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Primary and metastatic brain tumors present a significant therapeutic challenge, in large part because they are protected by the blood-brain barrier (BBB), a highly restrictive interface between the bloodstream and the brain that prevents most drugs from accessing the brain parenchyma.

Despite decades of research, our understanding of the BBB is still incomplete. Adding to the complexity are the changes the BBB undergoes during tumorigenesis, which are even less well understood, particularly their effect on the ability of therapeutics to access the brain.

Nevertheless, persistent efforts by investigators and pharmaceutical companies to find ways to breach the BBB and improve the treatment of brain tumors, as well as the growing inclusion of patients with active brain metastases in clinical trials, have brought about significant advances.

These include the FDA’s April 2020 approval of tucatinib (Tukysa), a HER2-targeted tyrosine kinase inhibitor (TKI), in combination with trastuzumab (Herceptin) plus capecitabine for the treatment of patients with HER2-positive breast cancer, including those with brain metastases, after prior therapy.

 Investigators said the regimen is the first to demonstrate improved activity against brain metastases in a randomized clinical trial in patients with this tumor type.

Much of the ongoing research focuses on honing the brain-penetrating capabilities of small-molecule drugs, which are more likely to be able to pass through the BBB.

 Numerous clinical trials testing TKIs in patients with brain metastases are underway, particularly in non–small cell lung cancer (NSCLC) and breast cancer.

Other strategies also are emerging. Immune checkpoint inhibitors are being evaluated in primary and metastatic brain tumors, most frequently in combination with other therapies. Additionally, investigators are concentrating on finding ways to disrupt or bypass the BBB to enhance drug delivery. In a technique termed ultrasound-induced blood-brain barrier disruption (US-BBBD), the acoustic pressure from focused ultrasound (FUS) is used to excite microbubbles, which leads to transient openings in the BBB that could facilitate drug delivery. Several ultrasound devices have been developed and, following promising preclinical findings, are now in the early stages of clinical testing in cancers with brain metastases.

Whether a molecule can penetrate the BBB is dependent on its size and physiochemical properties; nearly all large-molecule drugs and up to 98% of small-molecule drugs are thought to be unable to cross the BBB. Those that make it across the barrier may succumb to the activity of active efflux transporters that rapidly evict them.

As our understanding of the BBB in the context of cancer has evolved, it has become clear that the BBB is altered by the presence of both primary and metastatic tumors in the brain. The brain-tumor barrier (BTB), as this cancer-modified BBB is known, is more permeable than the normal BBB. However, this does not appear to always work in favor of drug delivery because of the heterogeneous nature of these changes across the BTB.

Brain metastases are the most common intracranial tumors in adults and a significant cause of morbidity and mortality. Across tumor types, metastasis to the brain occurs in an estimated 10% to 30% of patients, and its prevalence is believed to be increasing as treatments for extracranial disease become more effective.

Brain metastases are particularly common in patients with lung cancer, breast cancer, renal cell carcinoma, and melanoma, with primary lung cancer accounting for approximately half of all cases.

Although there have been significant advancements in the treatment paradigm for each of these cancer types in the past several decades, evidence of therapeutic efficacy against brain metastases has lagged in part because of the exclusion of patients with brain tumors from most clinical trials. This has begun to change in recent years; there was a steady decrease in the percentage of trials excluding patients with brain metastases from 2000 to 2019. The American Society of Clinical Oncology and Friends of Cancer Research have recommended that patients with treated or stable brain metastases should be routinely included in clinical trials and that those with active tumors should be considered for inclusion based on certain criteria.

-mutant NSCLC experience central nervous system (CNS) progression. The first generation of EGFR TKIs demonstrated poor ability to accumulate in the brain,

 but multiple lines of evidence suggest that the third-generation EGFR TKI osimertinib (Tagrisso) can cross the BBB and has significant activity in patients with brain metastases.

PET imaging studies have demonstrated BBB penetration of radiolabeled osimertinib in various animal models and healthy human volunteers.11,12 Similar findings were observed in patients with 

 T790M–mutant NSCLC in the recent ODIN-BM study (NCT03463525), in which the drug achieved rapid, high, and widespread brain exposure.

Osimertinib is approved for the frontline treatment of metastatic NSCLC and as adjuvant therapy for earlier-stage disease after resection for patients whose tumors harbor 

 exon 19 deletions or exon 21 L858R mutations; it also is approved as second-line therapy for metastatic NSCLC with 

 FLAURA (NCT02296125) and AURA3 (NCT02151981), the pivotal phase 3 trials in patients with metastatic disease, demonstrated a progression-free survival (PFS) benefit in the overall cohort, as well as in subgroups of patients both with and without CNS metastases.

Meanwhile, a recent analysis of results from the ADAURA trial (NCT02511106), the pivotal study for osimertinib’s adjuvant indication, demonstrated that the drug cut the risk of CNS disease recurrence or death by 82% (HR, 0.18; 95% CI, 0.10-0.33), suggesting that osimertinib can protect patients against the development of CNS metastases when used in the adjuvant setting.

Among other brain-penetrant EGFR TKIs in development, almonertinib (Ameile) is approved in China for the second-line treatment of 

 A recent study in mouse models found that almonertinib has a low affinity for BBB efflux transporters and that it readily penetrates the BBB.

 The phase 1/2 APOLLO study (NCT02981108) of almonertinib in patients with 

 T790M–mutant NSCLC who had progressed after prior EGFR TKI therapy demonstrated promising activity in patients with CNS metastases; the CNS objective response rate (ORR) was 60.9% (95% CI, 38.5%-80.3%) and median PFS was 10.8 months (95% CI, 5.5-12.6).

The first-generation ALK inhibitor crizotinib (Xalkori), which also inhibits ROS1 and MET, initially received accelerated approval for the treatment of locally advanced or metastatic ALK-positive NSCLC in 2011.21 Its indications have since expanded to include regular approvals for metastatic NSCLC tumors that test positive for ALK rearrangements or protein overexpression or for 

 A flurry of new and more potent ALK inhibitors have since been approved to address the resistance and disease progression that frequently occur.

As with EGFR inhibitors, there has been an increasing focus on honing the ability of ALK inhibitors to cross the BBB and tackle brain metastases, which are frequently seen in patients with ALK-positive NSCLC at baseline and also have been observed at progression, including after ALK inhibitor therapy.

Although ALK inhibitors have demonstrated efficacy in patients with ALK-positive NSCLC and brain metastases, the intracranial response rate varies among agents. Some investigators hypoth-esize that different drug mechanisms may play a role. Crizotinib and the second-generation ALK inhibitor ceritinib (Zykadia) are substrates for the efflux transporter P-glycoprotein (P-gp), which may hinder the accumulation of drugs in the brain, although intracranial ORRs exceeding 50% have been reported in cohorts of patients treated with these agents during clinical studies.

Another second-generation ALK inhibitor, alec-tinib (Alecensa), which is not transported by P-gp, has been shown to accumulate in the brain in preclinical mouse models.

 In phase 3 trials, alectinib was found to substantially reduce the rate of progression in patients with CNS metastases compared with crizotinib. In the J-ALEX study (JapicCTI-132316), 1-year cumulative incidence rates favored alectinib over crizotinib for both CNS progression (5.9% vs 16.8%, respectively) and non-CNS progression (17.5% vs 38.4%, respectively). In ALEX (NCT02075840), CNS progression occurred in 18 patients (12%) on alec-tinib vs 68 patients (45%) on crizotinib (HR, 0.16; 95% CI, 0.10-0.28; 

 < .001). The 12-month cumula-tive incidence rates of CNS progression were 9.4% vs 41.4%, respectively.

Brigatinib (Alunbrig) was approved in 2020 for the frontline treatment of ALK-positive metastatic NSCLC.

 In final results from the phase 3 ALTA-1L trial (NCT02737501), which was the basis for the approval, brigatinib reduced the risk of intracranial progression by 56% in all patients (HR, 0.44) and by 71% in patients with any brain metastases at baseline (HR, 0.29) compared with crizotinib.

Lorlatinib (Lorbrena) is currently the only third-generation ALK inhibitor approved for the treatment of patients with ALK-positive NSCLC. It was specifically designed for enhanced BBB pene-tration, and imaging studies have demonstrated its rapid uptake and accumulation in the brain.

 In the recent CROWN trial (NCT03052608), lorlatinib was shown to elicit significantly higher intracranial response rates than crizotinib. The intracranial response rates in patients with base-line brain metastases were 82% (95% CI, 57%-96%) and 23% (95% CI, 5%-54%) in the lorlatinib and crizotinib groups, respectively.

Ensartinib (X-396) is an investigational third-generation ALK inhibitor. Recently published results from the phase 3 eXalt3 trial (NCT02767804) demonstrated ensartinib’s superiority to crizotinib in patients with previously untreated ALK-positive NSCLC. Although only 11 patients with brain metastases at baseline were evaluated, the intracranial ORR was 63.6%, compared with 21.1% for crizotinib. Furthermore, significantly fewer ensartinib-treated patients went on to develop brain metastases at 12 months (4.2% vs 23.9% with crizotinib; HR, 0.32; 95% CI, 0.16-0.63; 

Breast cancer is the second most common cause of brain metastases after lung cancer, and CNS progression is particularly frequently associated with HER2-positive disease.

 HER2-targeted therapies have markedly improved the prognosis of patients with this subtype of cancer.

Investigators have thought that HER2-targeted antibody-drug conjugates (ADCs) were too large to cross the BBB. However, this concept may be challenged by the novel ADC fam-trastuzumab deruxtecan-nxki (Enhertu), which demonstrated a promising intracranial response rate of 83.3% (5 of 6 patients) in preliminary results from the phase 2 TUXEDO-1 trial (NCT04752059).

Several small-molecule HER2 inhibitors with varying degrees of brain penetration are on the market. Most recently approved is the third-generation drug tucatinib. Tucatinib has not been directly shown to cross the BBB, but physiologically based pharmacokinetic modeling has predicted that it will be able to penetrate both the BTB and BBB and achieve pharmacologically active concentrations.

Approval of tucatinib was largely based on results from the phase 2 HER2CLIMB trial (NCT02614794), in which the agent was combined with trastuzumab (Herceptin) and capecitabine for patients with previously treated metastatic HER2-positive breast cancer. Participants with brain metastases made up 48% of the cohort, and both this subgroup and the overall population displayed significantly higher 1-year PFS rates among patients who received the tucatinib combination compared with placebo plus trastuzumab and capecitabine.

The FDA approval includes patients with brain metastases, making tucatinib the first targeted therapy specifically approved in this patient population. In a follow-up report, the tucatinib combination was also found to improve overall survival (OS)—the first drug to achieve this feat in HER2-positive patients with brain metastases—reducing the risk of death by 42% (HR, 0.58; 95% CI, 0.40-0.85; 

Although significant advancements have been made in the development of small molecules that cross the BBB, the fact remains that almost all large drugs, including monoclonal antibodies and most chemotherapy agents, are unable to penetrate the protective barrier without assistance.

Numerous strategies have been tested to bypass the BBB, including convection-enhanced delivery, which uses a pressure gradient to facilitate direct delivery of the drug into the target tissue; intranasal delivery, which is thought to allow drug access to the brain through the olfactory and trigeminal neural pathways; and intra-arterial drug delivery, which involves administration of the drug directly into an artery in the proximity of the tumor. These methods have had limited success treating brain tumors to date, but clinical trials are ongoing.

There also have been significant efforts to penetrate the BBB via transcytosis by encapsulating drugs in nanoparticles or conjugating them to ligands that trigger receptor-mediated uptake. A notable example of the latter approach is ANG1005, which consists of angiopep-2, a peptide that recognizes the LRP1 receptor on the surface of brain endothelial cells, conjugated to paclitaxel.

In a phase 2 trial of ANG1005 in patients with breast cancer and brain metastases, a subset with leptomeningeal carcinomatosis (n = 28) had prolonged OS compared with historical controls. The ongoing phase 3 ANGLeD study (NCT03613181) is evaluating ANG1005 in patients with HER2-negative breast cancer who have newly diagnosed leptomeningeal carcinomatosis and previously treated brain metastases.

Physical disruption of the BBB to temporarily increase its permeability is another strategy that is gaining in popularity. Several methods have been tested, but the use of FUS coupled with intravenously administered microbubbles, or US-BBBD, has shown the most promise.

The acoustic pressure from the ultrasound causes the microbubbles to expand and contract, placing mechanical stress on the endothelial cells of the BBB and temporarily opening tight junctions between these cells, creating gaps through which drugs may pass in a process termed paracellular transport. The integrity of the BBB is typically fully restored within 24 hours after disruption.

A major obstacle to delivering ultrasound to the brain is the thickness of the skull; the resulting ultrasound distortion necessitates the use of MRI or neuronavigation for safe guidance of the device. At least 3 specialized systems are in development for US-BBBD in the brain. ExAblate and NaviFUS are extracranial devices; the former consists of a hemispherical ultrasound helmet containing over 1000 transducers coupled with a magnetic resonance scanner, and the latter is a frameless neuronavigation-guided device. The SonoCloud system has an implantable ultrasound emitter, which is activated by a transcutaneous needle. Extracranial FUS can be radiologically guided by concurrent MRI or neuronavigation.

US-BBBD has had significant success in preclinical studies, demonstrating the ability to safely, effectively, and transiently open the BBB to enhance the penetration of various drugs, thus improving antitumor efficacy.

Early-phase clinical trials have begun, and promising preliminary data are emerging for both MRI- and neuronavigation-guided US-BBBD in patients with primary brain tumors and brain metastases.

 For example, in a first-in-human trial in 4 patients with HER2-positive breast cancer with brain metastases (NCT03714243), MRI-guided FUS safely enhanced the delivery of trastuzumab to the brain.

Steeg PS. The blood-tumour barrier in cancer biology and therapy. 

. 2021;18(11):696-714. doi:10.1038/s41571-021-00529-6

United States Food and Drug Administration. Cancer clinical trial eligibility criteria: brain metastases. Guidance for industry. July 2020. Accessed December 8, 2021. 

https://www.fda.gov/media/121317/download

Abrey LE. Inclusion of patients with brain metastases in clinical trials. 

Corbett K, Sharma A, Pond GR, et al. Central nervous system-specific outcomes of phase 3 randomized clinical trials in patients with advanced breast cancer, lung cancer, and melanoma. 

. 2021;7(7):1062-1064. doi:10.1001/jamaoncol.2021.1359

FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. Updated April 20, 2020. Accessed July 9, 2020. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer

Lin NU, Borges V, Anders C, et al. Intracranial efficacy, and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial. 

. 2020;38(23):2610-2619. doi:10.1200/JCO.20.00775

Beccaria K, Canney M, Bouchoux G, et al. Ultrasound-induced blood-brain barrier disruption for the treatment of gliomas and other primary CNS tumors. 

. 2020;479:13-22. doi:10.1016/j.canlet.2020.02.013

Liu Q, Tong X, Wang J. Management of brain metastases: history and the present. 

. 2019;5:1. doi:10.1186/s41016-018-0149-0

Loeffler JS. Epidemiology, clinical manifestations, and diagnosis of brain metastases. Updated January 27, 2021. Accessed January 11, 2022. 

https://www.uptodate.com/contents/epidemiology-clinical-manifestations-and-diagnosis-of-brain-metastases

Sprowls SA, Arsiwala TA, Bumgarner JR, et al. Improving CNS delivery to brain metastases by blood-tumor barrier disruption. 

. 2019;5(8):495-505. doi:10.1016/j.trecan.2019.06.003

Varrone A, Varnäs K, Jucaite A, et al. A PET study in healthy subjects of brain exposure of 11C-labelled osimertinib - a drug intended for treatment of brain metastases in non-small cell lung cancer. 

. 2020;40(4):799-807. doi:10.1177/0271678X19843776

Ballard P, Yates JWT, Yang Z, et al. Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLC brain metastases models, and early evidence of clinical brain metastases activity. 

. 2016;22(20):5130-5140. doi:10.1158/1078-0432.CCR-16-0399

Ekman S, Cselényi Z, Varrone A, et al. P76.72 A PET and MRI study exploring osimertinib brain exposure and efficacy in EGFRm NSCLC CNS metastases. 

. 2021;16(3):S620. doi:10.1016/j.jtho.2021.01.1129

Tagrisso. Prescribing information. AstraZeneca; 2021. Accessed January 6, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208065s022lbl.pdf

Soria JC, Ohe Y, Vansteenkiste J, et al; FLAURA Investigators. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. 

. 2018;378(2):113-125. doi:10.1056/NEJMoa1713137

Mok TS, Wu YL, Ahn MJ, et al; AURA3 Investigators. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. 

. 2017;376(7):629-640. doi:10.1056/NEJMoa1612674

Wu YL, Tsuboi M, He J, et al; ADAURA Investigators. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. 

. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071

Hansoh Pharma’s Ameile (almonertinib) receives marketing authorization in China for second-line treatment for patients with EGFR T790M-mutation non-small cell lung cancer. News release. Hansoh Pharma; March 19, 2020. Accessed January 11 12, 2022. 

https://www.prnewswire.com/news-releases/hansoh-pharmas-ameile-almonertinib-receives-marketing-authorization-in-china-for-second-line-treatment-for-patients-with-egfr-t790m-mutation-non-small-cell-lung-cancer-301026745.html

Zhang Y, Zhang Y, Niu W, et al. Experimental study of almonertinib crossing the blood-brain barrier in EGFR-mutant NSCLC brain metastasis and spinal cord metastasis models. 

. 2021;12:750031. doi:10.3389/fphar.2021.750031

Lu S, Wang Q, Zhang G, et al. A multicenter, open-label, single-arm, phase II study: the third generation EGFR tyrosine kinase inhibitor almonertinib for pretreated EGFR T790M-positive locally advanced or metastatic non-small cell lung cancer (APOLLO). 

. 2020;80(suppl 16):CT190. doi:10.1158/1538-7445.AM2020-CT190

Sullivan I, Planchard D. ALK inhibitors in non-small cell lung cancer: the latest evidence and developments. 

. 2016;8(1):32-47. doi:10.1177/1758834015617355

Xalkori. Prescribing information. Pfizer Inc; 2021. Accessed January 6, 2022. 

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202570s031lbl.pdf

Griesinger F, Roeper J, Pöttgen C, Willborn KC, Eberhardt WEE. Brain metastases in ALK-positive NSCLC - time to adjust current treatment algorithms. 

. 2018;9(80):35181-35194. doi:10.18632/oncotarget.26073

Chow LQ, Barlesi F, Bertino EM, et al. Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain. 

. 2019;30(suppl 5):v602-v603. doi:10.1093/annonc/mdz260

Kodama T, Hasegawa M, Takanashi K, Sakurai Y, Kondoh O, Sakamoto H. Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases. 

. 2014;74(5):1023-1028. doi:10.1007/s00280-014-2578-6

Tomasini P, Egea J, Souquet-Bressand M, Greillier L, Barlesi F. Alectinib in the treatment of ALK-positive metastatic non-small cell lung cancer: clinical trial evidence and experience with a focus on brain metastases. 

. 2019;13:1753466619831906. doi:10.1177/1753466619831906

FDA approves brigatinib for ALK-positive metastatic NSCLC. FDA. Updated May 26, 2020. Accessed December 8, 2021. 

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brigatinib-alk-positive-metastatic-nsclc

Camidge DR, Kim HR, Ahn MJ, et al. Brigatinib versus crizotinib in ALK inhibitor-naive advanced ALK-positive NSCLC: final results of phase 3 ALTA-1L trial. 

. 2021;16(12):2091-2108. doi:10.1016/j.jtho.2021.07.035

Bauer TM, Shaw AT, Johnson ML, et al. Brain penetration of lorlatinib: cumulative incidences of CNS and non-CNS progression with lorlatinib in patients with previously treated ALK-positive non-small-cell lung cancer. 

. 2020;15(1):55-65. doi:10.1007/s11523-020-00702-4

Shaw AT, Bauer TM, de Marinis F, et al; CROWN Trial Investigators. First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. 

. 2020;383(21):2018-2029. doi:10.1056/NEJMoa2027187

Horn L, Wang Z, Wu G, et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial. 

. 2021;7(11):1617-1625. doi:10.1001/jamaoncol.2021.3523

Leone JP, Leone BA. Breast cancer brain metastases: the last frontier. 

. 2015;4:33. doi:10.1186/s40164-015-0028-8

Bartsch R, Berghoff AS, Furtner J, et al. 280P Intracranial activity of trastuzumab-deruxtecan (T-DXd) in HER2-positive breast cancer patients with active brain metastases: results from the first stage of the phase II TUXEDO-1 trial. 

. 2021;32(suppl 5):S486. doi:10.1016/j.annonc.2021.08.563

Lee AJ, Jiang J, Kumar V, Alley SC, Peterson S, Li J. 295P Physiologically based pharmacokinetic (PBPK) modeling of the central nervous system (CNS) pharmacokinetics of tucatinib in patients with breast cancer brain metastasis. 

. 2020;31(suppl 4):S360. doi:10.1016/j.annonc.2020.08.397

Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer.

. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609

Haumann R, Videira JC, Kaspers GJL, van Vuurden DG, Hulleman E. Overview of current drug delivery methods across the blood-brain barrier for the treatment of primary brain tumors. 

. 2020;34(11):1121-1131. doi:10.1007/s40263-020-00766-w

Papademetriou I, Vedula E, Charest J, Porter T. Effect of flow on targeting and penetration of angiopep-decorated nanoparticles in a microfluidic model blood-brain barrier. 

. 2018;13(10):e0205158. doi:10.1371/journal.pone.0205158

Kumthekar P, Tang SC, Brenner AJ, et al. ANG1005, a brain-penetrating peptide-drug conjugate, shows activity in patients with breast cancer with leptomeningeal carcinomatosis and recurrent brain metastases. 

. 2020;26(12):2789-2799. doi:10.1158/1078-0432.CCR-19-3258

Chen KT, Chai WY, Lin YJ, et al. Neuronavigation-guided focused ultrasound for transcranial blood-brain barrier opening and immunostimulation in brain tumors. 

. 2021;7(6):eabd0772. doi:10.1126/sciadv.abd0772

Mainprize T, Lipsman N, Huang Y, et al. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. 

. 2019;9(1):321. doi:10.1038/s41598-018-36340-0

Idbaih A, Canney M, Belin L, et al. Safety and feasibility of repeated and transient blood-brain barrier disruption by pulsed ultrasound in patients with recurrent glioblastoma. 

. 2019;25(13):3793-3801. doi:10.1158/1078-0432.CCR-18-3643

Meng Y, Reilly RM, Pezo RC, et al. MR-guided focused ultrasound enhances delivery of trastuzumab to Her2-positive brain metastases. 

. 2021;13(615):eabj4011. doi:10.1126/scitranslmed.abj4011

Articles

Primary and metastatic brain tumors present a significant therapeutic challenge, in large part because they are protected by the blood-brain barrier, a highly restrictive interface between the bloodstream and the brain that prevents most drugs from accessing the brain parenchyma.

Making Progress Against the Blood-Brain Barrier

Treatment of patients with metastatic cervical cancer remains challenging—the 5-year overall survival (OS) rate is just 17%.

 Whereas many other solid tumors have seen a plethora of FDA approvals of clinically meaningful treatments, there has been a paucity of new approvals for metastatic cervical cancer. However, the tide began to turn in 2021 with several new treatments receiving FDA approval and showing a meaningful incremental benefit over previously available agents.

®, a panel of experts in gynecologic cancer shared their insights on the treatment landscape for metastatic cervical cancer in the first- and second-line settings, including data for the newly approved agents and considerations for using them in clinical practice. They also discussed several promising checkpoint inhibitors on the horizon. “It’s exciting to see this flurry of activity in cervical cancer. We have tripled the survival [rate], which is heartwarming and incredible for our patients. This field is going to continue to evolve,” Bhavana Pothuri, MD, said.

First-Line Metastatic Cervical Cancer Treatment 

Managing metastatic cervical cancer in the firstline setting includes treating women with de novo stage IVB or recurrent cancer after chemotherapy or radiation, Bradley Monk, MD, FACOG, FACS, said. “We don’t count chemotherapy or radiation as a line of therapy,” he said.

In patients with metastatic cervical cancer, the standard chemotherapy backbone remains paclitaxel (Taxol) and platinum, either cisplatin or carboplatin. “We were originally using a cisplatin backbone and the JGOG [Japanese Gynecologic Oncology Group] trial demonstrated noninferiority between carboplatin and cisplatin, except for those [patients] who had not received cisplatin previously as a part of their RT [radiation therapy] planning,” Warner K. Huh, MD, FACOG, FACS, said.

The panelists proceeded to discuss 2 practice-changing, phase 3 clinical trials that have assessed additions to the standardof-care chemotherapy backbone of paclitaxel plus platinum in the firstline setting: the Gynecologic Oncology Group GOG 240 trial (NCT00803062), which investigated the addition of bevacizumab (Avastin), and KEYNOTE-826 (NCT03635567), which investigated the addition of pembrolizumab (Keytruda).

In 2014, the FDA approved bevacizumab in combination with standard-of-care chemotherapy based on data from the GOG 240 trial, making it the first drug approved for patients with late-stage cervical cancer since the 2006 approval of topotecan with cisplatin.2 “[GOG 240] showed that by incorporating antiangiogenesis therapy into platinum and nonplatinum chemotherapy doublets we could significantly improve survival in women with recurrent metastatic cervical cancer in the first line,” Krishnansu S. Tewari, MD, said.

The study randomly assigned 452 women with persistent, recurrent, or late-stage cervical cancer to receive paclitaxel and cisplatin with or without bevacizumab, or paclitaxel and topotecan with or without bevacizumab. In those receiving the triplet, OS reached 16.8 months, whereas those receiving chemotherapy alone had an OS of 12.9 months, showing a 3.9-month OS benef it with the addition of bevacizumab. Extended follow-up showed the benef it of incorporating bevacizumab to be sustained, with an OS of 16.8 months with the triplet and 13.3 months with the chemotherapy doublets, demonstrating a 3.5-month OS benefit with the addition of bevacizumab (HR, 0.77 95% CI, 0.62-0.95; P = .007).

Although there is a small OS benefit with the addition of bevacizumab to standard-of-care chemotherapy, the panelists indicated that not all patients are candidates for this treatment. “There are contraindications, [including] fistula, GI [gastrointestinal] perforation, nonhealing wounds, proteinuria, uncontrolled hypertension, inflammatory bowel disease, [and] a history of diverticulitis,” Monk said. 

Despite such contraindications, the panelists indicated that many of their patients are treated with the triplet. “Approximately 85% of my patients will get the triplet,” Pothuri said, noting she is thoughtful about counseling her patients on the benefits and drawbacks of treatment with bevacizumab.

On October 13, 2021, just a few weeks after the 

®, pembrolizumab received FDA approval in combination with chemotherapy with or without bevacizumab for patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 with a combined positive score (CPS) of at least 1, as determined by an FDA-approved test.

 This marked the first new first-line therapy approval for women with persistent, recurrent, or metastatic cervical cancer since bevacizumab’s approval in 2014. FDA approval of pembrolizumab was based on data from KEYNOTE-826, which showed improvements in the dual primary end point of progression-free survival (PFS) and OS with the addition of pembrolizumab to standardof-care chemotherapy.

Investigators of KEYNOTE-826 randomly assigned 617 women with persistent, recurrent, or metastatic cervical cancer in a 1:1 ratio to receive pembrolizumab 200 mg (n = 308) or placebo (n = 309) every 3 weeks for up to 35 cycles plus standard-of-care chemotherapy, with bevacizumab administered per investigator discretion.

 Of these patients, 548 had a PD-L1 CPS of at least 1 (273 in the pembrolizumab arm and 275 in the placebo arm) and 317 patients had a CPS of at least 10 (158 in the pembrolizumab arm and 159 in the placebo arm).

In the first protocol-specified interim analysis, among the 548 women with a PD-L1 CPS of at least 1, the median PFS was 10.4 months in the pembrolizumab arm and 8.2 months in the placebo arm. “That was a hazard ratio of 0.62, which is incredible. We have these results within the first 3 months, and you see those curves diverge,” Premal H. Thaker, MD, MS, said. A median PFS of 10.4 months was also observed when considering the 317 patients with a PD-L1 CPS of at least 10 (HR, 0.58; 95% CI, 0.44-0.77; P < .001) as well as the entire intention-to-treat population (N = 617; HR, 0.65; 95% CI, 0.53-0.79; P < .001).

“The OS hasn’t been accomplished yet,” Thaker said. Nevertheless, estimates of patients alive at 24 months significantly favor pembrolizumab versus placebo across all patient subgroups examined (TABLE 1

Thaker said that no unexpected adverse effects (AEs) were observed in the study. The most common grade 3 to 5 AEs included anemia, affecting 30.3% of patients in the pembrolizumab arm versus 26.9% in the placebo arm, and neutropenia, affecting 12.4% of patients in the pembrolizumab arm versus 9.7% in the placebo arm.

A little more than 60% of patients in both the pembrolizumab and placebo arms received bevacizumab in addition to standard-of-care chemotherapy. “What I can’t tease out from the data is if you need bevacizumab for the pembrolizumab to work,” Tewari said, who was a study investigator and coauthor of the 

 Although the data are challenging to interpret, the panelists agreed that clinicians should continue to use bevacizumab when they deem it appropriate for their patients. “Pembrolizumab shouldn’t confuse that decision,” Monk said.

Second-Line Metastatic Cervical Cancer Treatment 

Despite the recent advancement in treating patients with metastatic cervical cancer in the first-line setting, most patients progress and require second-line treatment. Although there are many second-line options available (TABLE 2

), response and OS rates associated with these agents have been “fairly minimal,” Huh said. The panelists explained that response rates have ranged from 0% to 10% with physician’s choice of chemotherapy to 14.3% with pembrolizumab, demonstrating a great unmet need in this area.

Since response with available treatments is so low, Huh said he tries to put his patients on clinical trials whenever possible. Tewari agreed with this approach. “The space has blown up with trials, so fortunately most of our patients in need of second-line therapy in the last few years were able to secure a place on a study,” he said. 

The panelists noted that numerous promising agents are currently in clinical trials, with one such agent, tisotumab vedotin (Tivdak), recently approved by the FDA.7 The panelists said that the approval of tisotumab vedotin is particularly exciting because it has shown unprecedented response rates, reaching almost 25%.

On September 20, 2021, tisotumab vedotin was granted FDA accelerated approval for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

 “It is the first antibody-drug conjugate [ADC] to get approved in a gynecologic malignancy,” Monk said. He explained that this agent “has a target, an antibody, a linker, and a cytotoxin” and that its promising efficacy may result from its multiple mechanisms of action, including monomethyl auristatin E–directed cytotoxicity and bystander and immunogenic effects.

Tisotumab vedotin received an accelerated approval from the FDA based on data from the phase 2, open-label, multicenter, singlearm innovaTV 204/GOG-3023/ENGOT-cx6 trial (NCT03438396).

 In the study, 101 women with recurrent or metastatic previously treated cervical cancer (ie, squamous cell, adenosquamous, or adenocarcinoma treated with no more than 2 previous systemic regimens for recurrent or metastatic disease) received at least 1 dose of tisotumab vedotin. After a median follow-up of 10 months, the confirmed objective response rate (ORR) was 24% (95% CI, 16%-33%), with 7 patients (7%) achieving complete responses and 17 patients (17%) achieving partial responses (TABLE 3

“It’s game-changing….I have several patients who are excited to go on this drug,” Huh said. Other panelists reported similar sentiments among their patients because of the paucity of meaningful treatments, particularly for those who are PD-L1 negative and do not qualify for immune checkpoint inhibitors. Monk recounted the emotional response of one of his patients when he informed her of her biopsy results, tisotumab vedotin’s approval, and that it was a viable option for her. “This is an opportunity,” he said. Tewari agreed and said he is thrilled this agent has been approved because he has already seen some “phenomenal objective responses” in some of the study patients he treated.

Tisotumab vedotin was found to have a manageable toxicity profile. The most common AEs included alopecia (38%), epistaxis (30%), nausea (27%), conjunctivitis (26%), fatigue (26%), and dry eye (23%).

 Treatment-related AEs grade 3 or higher were reported in 28% of patients and included neutropenia (3%), fatigue (2%), ulcerative keratitis (2%), and peripheral neuropathies (2%). Serious treatment-related AEs occurred in 13% of patients, with peripheral sensorimotor neuropathy (2%) and pyrexia (2%) being the most common. There were 4 deaths, 3 of which were deemed unrelated to treatment and 1 attributed to septic shock from treatment. 

Tisotumab vedotin has been found to cause changes to the corneal epithelium and conjunctiva, and its prescribing information has a boxed warning regarding its ocular toxicity.

 “It’s the linker that’s causing the ocular toxicity. It’s not the payload or the antibody,” Tewari said, noting that the mitigation strategies required by the FDA are highly effective in reducing the risk of ocular AEs, particularly severe AEs that can result in permanent vision loss. An ophthalmic exam is required at baseline, before each infusion, and as clinically indicated. Additionally, 3 types of eye drops are required throughout tisotumab vedotin treatment: vasoconstriction eye drops immediately before the infusion, topical corticosteroid eye drops for 72 hours after the infusion, and topical lubricating drops for the duration of treatment and up to 30 days after the f inal infusion.

Monk said when ocular AEs occur, they tend to happen early in treatment and are completely reversible. “You have to emphasize that,” he said, noting that eye concerns can be unsettling for patients. “For conjunctivitis, it’s primarily red eye. I’ve seen patients [who have] someone ask, ‘What’s wrong with your eye? Is that pink eye? Is that contagious?’ It’s disturbing, but it’s not serious,” he explained. 

The panelists noted that dealing with intensive ocular care requirements can pose challenges for oncologists and patients, especially if patients need to see an ophthalmologist before every cycle, but they explained that such situations are not new for oncologists. “When I first started using this drug, I was scared and apprehensive, but now that I’ve seen the mitigation strategy I understand it, similarly to how we were scared with BEV [bevacizumab]. I remember learning about antihypertensives, and asking how many can we give? What should we give? But we’ve gotten better, and we will continue to improve,” Thaker said.

The panelists noted that several new immune checkpoint inhibitors are being investigated for patients with metastatic cervical cancer, including balstilimab and cemiplimab (Libtayo). Balstilimab was under consideration as a monotherapy for this indication, but its biologic license application (BLA) was voluntarily withdrawn in October 2021 following FDA approval of pembrolizumab, which came 4 months earlier than the FDA goal date.

 Despite this setback, development of this agent is moving forward but as part of a combination therapy for metastatic cervical cancer and other tumor types.

One partner for the anti–PD-L1 antibody balstilimab that has shown promise is zalifrelimab, a CTLA-4 antibody. In a phase 2 trial (NCT03495882), after a median follow-up of 21 months, the confirmed ORR with the combination was 25.6% (95% CI, 18.8%-33.9%), which included 10 complete responses and 22 partial responses.

 In patients with PD-L1–positive tumors, the ORR reached 32.8%, whereas it was 9.1% in PD-L1negative tumors. Although responses were observed across histologic subtypes, the ORR was highest for patients with squamous tumors, reaching 32.6% (vs 8.8% of cervical adenocarcinomas). The overall disease control rate was 52% (95% CI, 43.3%-60.6%). Hypothyroidism (14.2%) and hyperthyroidism (7.1%) were the most common immune-mediated AEs.

“The response rate with the combination appears to be superior to single-agent [balstilimab],” Pothuri said. She surmised that “the addition of the CTLA-4 may help overcome the lack of efficacy with a single-agent checkpoint inhibitor” and suggested this combination may receive wide adoption if approved.

Similar to balstilimab, cemiplimab is a PD-L1 inhibitor. It was accepted for priority review in September 2021 as a treatment for patients with recurrent or metastatic cervical cancer whose disease progressed on or after chemotherapy.

 The supplemental BLA was submitted to the FDA based on data from the phase 3, open-label, multicenter EMPOWER-Cervical 1 trial (NCT03257267), which showed significant benefit with cemiplimab vs chemotherapy in global health status/quality of life, physical functioning, and key symptom scales. Importantly, cemiplimab also was associated with a survival benefit.

“We showed a significant improvement in overall survival in the squamous cell population, which was the first part of our statistical hierarchy, 11 vs 8 months. We also showed a significant improvement in survival in the intention-totreat population [12.0 vs 8.5 months]. Although it wasn’t planned or part of the statistical hierarchy, the results with adenocarcinoma were thought-provoking [13.3 vs 7.0 months]. It was a tolerable monotherapy. We didn’t have to combine it with bevacizumab or chemotherapy. Going forward, this is an important option for patients,” Tewari said. The target action date for the FDA’s decision is January 30, 2022.

 A key feature of the trial is that patients were enrolled regardless of PD-L1 expression status, which may help extend checkpoint inhibitors to all-comers if ultimately approved.

In their concluding thoughts, the panelists expressed significant excitement for the future, noting that treatment development for patients with metastatic cervical cancer is only the tip of the iceberg but is progressing at a rapid pace. “In 2 years, I think the algorithm for how we treat patients with recurrent cervical cancer will be completely different. It’s the dawn of a new era. It’s incredibly exciting,” Huh said.

Survival rates for cervical cancer. American Cancer Society. Accessed January 1, 2022. https://www.cancer.org/cancer/cervical-cancer/detection-diagnosis-staging/survival.html

FDA approves Avastin to treat patients with aggressive and late-stage cervical cancer. News release. FDA. August 14, 2014. Accessed January 1, 2022. https://bit.ly/3pO7pph

Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654-1663. doi:10.1016/ S0140-6736(17)31607-0

FDA approves Merck’s Keytruda (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors FDA approves Merck’s Keytruda (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors

FDA approves Merck’s Keytruda (pembrolizumab) plus chemotherapy, with or without bevacizumab, as treatment for patients with persistent, recurrent or metastatic cervical cancer whose tumors

NCCN Clinical Practice Guidelines in Oncology. Cervical cancer, version 1.2022. Accessed January 1, 2022. https://www.nccn.org/ professionals/physician_gls/pdf/cervical.pdf

FDA grants accelerated approval to tisotumab vedotin-tftv for recurrent or metastatic cervical cancer. News release. FDA. Updated September 21, 2021. Accessed January 1, 2022. https://bit.ly/3JCyEeq

Coleman RL, Lorusso D, Gennigens C, et al; innovaTV 204/GOG3023/ENGOT-cx6 Collaborators. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021;22(5):609-619. doi:10.1016/S1470-2045(21)00056-5

Tivdak (tisotumab vedotin-tftv). Prescribing information. Seagen; 2021. Accessed January 1, 2022. https://seagendocs.com/Tivdak_Full_Ltr_Master.pdf

Agenus provides update on balstilimab development. News release. Agenus. October 22, 2021. Accessed January 1, 2022. https://bit.ly/3zCyuzf

O’Malley DM, Neffa M, Monk BJ, et al. Dual PD-1 and CTLA-4 checkpoint blockade using balstilimab and zalifrelimab combination as second-line treatment for advanced cervical cancer: an open-label phase II study. J Clin Oncol. Published online December 21, 2021. doi:10.1200/JCO.21.02067

FDA accepts Libtayo (cemiplimab-rwlc) for priority review for advanced cervical cancer. News release. Regeneron. September 28, 2021. Accessed January 1, 2022. https://bit.ly/3pSRVjL

Oaknin A, Monk BJ, Vergote I, et al. Impact of cemiplimab on quality of life (QoL), functioning and symptoms in patients (pts) with recurrent/metastatic (R/M) cervical carcinoma: results from EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9. Ann Oncol. 2021;32(suppl 5):S755-S756. Abstract 783P. doi:10.1016/annonc/annonc703

Tewari KS, Monk BJ, Vergote I, et al. EMPOWER-Cervical 1/GOG3016/ ENGOT-cx9: Interim analysis of phase III trial of cemiplimab vs. investigator’s choice (IC) chemotherapy (chemo) in recurrent/ metastatic (R/M) cervical carcinoma. Ann Oncol. 2021;32(7):940941. doi:10.1016/j.annonc.2021.04.009

Treatment of patients with metastatic cervical cancer remains challenging—the 5-year overall survival rate is just 17%.

Vol. 23/No. 2 | Oncology Live®

Making Progress Against the Blood-Brain Barrier

Cervical Cancer Treatment Paradigm Is Bolstered With Newly Approved Therapies

NCCN Recommends Full COVID-19 Vaccination ASAP for Most Patients With Cancer

Targeted Therapy Innovator Foresees New Paradigms in Breast Cancer

Robotic Navigational Bronchoscopy Advances Diagnosis of Early-Stage Lung Cancer

Subcutaneous Daratumumab Plus Kd Is a “Gamechanger” for Patients With Multiple Myeloma

The Clinical Utility of Surrogate End Points Sparks Debate in Oncology