American Society of Clinical Oncology 2021 Annual Meeting Updates on Primary Brain Tumors and CNS Metastatic Tumors

Abstract

In this report, select key studies presented at the American Society of Clinical Oncology (ASCO) 2021 annual meeting are reviewed. Two major phase III randomized controlled trials were presented at the meeting: GEINO 1401 and EORTC 1709/CCTG CE.8. Both are reviewed in this report. Moreover, important phase II trials, including Alliance A0716701, and key phase I trials are included. All trials presented cover important advances in the understanding of primary brain tumor management. In addition, case series papers, trials in progress and select work on exploratory CSF biomarkers are reviewed. Altogether, research presented at ASCO 2021 highlights important advances in neuro-oncologic topics that may inform future research and practice.

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Conference Report
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American Society of Clinical Oncology 2021
Annual Meeting updates on primary brain
tumors and CNS metastatic tumors
Archit B Baskaran1, Priya Kumthekar2,3, Amy B Heimberger3,4 & Rimas V Lukas*,2,3
1Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
2Department of Neurology, Northwestern University, Chicago, IL, USA
3Lou & Jean Malnati Brain Tumor Institute, Northwestern University, Chicago, IL, USA
4Department of Neurosurgery, Northwestern University, Chicago, IL, USA
*Author for correspondence: Rimas.lukas@nm.org
In this report, select key studies presented at the American Society of Clinical Oncology (ASCO) 2021 annual
meeting are reviewed. Two major phase III randomized controlled trials were presented at the meeting:
GEINO 1401 and EORTC 1709/CCTG CE.8. Both are reviewed in this report. Moreover, important phase II
trials, including Alliance A0716701, and key phase I trials are included. All trials presented cover important
advances in the understanding of primary brain tumor management. In addition, case series papers, trials
in progress and select work on exploratory CSF biomarkers are reviewed. Altogether, research presented
at ASCO 2021 highlights important advances in neuro-oncologic topics that may inform future research
and practice.
First draft submitted: 4 August 2021; Accepted for publication: 22 September 2021; Published online:
21 October 2021
Keywords: brain metastases •craniopharyngioma •glioblastoma •leptomeningeal metastases •meeting report
•neuro-oncology
The American Society of Clinical Oncology (ASCO) held its annual meeting virtually 4–8 June 2021. A wide
spectrum of health professionals and researchers participated in the meeting, covering all aspects of oncology.
Highlights of the neuro-oncologic topics are reviewed here with a focus on clinical studies of primary brain tumors
and cerebrospinal fluid biomarkers in central nervous system metastases. Due to the broad scope of the meeting,
select key clinical studies will be covered in this overview. The target group of this review includes: neuro-oncologists,
neurosurgeons, radiation oncologists and general oncologists. The research included in this review was chosen due
to relevance to the target audience. This involved subjectivity on the part of the authors, and all key work was
unable to be included.
Advances in primary brain tumors: phase III trials
Two late-stage clinical trials were presented that did not meet the primary endpoints. In Grupo Espanol de
Investigacion en Neurooncologia (GEINO) 1401, the optimal number of adjuvant temozolomide cycles for
patients with newly diagnosed glioblastoma was prospectively investigated [1]. Prior retrospective meta-analyses
had suggested that there was no enhanced survival benefit for treating patients with more than six temozolomide
cycles [2]; however, this had not been determined in a prospective, randomized fashion. GEINO 1401 enrolled
159 newly diagnosed nonprogressive glioblastoma subjects who had completed standard of care radiation with
concurrent temozolomide [3]. After six adjuvant temozolomide cycles, patients were randomized 1:1 to either
observation or six additional cycles of temozolomide. Study participants were stratified by MGMT-methylation
status and by residual measurable disease. Median overall survival (OS) was not significantly different between the
two groups: 22.0 months observation versus 18.2 months additional temozolomide, HR of 0.957 (95% CI: 0.806–
1.136; p = 0.615). Two-year survival rates were also not different: 62% for the observation group versus 61% for
the additional temozolomide group. MGMT methylation favorably influenced outcomes, whereas IDH mutational
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Conference Report Baskaran, Kumthekar, Heimberger & Lukas
status and residual disease did not. This aligns with traditional dogma, which finds that patients with glioblastoma
containing a methylated MGMT promoter benefit from temozolamide [4].
The phase III trial EORTC 1709/CCTG CE.8 examined the effectiveness of the proteasome inhibitor mari-
zomib in combination with standard of care for treatment of newly diagnosed glioblastoma [5]. Patients (n = 749)
were randomized 1:1 to either radiation with concurrent temozolomide, followed by six adjuvant cycles of temo-
zolomide or with the addition of marizomib beginning at the start of radiation. Marizomib was selected based
on preclinical data and its blood–brain barrier (BBB) penetration properties [6]. No difference in median OS was
noted: 15.9 months for the control cohort versus 15.7 months for the marizomib cohort (HR: 0.99). Additionally,
there was no difference in PFS between the two arms: 6.1 months control versus 6.2 months for marizomib (HR:
1.02). Adverse events (AEs) such as ataxia, hallucinations and headache were doubled in the marizomib-treated
group.
Advances in primary brain tumors: phase II trials
The clinical trial that will likely change the standard of care for craniopharyngioma patients is Alliance A071601.
This phase II trial (n = 36) used the combination of BRAF and MEK inhibitors (vemurafenib and cobimetinib,
respectively) for subjects with the BRAF V600E mutated papillary craniopharyngioma subtype [7]. All patients
underwent prior surgical resection. BRAF mutation was demonstrated via immunohistochemistry. This study was
based on previously published work demonstrating radiographic responses targeting this pathway in this patient
population [8,9] who have a very high incidence of BRAF mutations [10]. Patients receive oral vemurafenib twice
per day for 28 days concurrently with daily oral cobimetinib for 21 days. Results from Cohort A were presented
that evaluated subjects with no prior radiation (n = 16). Fifteen patients in Cohort A had evaluable volumetric
data. Among these patients, 14 demonstrated a response as defined by at least a 20% decrease in volume. The
single nonresponder received only 2 days of treatment, which was discontinued due to toxicity. The median tumor
volume reduction in Cohort A was ∼83%, and median progression-free survival (PFS) was not reached at a median
follow-up of 22 months. Seventy-five percent of patients experienced grade 3 toxicity, predominantly rash. Thirteen
percent of patients developed grade 4 toxicity (hyperglycemia, elevated creatine kinase). These exceptional response
rates are the first such examples of response to systemic therapy in this patient population within the context of
a prospective trial. Cohort B results have not yet been released but uses the same approach in patients who have
progressed after radiation.
Another randomized phase II trial evaluated two dosing regimens of the anti-VEGF antibody bevacizumab
(10 mg/kg intravenously [iv.] every 2 weeks [standard] vs 3 mg/kg iv. every 2 weeks [reduced]) used in combination
with a fixed dose of the anti-PD-1 antibody nivolumab (240 mg iv. every 2 weeks) in patients with recurrent
glioblastoma [11]. Patients with recurrent glioblastoma (n = 90) at first recurrence were randomized 1:1 and
stratified by age, Karnofsky Performance Score (KPS), extent of tumor resection and MGMT methylation status.
OS at 12 months (OS12) in the overall patient population was not significantly different. Subgroup analysis in older
adult patients (>60 years old) demonstrated a better OS12 for subjects who received the standard dose bevacizumab
(46.2 vs. 23.8%) and median OS (10.6 vs 5.9 months; p = 0.046). Grade 3/4 toxicities were as anticipated. A
prior phase II study has shown that there is no therapeutic benefit of the addition of anti-VEGF therapy to PD-1
blockade in recurrent glioblastoma [12]. The current study clarifies that the dosing of the bevacizumab (high dose
vs low dose) does not influence outcome in combination with anti-PD-1.
On the basis of preclinical studies of sensitivity to PARP inhibition in IDH-mutated gliomas, a phase II clinical
trial of olaparib was evaluated in recurrent IDH-mutant high-grade glioma (OLAGLI) patients (n = 35 total;
oliogodendroglioma n = 16; astrocytoma n = 14) [13–15]. The treatment was well tolerated, but median PFS was
only 2 months. Six-month PFS (PFS6) was 31% with a median duration of response of 9 months (4–18+months).
Median OS (mOS) was 15.9 months, supporting potential benefit of this approach despite unremarkable outcomes
based on radiographic endpoints. It is possible that the use of PARP inhibition may have greater value when used in
conjunction with other therapies such as DNA-damaging agents. Potential benefit may also be more pronounced
if used earlier in the treatment course as has been the case with other treatments for high-grade gliomas.
In a study evaluating the newly emerging technology of BBB disruption, a phase I/IIa study evaluated an
implantable ultrasound device in patients with recurrent glioblastoma treated with carboplatin [16].Duringthe
dose escalation phase (n = 9), the chemotherapy dose was fixed, and the number of sonications (n = 3, 6 or 9) was
escalated with no dose-limiting toxicities detected. The expansion cohort of an additional 12 subjects treated with
nine sonications proved tolerable with one grade 3 wound-related toxicity. Postprocedural MRI demonstrated clear
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evidence of successful BBB disruption. Other systemic therapies and immunotherapies in conjunction with this
approach are currently being considered for clinical trials [17–19].
Advances in primary brain tumors: phase I trials
In the domain of adoptive immunotherapy, a phase I trial examined the safety profile of autologous yδT cells
administered intracranially via a Rickham catheter (placed intracavitarily) in addition to standard radiation and
chemotherapy in patients with newly diagnosed glioblastoma [20].yδT cells are rare immune cells that possess both
innate and adaptive immune properties. Among the six patients at dose level 1, all were IDH wildtype, and five
were MGMT unmethylated. One patient was unable to generate an adequate amount of yδT cells – a potential
limitation of this type of approach. Toxicities were manageable with only one patient experiencing grade 3 adverse
events. Serum TNFαremained elevated through day 30 and beyond. This type of approach appears to be feasible
and well tolerated thus far. Additional correlative study results with dose escalation will be of interest.
Advances in primary brain tumors: case series
A multi-institutional case series of H3K27M diffuse gliomas were treated with the highly selective dopamine D2
receptor antagonist ONC201 was presented [21]. Partial responses (not centrally reviewed) in two of seven patients
raises interest for this type of approach especially in a patient population with limited treatment options. As proof
of concept has been demonstrated in only a small number of patients [22], studies such as this help lend further
support. Prospective trials (Clinicaltrials.gov: NCT03295396, NCT03416530 and NCT02525692) using this
approach are ongoing.
Advances in primary brain tumors: trials in progress
We highlight two ongoing clinical trials in which preliminary results are eagerly awaited. PVSRIPO (recombi-
nant oncolytic poliovirus) and Pembrolizumab in Patients with Recurrent Glioblastoma (LUMINOS-101) is an
ongoing phase II trial for recurrent glioblastoma [23]. The previous phase I trial of PVSRIPO as monotherapy
demonstrated safety and tolerability [24]. A number of key inclusion and exclusion criteria (enhancing tumor size
between 1 and 5.5 cm; exclusion of high-dose steroids, notable midline-crossing tumor or extensive subependymal
involvement) will need to be considered when interpreting the generalizability of the study results when available.
ThesecondisaphaseI/II study of the exportin-1 inhibitor selinexor for newly diagnosed or recurrent glioblastoma
in combination with current standard of care [21]. Blocking the transport of specific proteins out of the tumor cell
nucleus into the cytoplasm has long been an attractive target for the treatment of cancer [25]. In the ongoing study,
newly diagnosed glioblastoma patients all receive selinexor, and the MGMT-methylated glioblastoma patients also
receive radiation and temozolomide. The MGMT unmethylated subjects are treated with radiation but not the
temozlomide.
Advances in CNS metastatic tumors: CSF biomarkers
Our discussion of advances for CNS metastases is focused on the exciting work in the realm of CSF biomarkers. A
retrospective single-institution study was conducted evaluating CSF circulating tumor cells (CTCs) as a predictive
biomarker of benefit from proton craniospinal irradiation (CSI) for leptomeningeal metastases [26]. The patient
composition consisted of both lung (47%) and breast (38%) brain metastasis. Median OS was 8 months with
mPFS of 6 months, notably better than accepted historical comparisons, potentially due to selection bias. Low
baseline CSF CTCs were associated with a longer mOS, suggesting that this can be used as a biomarker to select
which patients should be offered more aggressive treatment strategies. It remains unclear, for now, as to how CSF
CTCs may guide on-treatment management of leptomeningeal metastases.
Another study evaluating CSF biomarkers examined circulating tumor DNA (ctDNA) in patients with triple-
negative breast cancer (TNBC) to evaluate their risk for the development of brain metastases [27].PatientsCSF
was analyzed for ctDNA after treatment with neoadjuvant chemotherapy. Thirty-nine percent of patients with
TNBC who underwent neoadjuvant chemotherapy were positive for ctDNA. Among these, 98.4% developed
radiographically evident brain metastases. Of the patients who were negative for CSF-ctDNA after treatment
(61%), the overwhelming majority (99%) did not develop brain metastases during the course of the study. Findings
from this study indicate that for patients with TNBC, positive CSF-ctDNA levels are associated with a higher
risk of recurrent brain metastases, poorer OS and poorer recurrence-free survival. Accordingly, this could influence
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Conference Report Baskaran, Kumthekar, Heimberger & Lukas
screening protocols and open up the possibility of prophylactic approaches to prevent brain metastases for this
patient population in the future.
Conclusion
Several new developments are underway for the treatment of primary CNS tumors and for the use of CSF
biomarkers in CNS metastases. Results from phase III trials for glioblastoma, including GEINO 1401 and EORTC
1709/CCTG CE.8, do not alter the standard of care but do help inform our understanding of the management of
this disease and future directions for investigation in the newly diagnosed setting. A nonrandomized phase II trial of
BRAF +MEK inhibitors in papillary BRAF V600E craniopharyngioma, on the other hand, demonstrated excellent
response rates in treatment-naive patients, influencing our therapeutic paradigm in these rare tumors. Studies of
CSF CTCs and CSF ctDNA help lay the groundwork for CSF studies and potentially important prognostic and
predictive biomarkers for CNS metastatic disease.
Acknowledgments
This meeting summary was presented at the Robert H. Lurie Comprehensive Cancer Center 2021 Oncology Review on 16 July
2021. The authors thank Lyndsey Van for assistance with manuscript preparation.
Financial & competing interests disclosure
The authors have no relevant afliations or nancial involvement with any organization or entity with a nancial interest in or
nancial conict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, hon-
oraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. NIH funding: Rimas V
Lukas, Priya Kumthekar, and Amy B Heimberger are all supported by: P50 CA221747 (CA/NCI NIH HHS/United States).
No writing assistance was utilized in the production of this manuscript.
References
Papers of special note have been highlighted as: •of interest; •• of considerable interest
1. Domenech M, Fabregat-Franco C, Mesia C et al. Long-term results of the GEINO 1401 TRIAL: randomizing patients to stop or to
continue temozolomide until 12 cycles. J. Clin. Oncol. 39(Suppl. 15), 2013 (2021).
•This negative phase III trial demonstrated lack of benefit from additional cycles of temozolomide for patients with newly
diagnosed glioblastoma, demonstrating stability of disease after six adjuvant cycles.
2. Blumenthal DT, Gorlia T, Gilbert MR et al. Is more better? The impact of extended adjuvant temozlomide in newly diagnosed
glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG. Neuro On col. 19(8), 1119–1126 (2017).
3. Stupp R, Mason WP, van den Bent MJ et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J.
Med. 352(10), 987–996 (2005).
4. Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N.Engl.J.Med.
352(10), 997–1003 (2005).
5. Roth P, Gorlia T, Reijneveld JC et al. EORTC 1709/CCTG CE.8: a phase III trial of marizomib in combination with
temozolomide-based radiochemotherapy versus temozolomide-based radiochemotherapy alone in patients with newly diagnosed
glioblastoma. J. Clin. Oncol. 39(Suppl. 15), 2004 (2021).
•This negative phase III trial demonstrated lack of benefit from adding the brain-penetrant proteasome inhibitor marizomib to
the standard of care treatment for newly diagnosed glioblastoma.
6. Roth P, Mason WP, Richardson PG, Weller M. Proteasome inhibition for the treatment of glioblastoma. Expert Opin. Invest. Drugs.
29(10), 1133–1141 (2020).
7. Brastianos PK, Twohy E, Geyer SM et al. Alliance A071601: phase II trial of BRAF/MEK inhibition in newly diagnosed papillary
craniopharyngiomas. J. Clin. Oncol. 39(Suppl. 15), 2000 (2021).
•• This is the first prospective clinical trial demonstrating substantial radiographic response in the majority of craniopharyngioma
patients receiving systemic therapy.
8. Brastianos PK, Shankar GM, Gill CM et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted
therapy. J. Natl Cancer Inst. 108(2), djv310 (2015).
9. Juratli TA, Jones PS, Wang N et al. Targeted treatment of papillary craniopharyngiomas harboring BAF V600E mutations. Cancer
125(17), 2910–2914 (2019).
10. Brastianos PK, Taylor-Weiner A, Manley PE et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat.
Genet. 46(2), 161–165 (2014).
4428 Future O ncol. (2021) 17(33) future science group

ASCO Neuro-Onc meeting report Conference Report
11. Ahluwalia MS, Rauf Y, Li H et al. Randomized phase 2 study of nivolumab (nivo) plus either standard or reduced dose bevacizumab
(bev) in recurrent glioblastoma (rGBM). J. Clin. Oncol. 39(Suppl. 15), 2015 (2021).
12. Nayak L, Molinaro AM, Peters K et al. Randomized phase II and biomarker study pembrolizumab plus bevacizumab versus
pembrolizumab alone for patients with recurrent glioblastoma. Clin. Cancer Res. 27(4), 1048–1057 (2021).
13. Ducray F, Sanson M, Chinot OL et al. KS02.4. A olaparib in recurrent IDH-mutant high-grade glioma (OLAGLI). J. Clin. Oncol.
35(Suppl. 15), 2007 (2021).
14. Lu Y, Kwintkiewicz J, Liu Y et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP-1 mediated DNA repair.
Cancer Res. 77(7), 1709–1718 (2017).
15. IDH-mutant tumors vulnerable to PARP inhibition. Cancer Discov. 7(4), OF4 (2017).
16. Idbaih A, Ducray F, Stupp R et al. A phase I/IIa study to evaluate the safety and efficacy of blood–brain barrier (BBB) opening with the
SonoCloud-9 implantable ultrasound device in recurrent glioblastoma patients receiving IV carboplatin. J. Clin. Oncol. 39(Suppl. 15),
2049 (2021).
•This phase I/IIa trial of implantable ultrasound for blood–brain barrier disruption in recurrent glioblastoma demonstrated
feasibility, safety and evidence of blood–brain barrier disruption.
17. Zhang DY, Dmello C, Chen L et al. Ultrasound-mediated delivery of paclitaxel for glioma: a comparative study of distribution, toxicity,
and efficacy of albumin-bound versus cremaphor formulations. Clin. Cancer Res. 26(2), 477–486 (2020).
18. Sonabend AM, Stupp R. Overcoming the blood–brain barrier with an implantable ultrasound device. Clin. Cancer Res. 25(13),
3750–3752 (2019).
19. Sabbagh A, Beccaria K, Ling X et al. Opening of the blood–brain barrier using low-intensity pulsed ultrasound enhances responses to
immunotherapy in preclinical glioma models. Clin. Cancer Res. 27(15), 4325–4337 (2021).
20. Nabors LB, Lamb LS, Beelen MJ et al. Phase 1 trial of drug resistant immunotherapy: a first-in-class combination of MGMT-modified
γδ t cells and temozolomide chemotherapy in newly diagnosed glioblastoma. J. Clin. Oncol. 39(Suppl. 15), 2057 (2021).
21. Odia Y, Sumrall AL, Cloughesy TF et al. Single agent activity of ONC201 in non-midline H3 K27M-mutant diffuse gliomas. J. Clin.
Oncol. 39(Suppl. 15), e14037 (2021).
22. Chi AS, Tarapore RS, Hall MD et al. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2
antagonist ONC201. J. Neurooncol. 145(1), 97–105 (2019).
23. Sloan AE, Buerki RA, Murphy C et al. LUMINOS-101: Phase 2 study of PVSRIPO with pembrolizumab in recurrent glioblastoma. J.
Clin. Oncol. 39(Suppl. 15), TPS2065 (2021).
24. Desjardins A, Gromeier M, Herndon JE 2nd et al. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379(2),
150–161 (2018).
25. Gravina GL, Senapedis W, McCauley D et al. Nucleo-cytoplasmic transport as a therapeutic target of cancer. J. Hematol. Oncol. 7, 85
(2014).
26. Wijetunga NA, Boire AA, Yamada Y et al. Cerebrospinal fluid circulating tumor cells as a predictive biomarker for proton craniospinal
irradiation for leptomeningeal metastases. JClinOncol.39(Suppl. 15), 2011 (2021).
•This study demonstrated the an association between cerebrospinal fluid circulating tumor cells and survival outcomes in patients
with solid tumor leptomeningeal metastases treated with craniospinal irradiation.
27. Raimondi L, Naso G, Lazzeroni R et al. Usefulness of assessment of circulating tumor DNA (ctDNA) of cerebrospinal fluid (CSF)
samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC). J. Clin. Oncol. 39(Suppl.
15), 507 (2021).
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