Rachel Narozniak, MA

Positive preliminary data from the phase 1 DUET-1 study (NCT03411915) examining XmAb18087 (tidutamab) in patients with neuroendocrine tumors (NETs) demonstrated promising safety and efficacy findings. The humanized anti–somatostatin receptor 2 (SSTR2), anti-CD3 bispecific antibody induced a disease control rate (DCR) of 43% across dose levels, thereby supporting further study of the agent in this patient population.

“XmAb18087 induced acute and sustained T-cell activation and proliferation…in peripheral blood and was generally well tolerated at the [0.3 to 1.0 μg/kg] expansion dose,” said Bassel El-Rayes, MD, during a presentation at the North American Neuroendocrine Tumor Society (NANETS) 2020 Multidisciplinary NET Medical Virtual Symposium.

Investigators enrolled 27 patients with low- and intermediate-grade, well-differentiated NETs in the trial. Patients were spread across 4 dosing groups and received XmAb18087 at the following levels: group 1 (n = 5) at 0.1 μg/kg; group 2 (n = 5) at 0.1 to 0.3 μg/kg; group 3 (n = 12) at 0.3 to 1.0 μg/kg; and group 4 (n = 5) at 1.0 to 2.0 μg/kg. The determined maximum tolerated dose (MTD) of XmAb18087 was 0.3 to 1.0 μg/kg. The pharmacokinetic (PK) profile was dose proportional at priming and repeated doses. The agent’s median half-life was 94 hours or approximately 4 days.

Specifically, the DCR among the 14 evaluable patients assessed at the August 26, 2020, data cutoff was 75% in group 1, 33% in group 2, and 29% in group 3. No patients in group 4 met the criteria for the objective response analysis and consequently were not included in the assessment. The best overall response was stable disease, with a median treatment duration of 7 months.

Across dosing levels, cytokine release syndrome (CRS) was restricted to grades 1 (22%) and 2 (19%) and limited to the first 2 doses of XmAb18087. In sum, investigators reported CRS in 41% of patients, which began at the 0.3 μg/kg dose.1 Notably, they observed 2 dose-limiting toxicities, nausea and vomiting, at the group 4 dose level, each of which affected 60% of patients treated at this dose.

“These events may be related to engagement of the somatostatin receptor 2 that has been identified in the gastrointestinal tract,” said El-Rayes, who is associate director for clinical research at Winship Cancer Institute of Emory University, and professor and vice chair for clinical research in the Department of Hematology and Medical Oncology at Emory University School of Medicine, both in Atlanta, Georgia.

A safety evaluation of grade 3 and 4 adverse effects (AEs) that investigators reported for 2 or more patients in the overall population showed that lymphopenia or decreased lymphocyte count was the most common toxicity affecting 41% of patients.1 However, “no apparent deleterious clinical effects” were observed in patients who experienced lymphopenia or decreased lymphocyte count, El-Rayes said, adding that “transient cytopenia is characteristic of CD3 antibody therapy after the first dose.”

Beyond lymphopenia or decreased lymphocyte count, the most frequently observed AEs were increased g-glutamyl transferase (19%), vomiting (19%), increased alanine aminotransferase/ aspartate transaminase (19%), and nausea (15%). Investigators reported no grade 5 treatment-emergent AEs. Most patients (n = 24) discontinued XmAb18087 monotherapy for various reasons, including disease progression (n = 12), withdrawn consent (n = 6), AEs (n = 4), physician decision (n = 1), and other (n = 1).

Anticancer activity seen with XmAb18087 stems from the antibody’s direction of T-cell– mediated cytotoxicity to SSTR2-positive tumor cells.

 SSTR2 is highly overexpressed in NETs, but existing evidence has shown that high SSTR2 expression correlates with favorable prognoses.

The DUET-1 study was initiated to test the safety and tolerability of XmAb18087 in patients with NETs of the pancreas, gastrointestinal tract, lungs, and of undetermined origin. The dual primary end points were to identify the MTD and/or recommended dose of XmAb18087 and the schedule. Secondary end points included characterization of PKs and immunogenicity and assessing preliminary antitumor activity via RECIST 1.1 criteria.

Samples were collected for PK and pharmacodynamic evaluation in peripheral blood “at multiple points throughout treatment,” said El-Rayes, who also serves as the director of the Gastrointestinal Oncology Program at Winship Cancer Institute. Antitumor activity was evaluated through objective response rate, duration of response, and progression-free survival PFS), with imaging performed at screening and at the end of every third treatment cycle for response assessment.

Examining biomarkers of CRS and characterizing immune response in peripheral blood based on changes in lymphocyte subsets and markers of T-cell activation and exhaustion were key exploratory end points of the study.

Regarding dosing, patients received XmAb18087 as a 2-hour intravenous infusion on days 1, 8, 15, and 22 of each 28-day cycle. Investigators administered a priming dose on day 1 of the first cycle and followed this initial dose with a higher, repeated dose of XmAb18087 on subsequent dosing days. All patients received at least 1 dose of XmAb18087. Prophylaxis for CRS, nausea, and vomiting was given to each of the 27 patients through cycle 1 at a minimum.

Trial eligibility requirements included histologically or cytologically confirmed grade 1 or 2 NETs that were either locally advanced and unresectable or metastatic. Patients must also have experienced disease progression within the past 12 months, progressed on or demonstrated unsuitability for somatostatin analogs and at least 1 other targeted therapy, and had an ECOG performance status of 0 or 1.

Most patients (56%) initially presented with a lesion in the pancreas. Initial intestinal and pulmonary lesions were each reported in 15% of patients, with other gastroenteropancreatic and NETs of unknown origin each accounting for 7% of patients.

Although the preliminary data from DUET-1 are encouraging, completion of enrollment in the MTD expansion cohort, which will enroll a maximum of 20 patients, and longer follow-up are required to evaluate PFS and the clinical utility of XmAb18087 in this patient population, El-Rayes concluded.

1. El-Rayes B, Pant S, Villalobos V, et al. Preliminary safety, PK/PD, and antitumor activity of XmAb18087, an SSTR2 x CD3 bispecific antibody, in patients with advanced neuroendocrine tumors. Poster presented at: NANETS 2020 Multidisciplinary NET Medical Virtual Symposium; October 2-3, 2020. Abstract 111.

2. Qian ZR, Li T, Ter-Minassian, et al. Association between somatostatin receptor expression and clinical outcomes in neuroendocrine tumors. 

. 2016;45(10):1386-1393. doi:10.1097/MPA.000000000000070

Articles

Positive preliminary data from the phase 1 DUET-1 study examining XmAb18087  in patients with neuroendocrine tumors demonstrated promising safety and efficacy findings. 





Clinical Investigation Into Antibody With Activity Against SSTR2 and CD3 Moves Forward

Adjuvant treatment with anti–PD-L1 therapy demonstrated a numerically increased but not statistically significant improvement in disease-free survival (DFS) compared with observation in patients with muscle-invasive urothelial carcinoma (MIUC) in a primary analysis presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program. DFS was the primary end point of the IMvigor010 study, which was not met. 

At a median follow-up of 21.9 months, the DFS rate in each arm was 52%. The median DFS was 19.4 months (95% CI, 15.9-24.8) with atezolizumab (Tecentriq) versus 16.6 months (95% CI, 11.2-24.8) for observation (HR, 0.89; 95% CI, 0.74-1.08; 2-sided 

IMvigor010 (NCT02450331), the first phase 3 study of an immune checkpoint inhibitor (ICI) in MIUC, enrolled 809 patients at a high risk of recurrence following primary resection, 406 of whom were randomized to atezolizumab, and 403 to observation.

"This difference did not translate to a significant hazard ratio," said lead author Maha H. A. Hussain, MD, deputy director of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University's Feinberg School of Medicine in Chicago, Illinois.

The 18-month DFS rate was 51% (95% CI, 46%-56%) and 49% (95% CI, 44%-54%) in the atezolizumab and observation arms, respectively. Beyond IMvigor010's overall population, atezolizumab also failed to confer a DFS advantage in patient subgroups stratified by PD-L1 status. "Irrespective of the PD-L1 status, there were no trends in favor of atezolizumab in both arms," Hussain said.

The PD-L1 IC0/1 subgroup included 210 patients who were randomized to atezolizumab and 207 assigned to observation. The rate of DFS events was 56% and 58%, respectively (HR, 0.81; 95% CI, 0.63-1.05). Among patients in the PD-L1 IC2/3 subgroup, the rate of DFS was 48% in the 196 patients in the atezolizumab arm and 45% in the 196 patients under observation (HR, 1.01; 95% CI, 0.75-1.35).

"I would point out that there appears to be a prognostic effect for IC23 PD-L1 status [when compared with] the IC0 and IC1, as reflected by a better disease-free survival," Hussain said.

No trends favored atezolizumab across any of the prespecified clinical subgroups including the overall population and patients with bladder staging (n = 755); upper tract staging (n = 54); patients who received prior neoadjuvant chemotherapy (n = 385); positive pathologic node status (n = 420), pT2N0 (n = 73), pT3N0 (n = 243), and pT4N0 (n = 65); as well as various geographic subgroups.





The median overall survival (OS) was not reached in either arm, and the rate of survival events was 29% with the ICI and 31% with observation. The HR was 0.85 (95% CI, 0.66-1.09; 

 = .1951). Data from the interim OS analysis is not yet mature and follow-up is ongoing, Hussain said. She added that additional exploratory biomarkers and subgroup analyses "may warrant further study."

Atezolizumab's safety profile was consistent with what was seen in prior investigations of the single-agent in the advanced UC setting, but investigators observed more treatment continuation due to adverse events (AEs) in IMvigor010 compared with other studies in metastatic UC with atezolizumab monotherapy. The events that prompted discontinuation were mostly skin and gastrointestinal in nature. AEs leading to atezolizumab discontinuation affected 16% of patients receiving the ICI; 33% of patients required AEs dose interruption. Data was not available for either of these measures in the placebo arm.

AEs of any cause were observed in 94% of atezolizumab-treated participants and in 79% of placebo-receiving patients. Serious AEs and grade 3/4 AEs of any cause were also more common with atezolizumab (31% vs 18%; 37% vs 20%). The rate of grade 5 AEs was 2% in each arm.

Grade 1/2 AEs of special interest also occurred at a higher incidence in the atezolizumab group according to Hussain, who said the most common treatment-emergent AEs were pruritus, fatigue, diarrhea, and rash.





To be eligible for IMvigor010, patients were required to undergo radical cystectomy or nephroureterectomy with lymph node dissection 14 weeks or earlier prior to registration. Patients were not permitted to receive postsurgical radiation or adjuvant chemotherapy. If a patient had not received neoadjuvant chemotherapy, the patient had to be ineligible for or declined cisplatin-based adjuvant chemotherapy. Additional eligibility criteria included an ECOG performance status of 0 to 2 and tissue available for PD-L1 testing.

Patients were randomized 1:1 to 1200 mg of atezolizumab once every 3 weeks for a maximum of 16 cycles or 1 year or observation, conducted once every 3 weeks. To assess disease recurrence and survival, tumor assessments were performed once every 12 weeks from years 1 to 3; once every 24 weeks from year 4 to year 5 and at year 6.

Although atezolizumab monotherapy did not translate to a statistically significant DFS benefit in this patient population, advancing the MIUC treatment paradigm is critical due to the lethality of the disease despite treatment with curative intent and the absence of conclusive, level 1 evidence for adjuvant chemotherapy in this setting, where up to 50% of patients are not eligible for standard-of-care neoadjuvant, cisplatin-based chemotherapy.

Evaluations of atezolizumab's efficacy in this space are ongoing, said Hussain. "Other clinical trials [of] atezolizumab monotherapy and [atezolizumab in] combination [with other agents] are underway in a variety of disease settings in UC," Hussain concluded.

Hussain MHA, Powles T, Albers P, et al. IMvigor010: primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31. Abstract 5000. doi:10.1200/JCO.2020.38.15_suppl.5000

<< View more of Targeted Oncology's coverage from the 2020 ASCO Virtual Annual Meeting

"Irrespective of the PD-L1 status, there were no trends in favor of atezolizumab in both arms."

DFS Improvement Falls Short With Anti–PD-L1 in Muscle-Invasive Urothelial Cancer

The long-term benefit of adjuvant dabrafenib (Tafinlar) plus trametinib (Mekinist) as treatment of patients with resected, stage III 

 V600E/K-mutant melanoma were validated by 5-year data from the phase 3 COMBI-AD study, according to a presentation from the 2020 American Soceity of Clinical Oncology (ASCO) Virtual Scientific Program.

The 4- and 5-year relapse-free survival (RFS) rates were 55% (95% CI, 50-60) and 52% (95% CI, 48-58) with the doublet therapy versus 38% (95% CI, 34-43) and 36% (95% CI, 32-41) with placebo.

"There is a longer than 50% relapse-free survival," said lead study author Axel Hauschild, MD, during a presentation at the 2020 ASCO Virtual Scientific Program. "The relapse-free survival curves for both treatment arms appear to be reaching a plateau, which is a good sign if we are talking about cure."

These data, assessed at a median follow-up of 60 months in the dabrafenib and trametinib arm and 58 months in the placebo arm, correlated with RFS estimates provided by the Weibull mixture cure rate model, which approximated the fraction of patients who would remain RF long-term, said Hauschild, a professor of dermatology at the University Hospital Schleswig-Holstein, Campus Kiel, in Germany.



Data showed that 43% (190/438) of patients assigned to dabrafenib/trametinib had an RFS event compared with 61% (262/432) of patients assigned to placebo. At the data cutoff of November 8, 2019, the median RFS was not reached (NR) with the regimen (95% CI, 47.9-NR) versus 16.6 months (95% CI, 12.7-22.1) with placebo (HR, 0.51; 95% CI, 0.42-0.61).

"I don't need to say that this is a highly statistically significant difference," Hauschild said.

Investigators observed a long-term RFS advantage associated with dabrafenib/trametinib across all AJCC 7 substages. The hazard ratio was 0.61 (95% CI, 0.35-1.07) for stage IIIA disease; 0.50 (95% CI, 0.37-0.67) for stage IIIB; and 0.48 (95% CI, 0.36-0.64) for stage IIIC.

In patients with stage IIIA disease, the 4-year RFS rate was 72% (95% CI, 62-83) with the doublet therapy versus 62% (95% CI, 51-76) with placebo. At 5 years, the RFS rate was 65% (95% CI, 55%-77%) and 58% (95% CI, 46%-72%), respectively.

In patients with stage IIIB disease, 5-year RFS rate also favored dabrafenib/trametinib, 55% versus 34% (HR, 0.50; 95% CI, 0.37-0.67). In patients with stage IIIC disease, the 5 -year RFS rate was 45% (95% CI, 38%-53%) in the dabrafenib/trametinib arm and 29% (95% CI, 23%-37%) in the placebo arm (HR, 0.48; 95% CI, 0.36-0.64).

Although "it is very clear that all patient groups [benefited] from dabrafenib and trametinib compared with placebo," the combination modality did not reach statistical significance in patients with a 

 V600K mutation (n = 78) and the continent subgroup comprising Australia and New Zealand (n = 107). Hauschild said that result could be due to the small number of patients in these subgroups.

Notably, the median distant metastasis-free survival was NR in either arm, but favored the combination approach (HR, 0.55; 95% CI, 0.44-0.70). The 5 year DFS rate was 65% (95% CI, 61-71) in the dabrafenib plus trametinib group and 54% (95% CI, 49-60) in the placebo group.

"DMFS was counted only if this was the patient's first relapse," Hauschild said. "If this was distant relapse after a local relapse, it was not counted in this analysis."

Overall survival was not updated at this data cutoff because the prespecified number of events for the final OS analysis had not yet occurred. The event-driven final OS analysis will be reported in the future, Hauschild said. Safety data were also not updated in this 5 year analysis because all patients completed treatment.





COMBI-AD (NCT01682083) enrolled 870 patients with completely resected, stage III cutaneous melanoma that harbored a 

 V600E or V600K mutation. Eligible patients were required to have undergone resection 12 weeks or earlier prior to randomization, must not have received prior systemic therapy, and had an ECOG performance status of 0 to 1.

The 438 patients assigned to the doublet therapy were treated with 150 mg of dabrafenib twice daily plus 2 mg of trametinib once daily. The remaining 432 patients received 2 matched placebo tablets. In both arms, treatment was administered for a period of 12 months.

At a median follow-up of 2.8 years, the estimated 3-year RFS rate was 58% with the regimen and 39% with placebo (HR, 0.47; 95% CI, 0.39-0.58; 

The 3 -year OS rate was 86% among dabrafenib/trametinib-treated patients and 77% among placebo-receiving patients (HR, 0.57; 95% CI, 0.42-0.79; 

 = .0006), however, this improvement did not cross the prespecified interim analysis boundary of 

 = .000019. Rates of DMFS were also higher in the combination therapy group compared with the placebo group.

1. Hauschild A, Dummer R, Santinami M, et al. Long-term benefit of adjuvant dabrafenib + trametinib (D+T) in patients (pts) with resected stage III BRAF V600-mutant melanoma: five-year analysis of COMBI-AD. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31. Abstract 10001.

2. Long GV, Hauschild A, Santinami M, et al. Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813-1823. doi: 10.1056/NEJMoa1708539

The long-term benefit of adjuvant dabrafenib plus trametinib as treatment of patients with resected, stage III BRAF V600E/K-mutant melanoma were validated by 5-year data from the phase 3 COMBI-AD study.

Long-Term Benefit of Dabrafenib Plus Trametinib in Melanoma Confirmed in 5-Year Follow-Up of COMBI-AD Study

muta&shy;tions may receive benefit by the use of PARP inhibitors, with investigators initi&shy;ating clinical trials in patients across multiple different tumor types to determine the efficacy of this strategy.

Encouraging preclinical data have indicated that mutations in

produce homologous recombination (HR) defects causing tumor cells to be sensitized to PARP inhibition.

&ldquo;The correct way [to approach these malig&shy;nancies] is not to think that all mutations are drivers that should be inhibited, but rather that there are mutations that are creating vulnerabil&shy;ities that can be exploited,&rdquo; said Louis Weiner, MD, who moderated the American Association for Cancer Research (AACR) Annual Meeting in 2017, where the findings from 2 studies of PARP inhibitors in

Data from Parker L. Sulkowski and colleagues were presented by study coauthor, Ranjit Bindra, MD, PhD, and showed that

mutations induce an HR defect in tumor cells. Cells that carry HR defects cannot perform the DNA repair necessary to reverse the damage that results from radiation and chemotherapy; consequently, these cells enter apoptosis, a pro&shy;cess of programmed cell death that eliminates dysfunctional cells.

mutations confer renders these cells sensitive to PARP inhibition, which further obstructs DNA repair. When used to treat tumors with HR defects, PARP inhibitors such as olaparib (Lynparza) lower tumor cells&rsquo; ability to repair DNA and cause them to die in a process known as syn&shy;thetic lethality. This mechanism of action causes PARP inhibition to be an effective approach in tumors with these defects.

Based on these findings, a single-arm phase II trial (NCT03212274) will evaluate olapa&shy;rib monotherapy in up to 145 patients with

&ldquo;By giving olaparib, we&rsquo;re capitalizing on the fact that tumors with

mutations don&rsquo;t repair DNA properly,&rdquo; Roman Groisberg, MD, principal investigator of the study&rsquo;s 2 sites at the Rutgers Cancer Institute of New Jersey and the Robert Wood Johnson University Hospital, both of New Brunswick, New Jersey, said in an interview with

&ldquo;We&rsquo;re giving these cells a double whammy, prompting them to go into cell death,&rdquo; added Groisberg, who is also a medical oncologist at the Rutgers Cancer Institute.

Research by Sulkowski and colleagues not only established that

-mutated cells have reduced DNA repair capability but also showed that 2-hydroxyglutarate (2-HG) may be the driving force of this cellular weakness.

mutations are neomorphic, meaning that the alterations induce a change in the traditional function of the IDH protein. Whereas normal, unmutated IDH proteins produce energy, mutat&shy;ed proteins generate the 2-HG oncometabolite, which amplifies HR deficiency, and consequently, sensitivity to PARP inhibitors.

mutations lead to decreased HR repair, which is the same thing as saying [

-mutated disease] has a &lsquo;BRCAness&rsquo; phenotype. Tumors with these HR defects also respond to PARP inhibitors, even if they don&rsquo;t have a

-altered tumor cells to resemble breast and ovarian cancer cells that harbor mutations in

, according to Bindra, an expert in therapeutic radiology at the Smilow Cancer Hospital Care Center at Yale New Haven in Connecticut. In breast and ovarian cancers,

mutations weaken cells&rsquo; DNA-repair ability, similarly ren&shy;dering these malignancies susceptible to PARP inhibition.

Data, Groisberg said, have shown that olaparib works particularly well in patients with

Findings from Sulkowski et al&rsquo;s study suggested that olaparib&rsquo;s efficacy extends to disease that harbors an

-mutated human glioma cells, bone marrow cultures from patients with

-mutated acute myeloid leukemia (AML), and xenograft models implanted with

-mutated human tumor cells were each sen&shy;sitive to PARP inhibition. Investigators treated the mice with either olaparib monotherapy at 50 mg/kg daily or vehicle control and noted an 8-fold difference in tumor growth delay that favored olaparib over the control (analysis of variance,

.001). The superiority of sin&shy;gle-agent olaparib over vehicle control was seen with the human glioma cells and bone marrow cultures, investigators said.

Moreover, data from Sulkowski et al&rsquo;s study also indicated that IDH inhibitors may not be the best therapeutic intervention for tumors with

driver mutations. Investigators tested 3 small molecule IDH inhibitors in

altered colon and cervical cancer cells and found that the precision therapies blocked production of 2-HG, consequently reducing cell sensitivity to PARP inhibition. The HR defect and consequent vulnerability to PARP inhibition that

mutations engender creates a cellular weakness that can and should be targeted in the treatment of

They added that the findings should motivate further clinical study of the agents in

- mutated gliomas specifically, as well as other cancers with

muta&shy;tions occur in approximately 60%, 20%, and 10% of chondrosarcomas, intrahepatic cholangiocar&shy;cinomas, and AMLs, respectively.

mutations are known to present in a vari&shy;ety of diseases, including melanoma, colon, and lung cancers, according to Simon Khagi, MD, principal investigator of the phase II study&rsquo;s site at UNC Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina, who was interviewed by

In the phase II study of olaparib in patients with

-mutated glioma, cholangiocar&shy;cinoma, and other solid tumors, investigators will use mass spectrometry at baseline and at various points throughout the trial to assess the 2-HG concentration in patients&rsquo; blood. They will also examine the levels of 2-HG present in tumor biopsies before treatment initiation and thereafter. In both cases, investigators will assess whether 2-HG concentration correlates with response to olaparib.

The primary end point is overall response rate in the 3 cohorts of glioma, cholangiocarcinoma, and other solid malignant tumors. Secondary end points include progression-free survival, overall survival, durations of response, and adverse events (

). Patients will receive olaparib twice a day on days 1 through 28. Treatment cycles will repeat every 28 days until disease progression or unacceptable toxicity.

Olaparib is currently indicated as a main&shy;tenance therapy for adults with deleterious or suspected deleterious somatic or germline

m) advanced epithelial ovarian, fallopian tube, or primary perito&shy;neal cancer who are in complete or partial response (CR; PR) to first-line platinum-based chemotherapy. It is also approved for the treat&shy;ment of patients with deleterious or suspected deleterious g

m, HER2-negative metastat&shy;ic breast cancer who have been treated with chemotherapy either in the neoadjuvant, adju&shy;vant, or metastatic setting.

The agent has additionally been cleared for use in g

m metastatic pancreatic adenocarcinoma, and is presently under priority review in combination with bevaci&shy;zumab (Avastin) as a potential front-line main&shy;tenance treatment for women with advanced ovarian cancer who are in CR or PR to first-line platinum-based chemotherapy with bevacizumab.

Gliomas, cholangiocarcinomas, and solid tumors such as chondrosarcomas are rare diseases, and the need for new treatment options is great, Groisberg said. Gliomas are central nervous system tumors that develop in approximately 6.6 per 100,000 individuals each year.

Cholangiocarcinomas affect a 8000 people annually in the United States; chondrosarcomas, 1 person in 1 million.

Because patients with high-grade gliomas (grade III to grade IV) are not candidates for surgery, radiation and temozolomide (Temo&shy;dar) chemotherapy are the standard of care, Groisberg explained.

&ldquo;In adults, gliomas are almost always univer&shy;sally high-grade and fatal. There is no curative treatment for these patients and they all will progress,&rdquo; Groisberg said. &ldquo;These patients are desperate for novel treatments, which have not come in many, many years,&rdquo; he added.

In high- and low-grade gliomas (grade I to grade II) and secondary glioblastomas,

mutations, which occur in >80% of low-grade gliomas and secondary glioblastomas, are biomarkers for longer survival and greater sensitivity to radiation and/or chemotherapy.4 Although

alterations can guide treatment in these patient populations, Khagi said there is nevertheless a &ldquo;significant need for improve&shy;ment in the management of all diseases with

is indicative of better over&shy;all survival in gliomas, high-grade or low-grade, the majority of these patients are still dying of their disease. They may just be dying a little bit later than someone without an

mutation,&rdquo; said Khagi, who directs UNC&rsquo;s neuro-oncology and brain metastases programs.

Prognoses for cholangiocarcinomas are not much better than those for high-grade gliomas, Groisberg said. Chemotherapy will elicit an initial response in patients with cholangio&shy;carcinomas, but eventually stops working, at which point few treatment options remain. A minority of cholangiocarcinomas harbor fibro&shy;blast growth factor receptor fusions that can be addressed with targeted therapy, but this constitutes a small percentage of the patient population, Groisberg added.

&ldquo;The rest of them don&rsquo;t have much by way of therapy,&rdquo; he said. &ldquo;Other [approaches] like immunotherapy have not been successful in cholangiocarcinomas, so there is a huge amount of unmet need.&rdquo;

Treatment options are especially dismal for those with chondrosarcomas, a disease for which there are &ldquo;no effective systemic ther&shy;apies,&rdquo; Groisberg said. &ldquo;No chemotherapies work for chondrosarcomas; once they progress beyond a surgeon&rsquo;s ability to cut out the disease, there is effectively no hope for these patients at all,&rdquo; he added.

Investigators of the phase II study will probe for benefit with olaparib monotherapy, but when it comes to advancing the treatment paradigm for each of these orphan diseases, a single-agent approach might not be the only anti-PARP intervention that warrants clinical exploration, Khagi said.

mutations in glioma, cholangiocarcinomas, and chondrosarcomas, and it may not just be single-agent PARP inhibition; it may be a com&shy;bination of PARP inhibition with chemotherapy to exploit multiple pathways of vulnerability,&rdquo; Khagi said.

Of note, research from Lu et al, also present&shy;ed at the AACR Annual Meeting 2017, showed that targeting the PARP-affiliated DNA repair pathway significantly sensitized

-mutat&shy;ed glioma cells to temozolomide. The finding supports the notion that PARP inhibition coupled with concurrent temozolomide-based chemotherapy represents a potential treatment strategy for gliomas, pending further investigation.

The phase II study of olaparib monotherapy is currently recruiting across 33 sites nation&shy;wide and is slated to conclude in July 2020.

Sulkowski PL, Corso CD, Robinson ND, et al. 2-hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity.

. 2017;9(375):eeaal2463. doi: 10.1126/scitranslmed.aal2463.

Ravoori S. AACR Annual Meeting 2017: challenging the dogma of treating

-mutant cancers with IDH inhibitors. American Association for Cancer Research website.

. Published April 11, 2017. Accessed January 14, 2019.

NCI staff. PARP inhibitors may be effective in brain, other cancers with IDH mutations. National Cancer Institute website. bit.ly/2IaxHeZ. Published April 24, 2017. Accessed January 14, 2020.

Molenaar RJ, Maciejewski JP, Wilmink JW, van Noorden CJF. Wild-type and mutated IDH1/2 enzymes and therapy responses.

. 2018;37(15): 1949-1960. doi: 10.1038/s41388-017-0077-z.

Lynparza [prescribing information]. Kenilworth, NJ: AstraZeneca; 2014. bit.ly/2TgB9K6. Accessed September 17, 2020.

Lynparza (olaparib) regulatory submission granted priority review in US for 1st-line maintenance treatment with bevacizumab in advanced ovarian cancer [news release]: Kenilworth, NJ. AstraZeneca and Merck & Co, Inc. Published January 13, 2020. bit.ly/2vmrxFF. Accessed January 17, 2020.

Leveille E, Taylor J. Glioma. National Organization for Rare Disorders. bit.ly/2PqzwIE. Published 2019. Accessed January 17, 2020.

The American Cancer Society medical and editorial content team. Key statistics for bile duct cancer. The American Cancer Society website. bit.ly/2wIgVB8. Updated July 3, 2018. Accessed January 17, 2019.

Boehme KA, Schleicher SB, Traub F, Rolauffs B. Chondrosarcoma: a rare misfortune in aging human cartilage? The role of stem and progenitor cells in proliferation, malignant degeneration and therapeutic resistance.

. 2018; 19(1). doi: 10.3390/ijms19010311.

Lu Y, Kwintkiewicz J, Liu Y, et al. Chemosensitivity of IDH1-mutated gliomas due to an impairment in PARP1-mediated DNA repair.

. 2017;77(7):1709-1718. doi: 10.1158/0008-5472.CAN-16-2773.

Patients harboring IDH1/2 muta&shy;tions may receive benefit by the use of PARP inhibitors, with investigators initi&shy;ating clinical trials in patients across multiple different tumor types to determine the efficacy of this strategy.

Benefit of PARP Inhibitors May Extend to Certain Tumors With IDH Mutations

In a presentation describing the utility of circulating tumor DNA (ctDNA) liquid biopsy assays at the

, Bob T. Li, MD, MPH, said that plasma genotyping demsonstrates practice-changing potential in nonsmall cell lung cancer (NSCLC).

Li, an expert in lung cancers at Memorial Sloan Kettering Cancer Center (MSK), said, "ctDNA is probably at the forefront in terms of its potential to transform clinical practice."

The potential benefits of ctDNA liquid biopsy assays are manifold and start with the noninvasive, nonsurgical nature of this evolving approach. ctDNA liquid biopsies measure the small amounts of DNA that tumor cells shed into a patient&rsquo;s bloodstream. Although &ldquo;finding these tiny fragments of ctDNA is not a simple exercise,&rdquo; according to Li, the blood tests can identify the actionable mutations that can guide precision therapy faster than tissue next-generation sequencing (NGS) assays, which constitute the standard biopsy in NSCLC.

ctDNA NGS was superior to tissue NGS in finding oncogenic drivers in a recent study of 210 patients with advanced lung cancers. All patients underwent plasma NGS and a subset (n = 106) also had concurrent tissue NGS using the MSK-IMPACT 468-gene panel.

Findings showed that plasma ctDNA NGS detected a variety of mutations with a shorter turnaround time (TAT) compared with tissue NGS: the median TAT from the time of blood draw to the time of the primary investigator receipt of the report was 9 days with liquid biopsy versus 20 days with tissue biopsy (

Moreover, findings on plasma NGS were highly concordant with those on tissue NGS. Patients who were positive for oncogenic drivers via plasma NGS testing had tissue NGS concordance of 96.1% (49 of 51 patients; 95% CI = 86.5% to 99.5%).

Investigators of the study, conducted by MSK in collaboration with Resolution Bioscience, were able to immediately treat those who tested positive for an oncogenic driver based on the oncogenic driver uncovered by plasma NGS.

&ldquo;We rendered a clinical response in 22% of [these] patients,&rdquo; Li said. &ldquo;This was without waiting for the tissue [result] to take action.&rdquo;

The quicker TAT with plasma NGS and the ability that the liquid biopsy afforded investigators to specify the appropriate targeted therapy and initiate treatment would be of greatest benefit to patients with advanced NSCLC due to the lethality of late-stage disease, Li said.

Li cited 2 patients he treated at MSK as examples of ctDNA liquid biopsy&rsquo;s ability to enhance care. Both patients had lung cancer, but how the diagnosis came into focus differed for each of them. Li&rsquo;s first patient came to MSK in search of a second opinion. He&rsquo;d been diagnosed with stage IV colorectal (CRC) cancer and had been advised to begin chemotherapy.

Li didn&rsquo;t think the patient&rsquo;s disease resembled CRC on a CT scan and ordered a liquid biopsy. What the blood test returned: a diagnosis of lung cancer with an

gene fusion. The discovery enabled Li to promptly treat the patient with the second-generation ALK inhibitor alectinib (Alecensa).

The other patient had been correctly diagnosed with stage IV lung cancer that had spread to her lungs, bone, brain, liver, and leptomeninges. Again, a liquid biopsy found a mutation present that could be attacked with an agent indicated for the treatment of the oncogenic driver.

&ldquo;These patients were on their deathbeds,&rdquo; Li said. &ldquo;There [had been] insufficient tissue analysis and indeterminate results, but liquid biopsy found the driver, got them to the therapy, and resurrected them from their deathbeds.&rdquo;

Emerging data suggests that ctDNA can be used to monitor patients for treatment response; this information can be gleaned &ldquo;much earlier&rdquo; via liquid biopsy than via a CT scan, according to Li.

&ldquo;You can do it perhaps just one week into treatment to discern whether or not the treatment is working, so this is an adjunct to all symptom reporting and tracks very nicely with RESIST measurements,&rdquo; Li said. His caveat: this specific application of plasma NGS is in a nascent stage.

Questions such as, &ldquo;What is considered a partial molecular response? What is a complete molecular response? and What do either really mean for the patient?&rdquo; remain and require additional prospective research. If these questions can be answered in the future, then ctDNA liquid biopsy could emerge as an effective means of treatment monitoring in NSCLC, Li said.

Furthering the value of plasma NGS in the field is liquid biopsy&rsquo;s potential to guide precision therapy in the adjuvant setting through the detection of minimum residual disease (MRD) in early-stage lung cancers.

&ldquo;In early-stage lung cancer this gets incredibly exciting because before surgery or radiation you can find the tumor DNA in the blood, cut it out, and get [the DNA count] to zero, [at which point] the patient is cured,&rdquo; Li said.

With radiation, it can be difficult to tell when the PET scan becomes faint, he added. &ldquo;You don&rsquo;t know if the radiation is still working or how well it&rsquo;s working, but you can do a blood test and if [the DNA count] has gone to zero, the patient is cured.&rdquo;

On the other hand, if MRD is detected in the blood, &ldquo;you know the cancer is not finished,&rdquo; said Li, who also explained that a ctDNA MRD-negative test result forecasts cure, whereas a ctDNA MRD-positive test result forecasts recurrence.

Data from a retrospective study in which investigators sought to measure MRD in 255 blood and tissue samples from 40 patients with stage I to stage III lung cancer who had been treated with curative intent and 54 healthy adults demonstrated that ctDNA analysis identified posttreatment MRD indicative of residual and recurrent disease earlier than standard of care radiologic imaging. Specifically, liquid biopsy detected disease recurrence sooner than imaging in 72% of patients.

Investigators also assessed patients&rsquo; freedom from progression (FFP). At 36 months from the MRD landmark, FFP was 0% in patients with detectable ctDNA MRD and 93% in those with undetectable ctDNA MRD, respectively (

&ldquo;If you have a blood test that&rsquo;s negative after surgery or radiation, your cure rate is very, very high, but if it&rsquo;s positive, you&rsquo;ll get a relapse with a HR of 43.4. That&rsquo;s an enormous difference,&rdquo; Li said.

Knowledge of whether or not ctDNA MRD remains in a patient&rsquo;s blood post-therapy can empower oncologists to preemptively intercept the cancer before it embeds in the lung and liver, according to Li.

&ldquo;Perhaps you could cure some of the patients who are destined to relapse,&rdquo; he said. &ldquo;Randomized trials are being designed to keep the cancer out before it takes root, [which could] perhaps elevate the cure rates of early-stage lung cancer.&rdquo;

There are several ongoing studies of NGS analysis of ctDNA for early detection or MRD assessment of NSCLC, such as CAPP-Seq, TEC-Seq, CancerSEEK, and TRACERx.

Although liquid biopsies have &ldquo;an emerging role in treatment monitoring and in the MRD setting&rdquo; in NSCLC, Li emphasized that plasma NGS &ldquo;is already in the clinic.&rdquo;

&ldquo;It&rsquo;s in the National Comprehensive Cancer Network guidelines and it&rsquo;s a standard of care in advanced metastatic NSCLC,&rdquo; Li said.

Notably, the FDA has permitted the clinical use of assays presuming that they are CLIA certified and conducted in a lab, to assess technical validity and reproducibility. To date, the FDA has only approved one liquid biopsy assay, Roche&rsquo;s Cobas

Mutation Test v2 Plasma ctDNA, for the detection of

mutations including exon 19 del, exon 21 L858R, and exon 20 T790M in advanced stage lung cancers.

Despite this singular approval, ctDNA assays are nevertheless a highly active area of division and some have already obtained clearance from the New York State Department of Health, which imposes different, more stringent requirements for regulatory approval than other states. Guardant Health, GeneStrat, FoundationOne Liquid, Resolution Bioscience ctDx Lung, and MSK-ACCESS are among them.

Many other assays are currently in development exemplifying Li&rsquo;s statement, &ldquo;the technology is constantly evolving.&rdquo;

Li BT. The next big thing in lung cancer: liquid-based biopsies. Presented at: 14th Annual New York Lung Cancers Symposium

; November 9, 2019; New York, New York.  &nbsp; &nbsp;

Sabari JK, Offin M, Stephens D, et al. A prospective study of circulating tumor DNA to guide matched targeted therapy in lung cancers [published online November 28, 2018].

Chaudhuri AA, Chabon JJ, Lovejoy AF, et al. Early detection of molecular residual disease in localized lung cancer by circulating tumor DNA profiling.

. 2017;7(12):1394-1403. doi: 10.1158/2159-8290.CD-17-0716.

In a presentation describing the utility of circulating tumor DNA liquid biopsy assays at the 14th Annual New York Lung Cancers Symposium, Bob T. Li, MD, MPH, said that plasma genotyping demsonstrates practice-changing potential in non&ndash;small cell lung cancer.

Plasma Genotyping May Change Practice in NSCLC, Says Li

According to Tina Cascone, MD, PhD, neoadjuvant immunotherapy is under investigation for patients with nonsmall cell lung cancer (NSCLC) and holds hope as a treatment for patients.

&ldquo;We have learned that immune checkpoint inhibitors have an important role in the neoadjuvant setting," said Cascone, an assistant professor of thoracic and head and neck cancer at The University of Texas MD Anderson Cancer Center, in a presentation during the

"but there are a lot of questions that remain, such as the best therapy, number of doses, sequence versus combination, as well as the spatiotemporal modulation of the immune tumor microenvironment with these agents."

However, neoadjuvant immunotherapy is a highly active area of investigation and evolving data from preclinical models and clinical trials are expected to yield answers. For example, the ongoing, phase III CheckMate 77T (NCT04025879), KEYNOTE-671 (NCT03425643), IMpower030 (NCT034056063), and AEGEAN (NCT03800134) studies are evaluating nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), and durvalumab (Imfinzi), respectively, in combination with chemotherapy in patients with stage II to stage III resectable disease.

&ldquo;These trials will give us an opportunity to evaluate major pathologic response (MPR) and pathologic complete response (pCR) as surrogate endpoints for improved survival after neoadjuvant therapy,&rdquo; Cascone said. &ldquo;[In NSCLC], MPR [has been recognized] as predictive of improvement in long-term overall survival.&rdquo;

Establishing surrogate endpoints for clinical benefit is of paramount importance in NSCLC, because &ldquo;trials can take decades to complete and are expensive,&rdquo; Cascone added.

Surrogate endpoints should be sufficiently well correlated with clinical endpoints, in order to justify their employment, and they should capture the full net effect of the treatment on the clinical outcome, Cascone said, adding that the FDA may approve an agent based on an improvement in a surrogate endpoint.

Cascone highlighted the phase II Lung Cancer Mutation Consortium (LCMC3; NCT02927301) and NEOSTAR (NCT03158129) studies as those in which MPR was a key predictor of response to immunotherapy.

LCMC3 investigators evaluated neoadjuvant atezolizumab in 180 patients with operable stage IB to IIIB NSCLC. The agent induced an MPR in 19% and a pCR in 5% of patients in the primary efficacy population (n = 77) who went on to have complete surgical resection. Atezolizumab had positive activity and a favorable safety profile, affirming the PD-L1 inhibitor to be a viable treatment option in the neoadjuvant setting.

Notably, LCMC3 was the first study to release findings on preoperative atezolizumab in resectable NSCLC.

Cascone was the lead author of NEOSTAR, which randomized 44 patients with operable stage I to IIIA NSCLC to either single-agent nivolumab or nivolumab with ipilimumab (Yervoy). NEOSTAR&rsquo;s study of neoadjuvant nivolumab/ipilimumab was predicated on earlier evidence showing that treatment is more efficacious when given earlier and in combination with another agent.

&ldquo;In murine models of lung cancer, we have tested neoadjuvant and adjuvant therapies and found that neoadjuvant combined treatment is superior to neoadjuvant monotherapy and adjuvant therapy in improving survival and reducing lung metastases,&rdquo; Cascone said.

Beyond lung cancer, Liu et al have noted the superiority of neoadjuvant antiPD-1 therapy to adjuvant therapy in eradicating metastases in a murine breast cancer model.

Neoadjuvant immunotherapy is an attractive treatment modality because it increases PD-L1 expression. Targeting PD-L1 on cancer cells reverses CD8-positive tumor-infiltrating lymphocyte (TIL) dysfunction and suppresses metastases.

Results from the phase I CheckMate-012 trial (NCT01454102) of nivolumab plus ipilimumab in advanced NSCLC corroborated the positive activity previously witnessed in the murine models: the doublet elicited high response rates and prolonged progression-free survival. Findings from the murine models and CheckMate-012 provided the motivation for the NEOSTAR study, Cascone said.

In NEOSTAR, investigators observed a combined MPR and pCR of 25% (11 patients) in the intent-to-treat population (n = 44).

The joint MPR and pCR rate was 17% (95% CI, 0.05-0.39) in the nivolumab arm and 33% (95% CI, 0.15-0.57) in the nivolumab/ipilimumab arm, causing NEOSTAR to meet its prespecified trial efficacy boundary. The combination of nivolumab/ipilimumab as neoadjuvant therapy was associated with higher frequencies of CD3-positive TILs and increases in CD8-positive/CD103-positive (TRM) and CD4-positive/CD28-positive cell compartments.

As the investigators further define the role of neoadjuvant immunotherapy in NSCLC, combinations that include an immune checkpoint inhibitor and an antiCTLA-4 agent, or an intratumoral immunotherapy, or even a simulator of interferon genes protein agonist, will warrant further investigation, Cascone said. The same is true for biomarkers predictive of patient response to neoadjuvant therapy. &ldquo;Translational analyses are critical for biomarker discovery and subsequent patient selection in the next-generational trials,&rdquo; she added.

Adjuvant treatment is intended to eliminate micrometastatic disease; neoadjuvant therapy has the potential to &ldquo;downstage&rdquo; primary tumors, thereby augmenting the efficacy of adjuvant therapy, Cascone said. Moreover, a neoadjuvant approach might also decrease the morbid effects of surgery and enable subsequent analysis of the treated tumor.

The central role of neoadjuvant immunotherapy in the investigative push to further define the role of this therapy in resectable NSCLC and advance the field is evidenced by the bevy of phase II trials currently exploring immune checkpoint inhibitors, such as the NEOMUN (NCT03197467) and NADIM (NCT03081689) studies, as well as the platform NeoCOAST (NCT03794544) trial, Cascone said.

Cascone T. Perioperative immunotherapy for nonsmall cell lung cancer. Presented at: 14th Annual New York Lung Cancers Symposium

Blumenthal GM, Bunn PA Jr, Chaft JE, et al. Current status and future perspectives on neoadjuvant therapy in lung cancer.

. 2018;13(12):1818-1831. doi: 10.1016/j.jtho.2018.09.017.

Kwiatkowski DJ, Rusch VW, Chaft JE, et al. Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).

. 2019;37(suppl; abstr 8503). doi: 10.1200/JCO.2019.37.15_suppl.8503.

Chen L, Gibbons DL, Goswami S, et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression.

Liu J, Blake SJ, Yong MC, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease.

. 2016;6(12):1382-1399. doi: 10.1158/2159-8290.CD-16-0577.

Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab (N) or nivolumab plus ipilimumab (NI) for resectable non-small cell lung cancer (NSCLC): Clinical and correlative results from the NEOSTAR study.

According to Tina Cascone, MD, PhD, in a presentation during the 14th Annual New York Lung Cancers Symposium, neoadjuvant immunotherapy is under investigation for patients with&nbsp;non&ndash;small cell lung cancer and holds hope as a treatment for patients.