after failing multiple therapies (median of 5) and the possible absence of crosstalk between PD-1/PD-L1 and Trop-2 signaling pathways.
- Subgroup analysis looking at BRCA1 status revealed better responses in the wild-type subgroup. Trop-2 staining analysis suggested a possible correlation with Trop-2 staining and clinical outcomes. Tumors with stronger Trop-2 staining appeared to have better tumor response and survival. However, these findings are merely suggestive and hypothesis-generating due to the small sample size.
- Other antibody-drug conjugates currently under investigation in mTNBC include SGN-LIV1A antibody conjugated to monomethyl auristatin. This combination targets the LIV-1 antigen, a zinc transporter expressed in about 80% of breast cancer; a phase 1/II trial is currently ongoing (ClinicalTrials.gov identifier: NCT01969643).
- Another drug conjugated to monomethyl auristatin is glembatumumab vedotin that targets glycopreotein NMB (gpNMB), a negative prognostic marker overexpressed in malignancies like breast cancer. In the phase II EMERGE study, women with refractory breast cancer and gpNMB expression ≥5% in epithelial or stomal cells were randomized to glembatumumab vedotin vs. investigator's choice (J Clin Oncol. 2015;33:1609-19). In the TNBC cohort ORR was better with glembatumumab vedotin vs. investigator's choice (8% vs. 0%). In gpNMB overexpressing tumors, ORR was 40% vs. 0% in favour of glembatumumab vedotin.
- The antibody-drug conjugate formulation of sacituzumab govitecan allowed for the effective delivery of highly toxic SN-38 resulting in good antitumor activity without significantly increasing toxicity. This novel drug demonstrated clinical efficacy and a tolerable safety profile in heavily pretreated mTNBC and warrants further investigation in larger head to head trials comparing it with standard treatment.
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Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma
Bellmunt J et al., N Engl J Med. 2017 Mar 16;376(11):1015-1026.
PubMed ID: 28212060
Pembrolizumab is an anti-PD-1 monoclonal antibody that demonstrated antiumor activity in advanced urothelial carinoma in phase I and II studies. To further investigate its efficacy and safety, researchers conducted the KEYNOTE 045 trial to compare pembrolizumab with chemotherapy as 2nd line treatment.
- Patients: Histologically confirmed advanced urothelial carcinoma (renal pelvis, bladder, ureter, urethra) with predominantly transitional cell features and progressed on platinum-based chemotherapy (advanced disease or neoadjuvant for muscle-invasive disease), ECOG 0-2
- Study design: Phase III open-label RCT
- Experimental: Pembrolizumab 200mg IV q3w
- Control: Investigator's choice, Paclitaxel 175 mg/m2 IV, or Docetaxel 75 mg/m2 IV or Vinflunine 320 mg/m2 IV q3w
- Primary: PFS, OS (PD-L1 expression ≥10%)
- Secondary: ORR, TTR, DOR, safety
- 542 patients randomized to pembrolizumab (n=270) and investigator's choice (n=272)
- 164 patients (30.3%) with combined tumor PD-L1 combined positive score ≥10%
- Baseline patient characteristics: median age 66 yrs., 556% ECOG 1, 65% current/former smoker, 71% pure transitional-cell histology, 86% bladder or urethra primary site, 88% visceral disease, 34% liver metastases, 16% Hgb <10g/dl, 35% with 1 Bellmunt risk factor
Table 1: Efficacy Outcomes
- OS advantage was observed with pembrolizumab in all prespecified subgroups, including patients with <1% combined PD-L1 expression score.
- Most common any grade adverse events with pembrolizumab: pruritus (19.5%), fatigue (13.9%), nausea (10.9%)
- Most common any grade adverse events with chemotherapy: alopecia (37.6%), fatigue (27.8%), anemia (24.7%)
- Most common grade 3-4 adverse events with pembrolizumab: pneumonitis (2.3%), colitis (1.1%), diarrhea (1.1%), nephritis (0.8%)
- One patient on pembrolizumab developed grade 5 pneumonitis.
- Most common grade 3-5 adverse events with chemotherapy: neutropenia (13.3%), decreased neutrophil count (12.2%), anemia (7.8%), febrile neutropenia (7.1%, decreased white cell count (5.1%)
Table 2: Adverse Event and Treatment Summary
- At a median follow-up of 14.1 mos., pembrolizumab significantly prolonged OS compared to investigator's choice (paclitaxel, docetaxel or vinflunine) in advanced urothelial carcinoma after progression on platinum-based chemotherapy. OS advantage was spread across all prespecified subgroups, including patients with combined tumor PD-L1 score of <1%. The greatest magnitude of benefit was observed in the subgroup with combined tumor PD-L1 score ≥10%. Pembrolizumab reduced the risk of death by 47% in this subgroup.
- No difference in PFS was observed between pembrolizumab and chemotherapy. This is consistent with results from studies of anti-PD-1 and anti-PD-L1 antibodies in other solid malignancies and suggests that PFS may not be the best surrogate endpoint in assessing response to immunotherapy. Moreover, it is possible that patients have pseudo progression and may continue to derive clinical benefit however it is unknown how often this occurs.
- Response rate doubled with pembrolizumab compared to chemotherapy. Although TTR was similar in both arms, pembrolizumab provided longer more durable responses.
- Chemotherapy was associated with higher rates of adverse events, particularly hematologic events. Grade 3-5 immune-mediated adverse events occurred in less than 5% of patients on pembrolizumab.
- In a single arm phase II study of atezolizumab, 15% achieved ORR after disease progression on platinum-based chemotherapy (Lancet 2016;387: 1909–20). Higher immune cell PD-L1 expression was associated with higher response rate, but not tumor cell PD-L1 expression.
- Similarly, in patients with advanced urothelial cancer who received 2nd line nivolumab, tumor response was observed in 19.6%, with 8.74 mos. OS (Lancet Oncol 2017;18:312.322). These findings are similar with KEYNOTE 045.
- In summary, pembrolizumab demonstrated superiority over chemotherapy as 2nd line treatment in advanced urothelial cancer after failing platinum-based chemotherapy. Durable responses and manageable safety profile provide better therapeutic index over conventional chemotherapeutic regimens. This is the first study to demonstrate OS benefit in the 2nd line setting. Pembrolizumab is another addition to nivolumab and atezolizumab as a treatment option in these patients.
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