P1, N=42, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Trial primary completion date: Apr 2028 --> Apr 2038

P1/2, N=51, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting

P1, N=54, Recruiting, M.D. Anderson Cancer Center | Not yet recruiting --> Recruiting | Initiation date: Mar 2024 --> Oct 2023

P1, N=54, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=48, Recruiting, Myeloid Therapeutics | Not yet recruiting --> Recruiting

P1, N=48, Not yet recruiting, Myeloid Therapeutics

P1/2, N=51, Not yet recruiting, M.D. Anderson Cancer Center

These results suggest that Dato-DXd may stimulate tumor immunity and sensitize tumors to PD-1/PD-L1 inhibitors. The combination of Dato-DXd and PD-1/PD-L1 blockers could be a valuable therapy for patients with TROP2-positive tumors.

Culture supernatant of Veillonella parvula NCTC11810 promoted the apoptosis and inhibited the proliferation and invasion ability of HN6 cells, while sodium propionate (SP), the main metabolite of Veillonella parvula NCTC11810, played a similar role through the inhibition of TROP2/PI3K/Akt pathway. Studies above supported the proliferation-inhibiting, invasion-inhibiting, and apoptosis-promoting function of Veillonella parvula NCTC11810 in OSCC cells which provided new insights into oral microbiota and their metabolite as a therapeutic method for OSCC patients with TROP2 high expressing.

A quality-of-life (QoL) analysis from IMPassion031 showed that adding atezolizumab to neoadjuvant chemotherapy was not associated with a detrimental effect on QoL, while the burden of treatment-induced side effects increased with each cycle of neoadjuvant therapy in both treatment arms. KEYNOTE-355 evaluated the addition of pembrolizumab to chemotherapy as first-line treatment in metastatic TNBC (mTNBC); a significant improvement of progression-free survival (PFS) was reported in the pembrolizumab arm...Disappointingly, the phase III IPATunity130 study could not confirm a PFS improvement with the AKT inhibitor ipatasertib when added to paclitaxel as first-line treatment in mTNBC. A biomarker analysis from the phase III ASCENT study showed that the antibody-drug conjugate sacituzumab govitecan was superior to chemotherapy by investigator's choice independent of Trop‑2 expression and BRCA mutation status...The HER2-specific tyrosine kinase inhibitor tucatinib when added to trastuzumab and capecitabine was shown to improve PFS and overall survival (OS) over trastuzumab and capecitabine alone in pretreated patients in the randomized HER2CLIMB trial; this benefit was apparently independent of hormone-receptor expression. An update from the DESTINY-Breast01 trial reported a median PFS of 19.4 months with trastuzumab deruxtecan in heavily pretreated patients. Finally, an analysis from the PERTAIN trial with > 6 years median follow-up showed excellent OS in patients with luminal B/HER2-positive receiving first-line trastuzumab/pertuzumab in combination with endocrine therapy suggesting that chemotherapy-free treatment is an option in highly selected patients.

Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate that contains the irinotecan active metabolite, SN-38, linked to a humanized monoclonal antibody targeting trophoblast cell surface antigen 2 (Trop-2), which is overexpressed in many solid tumors. Due to the rapid approval of sacituzumab govitecan, there is limited available information on adverse event (AE) management with this agent. As such, this article reviews the clinical development of the drug, the AE profile and provides recommendations regarding AE management to help optimize therapy with sacituzumab govitecan.

Sacituzumab govitecan, a conjugate of anti-Trop-2 antibody and SN-38 payload (an active metabolite of irinotecan), is the first in the class that has been clinically validated and approved by the Food and Drug Administration for the treatment of metastatic triple-negative breast (2020) and urothelial carcinomas (2021). In the current review, we summarize and critically appraise the most recent advances with Sacituzumab govitecan, emphasizing the predictive biomarker analysis.

TROP2 could have an important role in BCC and SCC pathogenesis. TROP2 targeting may have appraising effect in clinical application in BCC and SCC management.

Clinical, biologic and practical factors influencing the selection and sequencing of available therapies for patients with metastatic UBC Published efficacy and safety outcomes with atezolizumab or pembrolizumab in combination with chemotherapy as first-line therapy for patients with locally advanced or metastatic UBC Clinical implications of the recent withdrawal of atezolizumab from the treatment armamentarium for patients with pretreated UBC; negative survival results from the Phase III IMvigor211 trial Rationale for the FDA designation of the Phase III IMvigor130 trial evaluating atezolizumab with chemotherapy as the post-marketing requirement to confirm the atezolizumab’s clinical benefit in PD-L1-high advanced UBC Implications of the withdrawal of the durvalumab indication for pretreated patients with locally advanced or metastatic bladder cancer; final analysis of the results from the Phase III DANUBE trial Results from the Phase III JAVELIN Bladder 100 trial of first-line maintenance therapy with avelumab in combination with best supportive care (BSC) for patients with locally advanced or metastatic UBC; recent FDA approval of first-line avelumab maintenance Optimal approach to the management of patients who develop metastatic UBC on or after immune checkpoint inhibitor-based therapy for non-muscle invasive UBC or MIBC; clinical utility of rechallenging with an anti-PD-1/PD-L1 antibody in this setting Incidence of and biologic rationale for the use of targeted therapies directed at TROP2, nectin-4 or FGFR in progressive metastatic UBC Mechanism of action of and published data leading to the recent FDA approval of sacituzumab govitecan for patients with locally advanced or metastatic urothelial cancer who have received a platinum-based chemotherapy regimen and a PD-1/PD-L1 inhibitor (TROPHY-U-01 trial); optimal integration into current management algorithms Design, eligibility criteria and key endpoints of the ongoing Phase III TROPiCS trial comparing sacituzumab govitecan to single-agent treatment of physician’s choice in locally advanced or metastatic UBC with disease progression after a prior platinum-based regimen and an immune checkpoint inhibitor Optimal monitoring and management strategies for the toxicities (eg, infusion-related reactions, GI events, hypersensitivity) associated with sacituzumab govitecan Efficacy and safety findings from the pivotal Phase II EV-201 trial leading to the FDA approval of enfortumab vedotin in patients with locally advanced or metastatic UBC; primary results from the cohort of cisplatin-ineligible patients with platinum-naïve, locally advanced or metastatic disease who have received PD-1/PD-L1 inhibitors (Cohort 2) Key findings from the Phase III EV-301 study of enfortumab vedotin versus chemotherapy in pretreated locally advanced or metastatic UBC; management of adverse events (eg, hyperglycemia, ocular toxicities, peripheral neuropathy) associated with enfortumab vedotin Mechanism of action of and available data supporting the FDA approval of erdafitinib for patients with locally advanced or metastatic UBC with susceptible FGFR3 or FGFR2 genetic alterations who have experienced disease progression on or after chemotherapy Appropriate integration of erdafitinib into current management paradigms; incidence and severity of adverse events (eg, hyperphosphatemia, ocular toxicities, stomatitis) associated with erdafitinib

Currently, a couple of agents are approved for the management of this disease, including chemotherapy like eribulin, targeted therapy like PARP inhibitor, as well as an antibody-drug conjugate (ADC) to target TROP2. Like many other metastatic cancers, immune checkpoint inhibitors (ICIs) have also been approved for TNBC patients with PD-L1 positive tumors and high tumor mutational burden. In this review article, we discuss these newly approved and promising novel agents that may change the therapeutic landscape for advanced/metastatic TNBC patients.

In addition, the clinical focus is on understanding how to maintain fertility after breast cancer treatment. Here, pooled analyses provide new insights.

SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Furthermore, in vivo experiments on CHO/TROP2 and MCF7 xenografts revealed that TrMab‑6 significantly reduced tumor growth, whereas it did not show antitumor activities against parental CHO‑K1 and MCF7/TROP2‑knockout xenografts. The findings suggest that TrMab‑6 is a promising treatment option for TROP2‑expressing breast cancers.

Summary: The combination of chemotherapy and immunotherapy is a potential therapeutic option for PD-L1-positive mTNBC, as the FDA recently approved atezolizumab (Tecentriq) and pembrolizumab (Keytruda) in combination with chemotherapy. Also, 2 targeted therapies-olaparib (Lynparza) and talazoparib (Talzenna)-are FDA approved for the management of mTNBC with germline BRCA mutations, and sacituzumab govitecan, an anti-Trop2 antibody-drug conjugate (ADC), was recently approved for previously treated mTNBC...Key Message: The successful clinical development of immunotherapies, PARP inhibitors, and ADCs for the management of mTNBC has improved the survival outcome of patients. Over the coming years, the therapeutic developments in precision medicine will likely change the mTNBC landscape, and might make the current definition of TNBC as breast cancer that is estrogen receptor negative, progesterone receptor negative, and HER2 negative obsolete.

In this review, we summarize the recent treatment strategies post CDK4/6 inhibitors: 1) CDK4/6 inhibitors plus exemestane and everolimus; 2) phosphoinositide-3-kinase (PI3K) inhibitor alpelisib plus fulvestrant for patients with PIK3CA mutation; 3) poly (ADP-ribose) polymerase (PARP) inhibitor for patients with germline PALB2 mutations, somatic BRCA1/2 mutations, or germline BRCA1/2 mutations; 4) exemestane and everolimus; and (5) chemotherapy. These strategies are all supported by evidence from clinical trials and retrospective studies. We also describe potential future treatment strategies post CDK4/6 inhibitors, such as the trophoblast cell surface antigen 2 (Trop-2) directed antibody-drug conjugate, cyclin-dependent kinase 7 (CDK7) inhibitors, and B-cell lymphoma-2 (BCL-2) inhibitors.

One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.6 months in mTNBC with ≥2 prior lines of chemotherapy.1 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.2 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.3 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,4 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors . Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed . The trial is currently open and enrolling patients.

In HR+ MBC, the first randomized trial combining an ICI with chemotherapy demonstrated no clinical benefit with the addition of pembrolizumab to eribulin.1 The optimal ICI combination agent to overcome primary resistance in HR+ MBC is unknown . One promising agent is the anti-Trop-2-SN-38 antibody drug conjugate (ADC) SG, which led to median progression-free survival (PFS) of 5.5 months in HR+ MBC refractory to endocrine therapy.2 This ADC may boost anticancer immunity by binding immune cell receptors to promote antibody-dependent cellular cytotoxicity.3 In addition, the SN-38 payload of SG is the active metabolite of irinotecan, which depletes regulatory T cells, upregulates MHC class I and PD-L1 expression, and augments the antitumor activity of anti-PD-1/L1 antibodies in murine tumor models.4 The irinotecan analogue camptothecin also enhances CD8+ cytotoxic T cell effector functions and antitumor immune responses by inhibiting NR4A transcription factors,5 which have recently been shown to play a central role in inducing the T cell dysfunction associated with chronic antigen stimulation in solid tumors...Stool specimens will be submitted for microbiome analyses, and health-related quality of life will be assessed . The trial is currently open and enrolling patients.

A Dato-DXd dose of 6 mg/kg was selected for the randomized, phase 3, TROPION-Lung01 trial (NCT04656652) based on better tolerance and improved efficacy, including a trend toward increased PFS.

Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).

The antibody-drug conjugate enfortumab-vedotin acts by targeting nectin-4, a protein that is nearly ubiquitously expressed in conventional urothelial cancer. Whole transcriptome RNA sequencing revealed that compared with conventional urothelial carcinomas, most sarcomatoid carcinomas and all but 2 small cell carcinomas expressed very low levels of nectin-4 mRNA but expressed significant levels of either trop2 or ERBB2, which are the molecular targets of 2 other antibody-drug conjugates-sacituzumab gavitecan (trop2) or trastuzumab deruxtecan (ERBB2/HER2). In summary, our study demonstrates that there is heterogeneity of expression of nectin-4 in morphologic variants of urothelial cancer and nonurothelial histotypes, and suggests that testing expression of nectin-4 should be considered in morphologic variants or nonurothelial histotypes found to have lower expression.

This is the first study to demonstrate that several types of SGC express Trop-2 with variable intensity. Since there are currently few systemic treatment options for advanced SGCs, Trop-2 represents a promising target for further clinical studies, for instance, with sacituzumab govitecan.

In the case of HER2-positive tumours, these approaches have included, in particular, treatment with pertuzumab, T-DM1, neratinib and, soon, also tucatinib and trastuzumab deruxtecan (neither of which has yet been authorised in Europe). In patients with HER2-/HR+ breast cancer, CDK4/6 inhibitors and the PIK3CA inhibitor alpelisib are of particular importance...These therapeutic agents are not only being introduced into curative, (neo-)adjuvant therapeutic settings for HER2-positive tumours; a first favourable study on abemaciclib as an adjuvant therapy has now also been published. In patients with triple-negative breast cancer, after many years of negative study results with the Trop-2 antibody drug conjugate (ADC) sacituzumab govitecan, a randomised study has been published that may represent a significant therapeutic advance. This review describes the latest developments in breast cancer subsequent to the ESMO Congress 2020.

P1b/2, N=329, Active, not recruiting, Clovis Oncology, Inc. | Recruiting --> Active, not recruiting

Prior therapies were taxanes (83%), platinum-based TX (50%), immunotherapy (33%), and sacituzumab govitecan (8%). No cases of TX-related ILD (adjudicated) were observed. Conclusions Preliminary results show that Dato-DXd had highly encouraging antitumor activity and a manageable safety profile in pts with refractory mTNBC; further confirmatory studies are warranted.

Some targeted drugs were recently approved for these patients: two poly(ADP-ribose) polymerase inhibitors in patients with germline BRCA1/2 mutations (olaparib and talazoparib), immune checkpoint inhibitors in association with chemotherapy if programmed death-ligand 1 positive (atezolizumab plus nabpaclitaxel and pembrolizumab plus chemotherapy [nabpaclitaxel, paclitaxel, and carboplatin plus gemcitabine]), and an antibody-drug conjugate sacituzumab-govitecan in heavily pretreated patients (at least 2 previous lines for the metastatic setting). Soon, the treatment of metastatic TNBC could be based on personalized medicine using molecular testing for targeted drugs instead of only systemic chemotherapy. The authors present a review of emerging treatment options in metastatic TNBC, focusing on targeted drugs, including the recent data published in 2020.

Increased TROP2 expression was associated with poorer overall survival (OS) (P<0.01; log rank test), whereas increased pTROP2 expression was significantly associated with improved OS (P<0.01; log rank test). In conclusion, increased expression levels of TROP2, but not pTROP2, may be associated with the metastatic ability of GC, resulting in poor prognosis of patients with GC.

P1/2; N=70; Not yet recruiting; Sponsor:National Cancer Institute (NCI)

Because TNBC is by definition unresponsive to endocrine therapy (eg, tamoxifen, aromatase inhibitors) and HER2-directed therapies (eg, trastuzumab), chemotherapy continues to play an important role...Also reviewed was the wide range of emerging pathways and therapies currently under investigation to expand TNBC treatment options, including immunotherapies and poly(ADP-ribose) polymerase (PARP) inhibitors. This article summarizes the BCTEG discussion and highlights the key opinions relating to the treatment of patients with TNBC.