Jason Harris

Findings from the phase 2 REGOBONE study (NCT02389244) revealed that regorafenib (Stivarga) did not confer progression-free survival (PFS) benefit in patients with advanced or metastatic chordoma, according to a presentation given at the ESMO Congress 2021.

Investigators concluded that these findings show no benefit for regorafenib in patients with locally advanced or metastatic incurable chordoma. Furthermore, there is “no interesting activity” here to build on future combinations.

At 6 months, 40% (n = 6/14) of patients assigned to regorafenib were progression free (1-sided 95% CI, 20.6%). In the placebo arm, 2 of 5 patients were nonprogressive, for a progression-free rate (PFR) of 40% (1-sided 95% CI, 7.6). Regorafenib treatment would be deemed successful if at least 10 patients were progression-free at 6 months.

REGOBONE is a 5-arm, noncomparative study evaluating the efficacy and safety of regorafenib in patients with conventional high grade osteosarcoma, Ewing sarcoma of bone, intermediate or high-grade chondrosarcomas and chordomas and either bone or soft tissue metastatic CIC-rearranged sarcomas. Eligible adults had centrally confirmed locally advanced or metastatic chordoma without the possibility of cure and had progressive disease within 6 months of study entry.

Patients could have been treatment-naïve or received no more than 2 prior lines of therapy. All patients had ECOG performance score of 0 or 1.

Patients who received any prior treatment with a VEGFR inhibitor, had any other malignancy within 5 years, or had significant cardiovascular dysfunction were ineligible. Those who had undergone a major surgical procedure, open biopsy, or significant trauma within 28 days of enrollment were also excluded.

From March 2016 to February 2020, 27 patients with chordomas were enrolled onto the chordoma cohort. Sixteen patients were assigned to 160 mg regorafenib once daily for 21 days on a 28-day cycle plus best supportive care (BSC) until disease progression according to RECIST 1.1 criteria, intolerance or withdrawal of consent; 7 were assigned to placebo. Patients in the regorafenib arm who experienced disease progression could continue treatment if investigators determined the regorafenib was providing clinical benefit. Patients in the placebo arm crossed over to open-label regorafenib after objective tumor progression.

The primary end point was 6-month PFS rate, while main secondary end points were overall survival (OS) and safety. There was no formal statistical comparison between treatment groups.

The median age was 67.5 years (range, 33-85) in the experimental group and 54 years (range, 32-70) in the placebo group. Sixteen of the evaluable patients were men. Nine (56.2%) patients in the regorafenib group had an ECOG performance score of 1, as did 5 (71.4%) in the placebo group.

In the regorafenib group, 37.5% of patients had metastatic disease and 62.5% had locally advanced disease. Those numbers were 14.3% and 85.7%, respectively, in the placebo group.

At a median follow-up of 22.2 months, the median PFS was 8.2 months (95% CI, 4.5-12.9) and 10.1 months (95% CI, 0.8–not estimable) with regorafenib and placebo, respectively.

The median OS was 28.3 months in the experimental group but not reached with placebo. At 6 months, the OS rate was 88% (95% CI, 59%-97%) for regorafenib and 83% (95% CI, 27%-97%) for placebo. The 12-month OS rate was 88% (95% CI, 59%-97%) and 67% (95% CI, 19%-90%), respectively.

All patients in the placebo group had progressive disease, but only 4 (57%) crossed over. One patient withdrew consent, 1 died, and 1 was not eligible.

Twenty-five patients (n = 18 on regorafenib; n = 7 on placebo) were evaluable for safety. The most common grade 3 or higher regorafenib-related adverse events (AEs) during the double-blind period were hand-foot skin reaction (22.2%), hypertension (16.7%) and diarrhea (16.7%).

Two (11.1%) patients assigned to regorafenib had grade 3 or higher drug-related serious AEs. There was 1 incident each of pancreatitis and cholecystitis, and 1 patient developed pneumonia twice. There was one grade 3 or higher drug-related serious AE in the placebo group, which was a case of epilepsy.

No patient assigned to placebo discontinued treatment due to toxicity. Two (28.6%) had dose interruptions and 1 (14.3%) had a dose reduction.

Five (31.2%) discontinued treatment in the experimental group due to AEs. Eight (50.0%) had dose interruptions and 11 (68.8%) had dose reductions.

In findings from REGOBONE presented at the 2020 ESMO Virtual Congress, regorafenib improved 24-month PFS compared with placebo for patients with Ewing sarcoma but failed to meet the primary end point of non-progression at 8 weeks.

 At least 14 patients had to be progression free at 8 weeks for the trial to be considered a success. Thirteen (56.5%; 1-sided 95% CI, 37.5) patients in the regorafenib arm met the primary end point compared with 1 (7.7%; 95% CI, 0.4) in the placebo group.

1. Duffaud F, Chabaud S, Chereau CM, et al. Results of the randomized, placebo (PL)-controlled phase II study evaluating the efficacy and safety of regorafenib (REGO) in patients (pts) with relapsed advanced or metastatic chordoma, on behalf of the FrenchSarcoma Group (FSG) and Unicancer. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA58.

2. Duffaud F, Blay J-Y, Mir O, et al.. Results of the randomized, placebo (PL)-controlled phase II study evaluating the efficacy and safety of regorafenib (REG) in patients (pts) with metastatic relapsed Ewing sarcoma (ES), on behalf of the French Sarcoma Group (FSG) and UNICANCER. Presented at: 2020 ESMO Virtual Congress 2020; September 17- 21, 2020; virtual. Abstract LBA68.

Articles

Findings from the phase 2 REGOBONE study revealed that regorafenib did not confer progression-free survival benefit in patients with advanced or metastatic chordoma.





Regorafenib Shows No Survival Benefit in Advanced/Metastatic Chordoma

Post-hoc analysis results from the MRTX-500 trial (NCT02954991) show that the TAM and VEGFR2 targeted spectrum-selective tyrosine kinase inhibitor, sitravatinib (Sitra) administered in combination with nivolumab (Opdivo) elicited durable response and showed robust survival outcomes for patients with non-small cell lung cancer (NSCLC) who progressed after deriving benefit from treatment with a checkpoint inhibitor and/or platinum doublet chemotherapy.

According to results presented during the ESMO Congress 2021, the objective response rate (ORR) was 18%. Three percent of patients had a complete response (CR) and 15% of patients had a partial response (PR). The median duration of response (DOR) was 12.8 months.

The median progression-free survival (PFS) was 5.7 months (95% CI, 4.9-7.6). The median overall survival (OS) was 14.9 months (95% CI, 9.3-21.1). Fifty-six percent of patients were alive at 1 year and 32% were alive at 2 years.

“As many as 70% of patients with NSCLC have progression of their disease on or after receiving checkpoint inhibitor therapy, leaving these patients with a continued unmet medical need,” lead author Ticiana A. Leal, MD, director of the medical thoracic oncology program at the University of Wisconsin Carbone Cancer Center in Madison, said in a news release. “Targeting the TAM and VEGFR receptor tyrosine kinases has been shown to modulate the tumor microenvironment toward a less immunosuppressive state. The encouraging results presented today support combining sitravatinib with a checkpoint inhibitor to help augment the antitumor response.”

All patients with advanced NSCLC without oncologic addiction who are eligible for immunotherapy receive anti–PD-1/PD-L1 therapy plus a platinum-based doublet. Subsequent treatment is based on docetaxel and continuing treatment with the checkpoint inhibitor and adding another agent to overcome resistance is one option for improving outcomes. In this study, investigators added sitravatinib, a multikinase inhibitor with a strong rationale for boosting anti–PD-1/PD-L1 activity, to nivolumab.

As of October 2020, 68 patients had received 120 mg daily sitravatinib plus 240 mg nivolumab every 2 weeks or 480 mg nivolumab every 4 weeks in continuous 28-day cycles. Eligible patients had locally advanced, unresectable, or metastatic NSCLC and experienced progression after deriving benefit on or after treatment with a checkpoint inhibitor and/or platinum doublet chemotherapy. The anti–PD-1/PD-L1 treatment had to be the most recent line of therapy and patients had to have displayed CR, PR, or stable disease (SD) for at least 12 weeks. All patients had an ECOG performance score of 0 to 2.

Patients with uncontrolled brain tumors, actionable driver mutations, unacceptable toxicity with a checkpoint inhibitor, or impaired heart function were not eligible.

The median patient age was 66.0 years (range, 37-87). Most patients were women (57%), White (85%), and prior smokers (69%). Eighteen percent were never smokers.

Seventy-three percent of patients received platinum-based chemotherapy; 7% received cisplatin and 66% received carboplatin.

Nineteen (28%) received prior nivolumab, 45 (66%) received prior pembrolizumab, 3 (4%) received prior atezolizumab, and 1 (2%) received prior durvalumab. Two (3%) patients had CR, 30 (44%) had PR, and 36 (53%) had SD as the best response to prior therapy with a checkpoint inhibitor.

Most patients (66%) had an ECOG performance score of 1, 27% had a score of 0, and 7% had a score of 2.

The primary end point was ORR as defined by RECIST 1.1. Secondary end points included safety, tolerability, DOR, PFS, and OS.

Sixty-six percent of patients experienced grade 3/4 treatment-related adverse events, most often hypertension (22%) and diarrhea (16%). Sixty percent of patients required dose reductions of sitravatinib and 21% discontinued treatment.

“We have encouraging activity of this combination in patients with acquired and not primary resistance to anti–PD-1/PD-L1,” Maurice Perol, MD, of Centre Léon Bérard, Lyon, France, said in a discussant. “This benefit seems to be driven by some long-lasting responders or long lasting stability, but at the cost of a significant level of toxicity.”

1. Leal TA, Berz D, Rybkin I, et al. MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous (NSQ)non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1191O.

2. Phase 2 study of glesatinib, sitravatinib or mocetinostat in combination with nivolumab in non-small cell lung cancer. Accessed September 19, 2021. https://bit.ly/3koQ7MB

Results from the MRTX-500 trial show that sitravatinib administered in combination with nivolumab can elicit durable response and lead to robust survival outcomes for patients with non-small cell lung cancer who progressed after deriving benefit from treatment with a checkpoint inhibitor and/or platinum doublet chemotherapy.

Sitravatinib Plus Nivolumab Induces Durable Responses in Advanced NSCLC After ICIs, Chemotherapy

In the phase 3 SunRISe-2 trial (NCT04658862), investigators are assessing TAR-200 (GemRIS) plus cetrelimab as a treatment option for patients with muscle-invasive bladder cancer (MIBC). A presentation given by Stephen B. Williams, MD, MS, during the 2021 American Urological Association Annual Meeting indicated that the combination may offer superior outcomes for patients.

“Patients with MIBC often have poor prognosis and are at high risk for death. Standard treatment is neoadjuvant platinum-based chemotherapy for cisplatin-eligible patients followed by radical cystectomy, which is associated with high treatment burden,” said Williams, professor and chief of the Division of Urology at the University of Texas Medical Branch. “Trimodal therapy is another bladder sparing treatment, however, we have shown over 50% of MIBC patients receive no definitive therapy. The combination of TAR-200 and cetrelimab is being studied to determine whether it can improve patient outcomes.”

Williams went on to say that TAR-200 is a novel, intravesical drug delivery system enabling sustained release of gemcitabine into the bladder, which increases dwell time and local drug dose. “Treatment with TAR-200 has demonstrated early clinical benefit with favorable toxicity in patients with MIBC. Cetrelimab is an investigational immunoglobulin g4 antibody that targets the PD-1 receptor, blocking signaling from both PD-L1 and PD-L2.”

SunRISe-2 is a prospective, multicenter, open-label, randomized phase 3 study evaluating the efficacy and safety of intravesical TAR-200 plus systemic cetrelimab versus chemoradiotherapy in participants with MIBC. To be eligible, adults must have an ECOG performance status of 0 to 2, and histologically proven, newly diagnosed cT2 to T4a, N0, M0 MIBC, and they must be ineligible for or refuse radical cystectomy.

Investigators opened enrollment at 272 locations worldwide in December 2020 and hope to recruit 550 patients. Participants will be stratified based on transurethral resection of bladder tumor screening results (visibly complete vs incomplete) and screening tumor stage (T0 vs Ta/T1/Tis vs T2-T4a).

Participants in arm 1 will receive intravesical TAR-200 every 3 weeks for the first 18 weeks. Beginning at week 24, dosing will shift to every 12 weeks until 144 weeks. Cetrelimab will be dosed every 3 weeks until month 18. Patients in arm 2 will receive standard-of-care chemoradiotherapy with cisplatin or gemcitabine for up to 6 weeks, plus investigator’s choice of conventional hypofractionated chemotherapy.

The primary end point is bladder intact event-free survival (BI-EFS) defined as time from randomization to first BI-EFS event, including histologically proven MIBC, clinical evidence of nodal or metastatic disease per RECIST 1.1, radical cystectomy, or death.

Investigators will conduct primary disease assessment in both arms at week 18. They will conduct axial imaging and cystoscopy at week 24 and every 12 weeks thereafter through year 2 of the study, and then every 24 weeks through study year 5.

Key secondary end points include metastasis-free survival, overall survival, overall response rate at 18 weeks, and safety and tolerability. Exploratory end points include assessments of cancer-specific survival, time to symptomatic progression, pharmacokinetics, immunogenicity, health-related quality of life, healthcare resource utilization, and biomarkers.

MIBC is a potentially lethal disease, but many patients do not receive the recommended aggressive, curative therapy. The standard of care is radical cystectomy with pelvic lymphadenectomy or chemoradiotherapy, and the addition of platinum-based neoadjuvant chemotherapy improves survival outcomes.

 However, previous data show that neoadjuvant chemotherapy is underused, especially in the elderly and in groups with poor socioeconomic status.

In April 2018, the FDA granted Fast Track designation to TAR-200 for the treatment of patients with organ-confined or locally-advanced MIBC who are ineligible for curative therapy.

In 2019, investigators initiated a phase 1b clinical trial (NCT03518320) evaluating TAR-200 in combination with nivolumab (Opdivo) for safety, tolerability, and preliminary efficacy in patients with MIBC. The open-label, multi-center, single-arm study will enroll up to 25 patients who are scheduled for radical cystectomy. Prior to radical cystectomy, patients will receive both TAR-200 and nivolumab on day 1 of 4 consecutive 21-day dosing cycles.

1. Williams SB, Curtie C, Keegan KA, et al. SunRISe-2: A phase 3, multicenter, randomized study evaluating the efficacy of TAR-200 in combination with cetrelimab versus concurrent chemoradiotherapy in participants with muscle-invasive urothelial carcinoma of the bladder. Presented at: 2021 American Urological Association Annual Meeting; September 10-13, 2021; virtual. Abstract MP13-17.

2. Huo J, Ray-Zack MD, Shan Y, et al. Discerning patterns and quality of neoadjuvant chemotherapy use among patients with muscle-invasive bladder cancer

. 2019;2(5):497-504. doi:10.1016/j.euo.2018.07.009

3. Gray PJ, Fedewa SA, Shipley WU, et al. 

. 2013;63(5):823-829. doi:10.1016/j.eururo.2012.11.015

4. TARIS Bio. U.S. FDA grants Fast Track designation to TARIS for TAR-200 (GemRIS) in muscle invasive bladder cancer. News release. April 3, 2018. Accessed September 11, 2021. https://bwnews.pr/2XaB3ci

5. TARIS Bio. TARIS initiates clinical trial of TAR-200 in combination with Opdivo (nivolumab) for patients with muscle-invasive bladder cancer. News release. July 10, 2019. Accessed September 11, 2021. https://prn.to/3k4afn2

A phase 3 study is underway to evaluate the potential superiority of TAR-200 in combination with cetrelimab to chemoradiotherapy for the treatment of muscle invasive bladder cancer. 

SunRISe-2 Trial Explores TAR-200/Cetrelimab for Treatment of MIBC

During a presentation at the 2020 Society of Hematologic Oncology, Carsten Utoft Niemann, MD, PhD, explained that patients with chronic lymphocytic leukemia (CLL) have an increased risk for infection regardless of whether they are being treated.

With the help of the machine learning–based algorithm CLL Treatment-Infection Model (CLL-TIM), Niemann and his colleagues hope to learn whether the natural history of immune dysfunction and infections in CLL can be changed.

Investigators have made great strides in improving survival for patients with CLL, following the advent of chemoimmunotherapy and targeted therapy approaches. Unfortunately, mortality due to infection in these patients has not changed in 4 decades, Niemann explained, and infections are now the leading cause of death among patients with CLL.

“Looking at patients diagnosed with CLL, [they] tend to have a higher risk of having a serious infection within the first 5 years,” said Niemann, an associate professor, head of the CLL Lab, and chair of the Nordic CLL Study Group, in the Department of Hematology, Rigshospitalet, Copenhagen, Denmark. “The 30-day mortality [rate] upon a serious infection for patient diagnosed with CLL is 10%; the 1-year mortality [rate] is only 11% for patients starting treatment for CLL even though 50% of them will have a serious infection after starting treatment. This means that infections are actually more dangerous for patients with CLL who are untreated.”

Niemann is a coinvestigator in the phase 2 PreVent-ACaLL trial (NCT03868722), in which investigators will use the CLL-TIM algorithm to determine whether short-term treatment with the BTK inhibitor acalabrutinib (Calquence) plus the BCL-2 inhibitor venetoclax (Venclexta) can improve immune function and reduce the risk for infection compared with observation in patients with high-risk, newly diagnosed CLL.

“The aim here by this short 3-month treatment is not to 

 CLL,” he said. “The aim is to reduce the CLL clone back into what we consider monoclonal B lymphocytosis and, at the same time, treat the natural history of CLL and immune dysfunction. Thus, we aim to turn back the CLL into a normal immune function, and the outcome here is actually infection-free, treatment-free survival.”

Twenty-five patients will be randomly assigned to the treatment arm, which will be given in 3 cycles of 28 days, and 25 will be assigned to observation. Enrollment has opened in Denmark and is scheduled to open soon in the Netherlands and Sweden. The primary end point is grade 3 or higher infection-free survival in the treatment arm compared with the observation arm after 24 weeks.2

CLL-TIM identifies patients at risk for infection or CLL treatment within 2 years of diagnosis as validated on both internal and external cohorts. The ensemble algorithm incorporates 28 machine learning algorithms based on data collected from 4149 patients with CLL. The model is capable of dealing with heterogeneous data, including high rates of missing data to be expected in the real-world setting, with a precision rate of 72% and a recall rate of 75%.3

Niemann added that 6 European nations are collaborating in the CLL-CLUE consortium to assess immune dysfunction and drug sensitivity in primary samples collected from patients and clinical trials, and biobanks. Long term, the goal is to better individualize CLL treatment.

Immune Disfunction Starts Long Before Diagnosis

Niemann said that patients with CLL are more likely to be prescribed macro lights, antibiotics, and/or antivirals as much as 20 years before diagnosis. “This indicates that the immune dysfunction, at least, happens decades prior to diagnosis of CLL,” he added.

Going beyond the patient’s CLL and looking at their entire medical history, Niemann said physicians can see the burden of comorbidity in this population. “Almost all types of comorbidities for patients with CLL will increase the overall mortality and also for most of these comorbidities, will increase the CLL-related mortality,” he said.

That said, it appears both treatment and CLL itself play a role in incidence of infection. Niemann noted that lower respiratory tract infections and urinary tract infections are common for the 6 months of treatment with ibrutinib (Imbruvica). “This may indicate that we have an improvement in immune function and lower degree of infections after the first half year on targeted therapy.”

Niemann pointed out that, outside of clinical trials, close to 50% of patients discontinue ibrutinib by 30 months, many due to infections. Physicians must consider that infections might also affect the continuous treatment of patients, he added.

“On the other hand, [there is] no doubt that we may, for patients who are treated, actually improve the immune function over time,” Niemann said. Patients with less disease burden in terms of being treatment-naïve have a lower risk of infections than patients who are relapsed/refractory and would be expected to have had more aggressive or longer duration of CLL.”

Cumulative mean number of infections are lower in patients whose immune globulin levels increase during ibrutinib treatment. However, Niemann said there is no clear correlation between immunoglobulin deficiency and the risk for infections.

“That is what we’ve been working on predicting the risk of infections or risk of needing treatment for CLL,” he said.

To help the patient in the clinic, Niemann said all patients with CLL may have increased infection risk, but investigators need to identify those who at greatest risk for serious infections. Further, patients with CLL are at risk for both increased frequency of infections and also in the distribution of infections, especially for pneumococcal disease.

“Vaccine responses in CLL are impaired due to immune dysfunction. Thus, it should be encouraged to have early vaccination of patients with CLL, and repeat vaccination during treatment and after treatment,” he said. “Immunoglobulin substitution should only be used for patients who both have low IgG [immunoglobulin G] levels and frequent infections as we cannot clearly define these patients just by measuring the IgG levels.”

1. Niemann CU. Management of infections in patients with CLL. Presented at: the 2021 SOHO Annual Meeting. Virtual. September 8-13, 2021.

2. Da Cunha-Bang C, Agius R, Kater AP, et al.PreVent-ACaLL short-term combined acalabrutinib and venetoclax treatment of newly diagnosed patients with CLL at high risk of infection and/or early treatment, who do not fulfil IWCLL treatment criteria for treatment. A randomized study with extensive immune phenotyping. 

. 2019;134(supplement_1):4304. doi:10.1182/blood-2019-121907

3. Agius R, Brieghel C, Andersen MA, et al. Machine learning can identify newly diagnosed patients with CLL at high risk of infection. 

. 2020;11(1):363. doi:10.1038/s41467-019-14225-8

Controlling infection in patients with chronic lymphocytic leukemia who have an increased risk for infection, may be key for improving survival rates.

Infection Control in Patients With CLL May Be Pivotal for Survival Outcomes

A phase 2 study has shown that adding selective internal radiation therapy (SIRT) with Y90 resin microspheres to gemcitabine/cisplatin can extend overall survival in patients with inoperable intrahepatic cholangiocarcinoma (ICC), according to a poster presented during the 2021 International Liver Cancer Association (ILCA) Conference.

The median overall survival (OS) observed was 21.6 months (95% CI, 7.3-25.2) for patients with ICC.

Results of the trial (NCT02167711), which involved 3 Asian centers, also showed that the median progression-free survival (PFS) was 9 months (95% CI, 3.2-13.1).

For patients treated with SIRT-Y90 who did not receive chemotherapy, the median PFS was 6.6 months (95% CI, 2.5-9.8) and the median OS was 13.6 months (95% CI, 5.4-21.6).

“Our data was comparable to the Western data [NCT01912053], and we consider further clinical development to be warranted,” said lead author Stephen L. Chan, MBBS, an associate clinical professor of the Department of Clinical Oncology at the Chinese University of Hong Kong, China, in a virtual presentation during the meeting.

In the phase 2 Yttrium-90 Microspheres in Cholangiocarcinoma (MISPHEC trial), which is the Western study that Chan referenced, 41 patients with unresectable inoperable intrahepatic cholangiocarcinoma who had not received chemotherapy or intra-arterial therapy were treated at 7 centers in France from November 2013 through June 2016.

Patients were assigned to 8 cycles of concomitant first-line chemotherapy with 25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine; that was reduced to 300 mg/m2 for the cycles just prior to and after SIRT, on days 1 and 8 of a 21-day cycle. Investigators administered SIRT during cycle 1 for those with 1 hemiliver disease or cycles 1 and 3 for disease involving both hemilivers.

After a median follow-up of 36 months (95% CI, 26-52), the median PFS was 14 months (95% CI, 8-17) and the median OS was 22 months (95% CI, 14-52). The 1- and 2-year OS rates were 75% and 45%, respectively; the 1- and 2-year PFS rates were 55% and 30%.

Similarly, the randomized, phase 3 ABC-02 trial (NCT00262769) established gemcitabine plus cisplatin as the standard of care in locally advanced or metastatic biliary tract cancer.

 In those results, the median OS was 11.7 months for the combination compared with 8.1 months for gemcitabine monotherapy (HR, 0.64; 95% CI, 0.52-0.80; 

<.001). The median PFS was 8.0 months vs 5.0 months, in favor of the combination (

In the single-arm findings reported at the 2021 ILCA Conference, 24 patients with intrahepatic cholangiocarcinoma were assigned to 1 course of SIRT-Y90 administered via the hepatic artery at a dose of at least 120 Gy to the intrahepatic tumor. Patients then received a maximum 8 cycles of chemotherapy with cisplatin at a dosage of 25 mg/m2 on days 1 and 8, followed by gemcitabine at a dosage of 1000 mg/m2 on days 1 and 8 every 3 weeks

Investigators assessed patients for acute toxicity related to SIRT-Y90 1 week after the treatment. Patients with grade 1 or lower treatment-related toxicities and adequate hematological, renal, and hepatic functions then proceeded to gemcitabine/cisplatin chemotherapy.

Investigators performed CT scans every 6 weeks until progressive disease according to RECIST criteria. For patients who stopped chemotherapy for any reason other than withdrawal of consent, investigators continued regular follow-up to watch for delayed toxicity until 9 months following SIRT-Y90, death, or the patient was lost to follow-up.

The primary end point was OS. Secondary endpoints included PFS, response rate, disease control rate (DCR), toxicity, and time from Y90 to commencement of chemotherapy.

Patients were treated at participating centers in Hong Kong (28.2%), Singapore (25.0%), and Thailand (45.8%). All patients had an ECOG score of 0 or 1. Most patients were diagnosed with stage IVA (50.0%) or stage IVB (25%) stage disease. The remainder were diagnosed with stage III (16.6%), stage II (4.2%), or stage I (4.2%) disease.

The median age was 62 years (range, 35-79), and men to female ratio was 15:9.

All patients received SIRT-Y90 according to the protocol. Sixteen (67%) proceeded to chemotherapy and received a median of 4.5 cycles (range, 1-8). The median time from completion of SIRT-Y90 to start of gemcitabine/cisplatin treatment was 29 days (range, 7-42).

The overall response rate (ORR) was 25% (95% CI, 3.8%-46.2%) among the 16 patients who received at least 1 cycle of chemotherapy following SIRT-Y90 with a DCR of 75% (95% CI, 53.8% -96.2%). In the intent-to-treat (ITT) population, the ORR was 16.7% (95% CI, 1.8%-31.6%) with a DCR of 58.3% (95% CI, 38.6%-78.1%) following administration of SIRT-Y90.

Among the 8 patients who were unable to receive subsequent chemotherapy, 12.5% experienced disease progression. The others had poor underlying conditions such as presence of liver and splenic abscess and inadequate renal function before commencement of chemotherapy (8%), abdominal pain after SIRT-Y90 (4%), consent withdrawal (4%), or death (4%).

At a median follow-up of 8.5 months (range, 1.1-30), 19 patients died, 17 of whom had disease progression.

The rate of grade 3/4 toxicities was less than 10% in the ITT population. During the SIRT portion, the most common grade 3/4 toxicities included abdominal pain (4%), vomiting (4%), ascites (4%), elevated aspartate aminotransferase (AST; 4%), increased blood bilirubin (4%) and hypercalcemia (4%).

During the chemotherapy phase, common grade 3/4 treatment-induced toxicities included grade 3 elevated alanine aminotransferase (4%) grade 3 elevated AST (8%), grade 4 elevated alkaline phosphatase (4%) and grade 3/4 increased bilirubin (8%).

Among other grade 3/4 toxicities, investigators observed leukopenia in 1 (4%) patient, neutropenia in 4 (17%), anemia in 2 (8%) and thrombocytopenia in 2 patients (8%). Investigators also recorded 1 (4%) case of grade 4 hypercalcemia.

1. Chan SL, Chotipanich C, Choo SP, et al. Selective internal radiation therapy with Yttrium-90 resin microspheres followed by gemcitabine plus cisplatin for treatment of intra-hepatic cholangiocarcinoma: a phase 2 single-arm multicenter clinical trial. Presented at: 2021 International Liver Cancer Association Conference; September 2-5, 2021; virtual Abstract P-42.

2. Edeline J, Touchefeu Y, Guiu B, et al. Radioembolization plus chemotherapy for first-line treatment of locally advanced intrahepatic cholangiocarcinoma: a phase 2 clinical trial. 

. 2020;6(1):51-59. doi:10.1001/jamaoncol.2019.3702

3. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. 

. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721

Patients with inoperable intrahepatic cholangiocarcinoma have demonstrated tendency to live longer when  elective internal radiation therapy with Y90 is added to chemotherapy.

Prolonged Survival Shown With SIRT and Y90 Plus Chemotherapy in Intrahepatic Cholangiocarcinoma

With further follow-up from the phase 3 CLL14 trial (NCT02242942), the median progression-free survival (PFS) was still reached with the fixed-dose regimen of venetoclax (Venclexta) and obinutuzumab (Gazyva) in patients with previously untreated chronic lymphocytic leukemia (CLL).

At a median follow-up of 52.4 months, the median PFS was not reached in the experimental arm vs 36.4 months in the chlorambucil/obinutuzumab control arm (HR, 0.33; 95% CI, 0.25-0.45; 

 <.0001). The 4-year PFS rate was 74.0% compared with 35.4% in favor of chlorambucil/obinutuzumab, according to findings presented during the European Hematology Association 2021 Virtual Congress.

“With longer follow-up, we see that PFS is still favored in the venetoclax arm,” said lead author Othman Al-Sawaf, MD, a physician with the University Hospital of Cologne in Germany, in a virtual presentation of the data. “The majority of patients remain without disease progression even 3 years after completing their treatment.”

He added that the combination of venetoclax/obinutuzumab conferred a PFS benefit over chlorambucil/obinutuzumab, irrespective of 

 mutation status. In the experimental arm, the median PFS was not reached vs 38.9 months for those on chlorambucil/obinutuzumab in patients without 

 aberrations, the median PFS was 49.0 months and 20.8 months, respectively.

, the median PFS with the venetoclax arm was not reached vs 54.5 months for the control arm. In those with unmutated 

, the median PFS was 57.3 months and 26.9 months, respectively.

In the open-label, multicenter, CLL14 trial, investigators compared the combination of fixed-duration venetoclax and obinutuzumab vs obinutuzumab and chlorambucil in 432 treatment-naïve patients with CLL and coexisting medical conditions. Patients were evenly randomized to receive either regimen for 12, 28-day cycles.

The primary end point was investigator-assessed PFS. Secondary end points included independent review committee–assessed PFS, minimal residual disease (MRD) status, overall response rate (ORR), complete response (CR) or CR with incomplete hematologic recovery rates (CRi), overall survival (OS), duration of response, event-free survival, median time to next treatment (TTNT), and safety.

Baseline characteristics were well balanced between the 2 treatment arms. Overall, the median age was 71.5 years (range, 41-89), 43.5% had Binet stage C disease, the median total Cumulative Illness Rating Scale score was 8.3, and the median estimated creatinine clearance was 66.2 ml/min. Most patients (66%) were in the intermediate tumor lysis syndrome (TLS) category. Sixty percent of patients had unmutated 

 aberrations. Additionally, patients had 17p deletions (7.5%), 11q deletions (17.5%), 12 trisomy (18%), 13q deletion (35%), or no abnormalities (22%).

The median OS has not yet been reached in either arm (HR, 0.85; 95% CI, 0.54-1.35; 

 = .4929); the 4-year OS rates are 85.3% for the venetoclax arm vs 83.1% for the control arm.

The median TTNT was not reached in either treatment arm. The 4-year TTNT rate was 81.08% in the venetoclax/obinutuzumab arm compared with 59.9% for chlorambucil/obinutuzumab. Thirty-five patients in the experimental arm had progressive disease, 17 of whom required anti-leukemic treatment, compared with 122 and 70, respectively, in the control arm (HR, 0.46; 95% CI, 0.32-0.65; 

Assessment of MRD in peripheral blood 30 months after the end of treatment showed that 26.9% of patients in the experimental arm still had undetectable MRD compared with 3.2% of patients in the chlorambucil/obinutuzumab arm.

 Al-Sawaf added that patients in the control arm tended to lose MRD status after a median of 6 months vs 21 months with the venetoclax/obinutuzumab combination.

Regarding safety, there was no late onset or long-term toxicities with venetoclax/obinutuzumab in those evaluable for safety (n = 212 venetoclax/obinutuzumab; n = 214 chlorambucil/obinutuzumab). Posttreatment, most frequent adverse events that were grade 3 or higher with venetoclax/obinutuzumab and chlorambucil/obinutuzumab was neutropenia (4.0% vs 1.9%, respectively), thrombocytopenia (0.5% vs 0%), anemia (1.5% vs 0.5%), febrile neutropenia 1.0% vs 0.5%), pneumonia (3.0% vs 1.4%), and infusion-related reaction (0% vs 0.5%).

There were 34 deaths in the experimental arm, 7 (20.5%) of which were related to CLL. Forty-one deaths occurred in the control arm, 16 (39%) of which were related to CLL. Al-Sawaf said most deaths on study were related to comorbid conditions.

“We are really able to mitigate the risk features of CLL by effectively controlling the disease,” Al-Sawaf said. “Therefore, our patients do not die of their cancer anymore, which is quite a substantial improvement.”

Investigators recorded secondary primary malignancies in 42 in the chlorambucil/obinutuzumab group vs 47 in venetoclax/obinutuzumab group, which Al-Sawaf said was not statistically significant.

“One of the advantages of fixed-duration treatments is that there is virtually no toxicity when the patients get off treatment,” Al-Sawaf said. “Once they have completed those 12 cycles of treatment, we don’t see any long-term toxicity or late-onset toxicities, suggesting that fixed-duration treatments allow patients to really benefit from a lower risk of toxicity, a lower risk of drug-drug interactions—which is particularly relevant in these comorbid patients—and is therefore quite favorable for the majority of patients.”

The FDA approved the venetoclax/obinutuzumab combination as frontline treatment for patients with CLL or small lymphocytic lymphoma in May 2019. Previous data from the CLL14 trial showed that the combination reduced the risk for disease progression or death by 67% compared with chlorambucil/obinutuzumab (HR, 0.33; 95% CI, 0.22-0.51; 

 In this earlier dataset, the ORR was 85% with venetoclax/obinutuzumab vs 71% in the control arm (

1. Al-Sawaf O, Zhang C, Robrecht S, et al. Venetoclax-obinutuzumab for previously untreated chronic lymphocytic leukemia: 4-year follow-up analysis of the randomized CLL14 study. Presented at: European Hematology Association 2021 Virtual Congress; June 9-17, 2021. Abstract S146.

2. New data shows AbbVie's Venclyxto/Venclexta fixed duration combination demonstrates sustained progression-free survival in chronic lymphocytic leukemia patients after three years off treatment. News release. Abbvie. June 11, 2021. Accessed June 11, 2021. 

3. FDA approves venetoclax for CLL and SLL. FDA. May 15, 2019. Accessed June 11, 2021. 

With further follow-up from the phase 3 CLL14 trial, the median progression-free survival was still reached with the fixed-dose regimen of venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia.