Sara Karlovitch is an associate editor with Targeted Oncology. She received a duel degree in Journalism and Government and Politics from the University of Maryland. 

Sara Karlovitch

Sintilimab (Tyvyt) in combination with the bevacizumab (Avastin) biosimilar, IBI305, is associated with a significant overall survival (OS) and progression-free survival (PFS) benefit over sorafenib (Nexavar) in the first-line setting for the treatment of Chinese patients with unresectable, hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), according to published results from the ORIENT-32 study.

HBV infection is the main causative factor for HCC in China. These patients, who have substantial unmet clinical needs, often have a poor prognosis. The combination of a PD-1 inhibitor and the bevacizumab (Avastin) biosimilar, IBI305, may help to improve survival in this vulnerable patient population. 

The phase 2/3 ORIENT-32 study (NCT03794440) enrolled 24 patients in the phase 2 portion of the study and 571 patients in the phase 2 portion. The study follows an open-label, randomized, parallel assignment design and has coprimary end points of OS and PFS. Secondary end points include objective response rate (ORR), disease control rate (DCR), duration of response, time to progression, and anti-drug antibodies.

In order to participate in the study, individuals must have a documented HCC diagnosis, an ECOG performance status between 0 and 1, no systematic anti-tumor treatment, at least 1 lesion with measurable disease at baseline per RECIST v1.1, and adequate organ and bone marrow function. Patients with fibrous lamellar HCC, a history of hepatic encephalopathy, clinical symptoms requiring drainage of pleural effusion, central nervous system metastasis, uncontrolled high blood pressure, or local treatment for liver lesions within 4 weeks were not eligible to participate. 

Patients were enrolled between February 11, 2019, and January 15, 2020, during phase 3, and 380 patients were entered into the combination arm versus the sorafenib monotherapy arm, which included 191 patients. All patients were evaluable for efficacy and safety. 

During phase 3, the median follow-up was 10.0 months in the combination cohort and 10.0 months in the monotherapy cohort. At that time, 64% of the experimental group had progressive disease or had died while 74% in the sorafenib group had progressive disease or had died. By independent review committee assessment (IRRC), the median PFS was 4.6 months for the combination group (95% CI, 4.1-5.7) and 2.8 months (95% CI, 2.7-3.2) for the monotherapy arm (stratified HR, 0.56; 95% CI, 0.46-0.70; 

 <.0001). Median OS was not reached in the combination arm while it was reached at 10.4 months in the monotherapy arm. Additionally, patients who received the combination had a longer time to the deterioration of global health status 6.7 months (95% CI 5.5-7.3) compared with at 4.1 months (95% 2.9-5.2) in the sorafenib arm (stratified HR, 0.73; 95% CI, 0.56-0.94). 

The median duration of treatment for sintilimab was 7 months, 6.6 months for the bevacizumab biosimilar, and 3.5 months for sorafenib. AEs interrupted the treatment of 49% of patients in the combination group and 41% of patients in the monotherapy group. 

Of the 571 patients, 565 were included in the safety analysis. The safety profile of the combination was tolerable, with the most common grade 3/4 adverse event (AE) being hypertension and palmar planter erythrodysaesthesia syndrome. In the combination group the rate of hypertension was 14% versus 6% in the monotherapy group. For palmer-plantar erythrodysaesthesia syndrome, the rate of occurrence was 0% in the combination group and 12% in the monotherapy group. Overall, 32% of patients in the experimental arm had a serious AEs compared to the 19% in the control group. TRAEs lead to death in 6 patients in the experimental group due to 1 patient with abnormal liver function, 1 patient with both hepatic failure and gastrointestinal hemorrhage, 1 patient with interstitial lung disease, 1 patient with both hepatic failure and hyperkalemia, 1 patient with upper gastrointestinal hemorrhage, and 1 patient with intestinal volvulus). TRAEs lead to 2 deaths in the sorafenib group due to 1 patient with gastrointestinal hemorrhage and 1 patient with death of unknown cause.

According to IRRC-assessed modified RECIST, the confirmed objective response rate (ORR) was 21% (95% CI, 17%-25%) in the combination cohort and 4% in the monotherapy cohort (

 <.0001). All responses in both treatment arms were partial response (PRs). In terms of stable disease (SD), 52% in the combination cohort saw stable disease compared to 60% in the monotherapy cohort. Twenty seven percent of patients in the experimental arm had progressive disease (PD) compared to 33% in the control cohort.

In the combination arm, there was a confirmed DCR of 72% (95% CI, 67%-77%) versus 64% in the monotherapy cohort (95% CI, 56%-71%). DOR was not evaluable (NE) in the combination cohort compared with 9.8 months in the monotherapy cohort (2.6-NE.). In the combination cohort. Finally, the duration of disease control was 7.0 months (95% CI, 5.1-8.2) in the experimental arm versus 2.9 months (95% CI, 2.6-3.7) in the control arm.

The prior part of the study (phase 2) followed patients for a median of 15.8 months (interquartile range [IQR], 15.2-16.1 months), investigators assessed an ORR 25.0% (95% CI, 10%-47%) per RECIST 1.1. All responses were PRs. SD was observed in 58% of patients and 17% had PD. The DCR was 83% (95% CI, 63%-95%). The median duration of response was 12.6 months the median TTP was 8/2 months and the median TTR was 2.9 months. Death occurred in 5% of patients. The PFS at 6 months was 61% (38%-78%) and at 9 months it was 42% (22%-61%). The 9-month survival rate was 8% and the 12-month survival was 83%.

The median age of phase 2 participants was 53 years old (43-71), 83% were male, and 54% had an ECOG score of 1. Ninety-six percent of patients had a Child-Pugh classification of A and 79% had a Barcelona Clinic Liver Cancer Stage of C, 58% ad alpha-fetoprotein levels of less than 400ng/mL. The rate of extrahepatic metastasis was 75% and the rate of hepatitis C virus infection was 4%. All patients in this cohort received prior local therapy for HCC at least once. Half had undergone surgery, 8% have received radiation therapy, and 46% had received ablation. 

Overall, the safety profile of sintilimab plus IBI305 was acceptable. All patients experienced treatment-emergent adverse events (TEAEs), and 92% experienced treatment-related AEs (TRAEs). Grade 3-4 AEs occurred in 29% of patients. No AEs leading to death were reported. TEAEs lead to interruption of therapy in 46% of patients, and discontinuation in 8% of patients.

The most common any-grade TRAEs observed with the patients treated in phase were proteinuria (42%), platelet count decreased 8 (33%), alanine aminotransferase increased (29%), Aspartate aminotransferase increased (29%), and hypertension (25%). The grade 3/4 TRAE most commonly observed during the phase 2 analysis was proteinuria (13%).

During phase 2, serious adverse events related to either study drug occurred in 25% of patients, with the most common being hepatobiliary disorders (17%). Broken down, abnormal hepatic function occurred in 13% of patients and immune-mediated hepatitis occurred in 4% of patients. Hyperthyroidism occurred in 4% of patients and immune-mediated pneumonitis occurred in 4% of patients. Additionally, 4% of patients experienced a duodenal ulcer. 

Concluding the research, the study authors wrote “…sintilimab–bevacizumab biosimilar showed a significant overall survival and PFS benefit compared with sorafenib in Chinese patients with previously untreated, HBV-associated hepatocellular carcinoma with a tolerable and manageable safety profile. This combination regimen could provide a novel treatment option for this patient population.”

Ren Z, Xu J, Bai Y, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2–3 study. 

Articles

Sintilimab in combination with the bevacizumab biosimilar, IBI305, is associated with a significant overall survival and progression-free survival benefit over sorafenib in the first-line setting for the treatment of Chinese patients with unresectable, hepatitis B virus-associated hepatocellular carcinoma. 

Chinese Study Finds That Sintilimab and Biosimilar Bevacizumab Prolong HCC PFS 

A phase 3 study has been initiated in order to evaluate the efficacy of the oral MDM2 inhibitor milademetan (RAIN-32) for the treatment of de-differentiated liposarcoma (LPS), according to a press release by Rain Therapeutics.

MDM2 is an oncogene present in numerous cancers. The milademetan inhibitor has proven effective in a phase 1 trial on a MDM2-amplified subtype of LPS and other solid tumor types. The agent received an orphan drug designation from the FDA for its use in patients with LPS.

The phase 3 MANTRA study will be a randomized, multicenter, open-label, phase 3 registrational study with an aimed enrollment of 160 patients. Patients will be randomized 1:1 to receive either milademetan or trabectedin (Yondelis). The primary end points are progression-free survival (PFS) by blinded independent review. Secondary end points include overall survival, PFS by investigator assessment, objective response rate, duration of response, disease control rate, safety, and patients reported outcomes.

“The start of our phase 3 MANTRA study evaluating milademetan marks an important step forward in addressing a high unmet need for patients with de-differentiated LPS,” said Richard Bryce, MBChB, chief medical officer at Rain Therapeutics, in s statement. “We are proud to have advanced milademetan into a pivotal study less than 12 months after acquiring the program, and believe it has the potential to be the best-in-class MDM2 inhibitor.”

The phase 3 study comes on the heels of the phase 1 dose escalation and expansion study. Three patients have with well-differentiated or de-differentiated LPS have received milademetan monotherapy for more than 51 months as of July 1, 2021. Of those 3 patients, 1 patient continues to receive therapy at 51 months and 1 other continues to receive therapy at 57 months without disease progression. Another patient received therapy for more than 59 months before discontinuing treatment in the second quarter of 2021.

Plans to test the agent in combination with quizartinib (NCT03552029) with 5-azacitidine (Vidaza) (NCT02319369) are also underway.

The study of the agent in combination with quizartinib has a planned enrollment of 10 participants. The primary end points of the study include the number of participants with dose limiting toxicities, the number of participants with adverse events (AEs), and the number of participants who respond to treatment. Secondary end points include the maximum concentration of study drug in plasma.

During part 1 of the study, patients with relapsed/refractory 

-mutant acute myeloid leukemia (AML) at various doses and schedules. Part 2 will be split into 2 cohorts. In cohort 1, patients with AML will receive the recommended phase 2 dose. Cohort 2 will include AML patients who are unfit for chemotherapy.

That study is currently recruiting in California, Connecticut, Kansas, Michigan, New York, North Carolina, Pennsylvania, and Texas.

The study testing milademetan alone and in combination with 5-azacitidine has an actual enrollment of 74 participants. The primary end point of the study is the number of participants with dose-limiting toxicities, the number of patients with TEAEs, and participants who achieved a complete remission. Secondary end points include pharmacokinetics and pharmacodynamics.

Milademetan will be tested as both a monotherapy and combination at different dose levels.

Rain Therapeutics initiates phase 3 MANTRA clinical trial of milademetan for de-differentiated liposarcoma and provides patient update from prior clinical program. News release. Rain Therapeutics. July 20, 2021. Accessed July 22, 2021. 

A phase 3 study has been initiated in order to evaluate the efficacy of the oral MDM2 inhibitor milademetan for the treatment of de-differentiated liposarcoma.

Oral MDM2 Inhibitor Milademetan Enters Phase 3 Study for Patients with De-Differentiated Liposarcoma

Despite being highly preventable with human papillomavirus (HPV) vaccines and testing, cervical cancer remains a leading cause of cancer-related death in women ,. Concurrent chemotherapy has proven to be effective in this patient population, but in the case of distant metastatic diseases, high death rates continue.

The OUTBACK trial (NCT01414608), which began in 1999, aimed to determine if additional cycles of chemotherapy would further improve survival in this patient population. The end points of the study were overall survival (OS), PFS, acute and long-term toxicities, patterns of disease recurrence, and quality of life. 

The final analysis found that despite the additional cycles of chemotherapy, the 5-year OS was similar same between the 2 groups. The 5-year OS for the chemotherapy alone was 71% and 72% for the chemotherapy plus adjuvant chemotherapy group. PFS told a similar story, with the PFS for the control group being 61% and 63% for the experimental group. Disease recurrence patterns between the 2 groupa were also similar.

 Bradley Monk, MD, FACCOG, FACS, a gynecologic oncologist at Arizona Oncology and the medical director of gynecologic oncology research at the US Oncology Network, discusses the OUTBACK trial, including the results, strengths, and challenges.

Can you provide a brief overview of the OUTBACK Trial?

 I have a passion for trying to help those women who develop cervical cancer. I get it's a disease that should be prevented with HPV vaccination, PAP testing, and testing for the HPV virus from the cervix. I think we all know that's not happening how we would like and there's still women even in this country, battling, and even dying from cervical cancer. At the 2021 American Society of Clinical Oncology Annual Meeting in the plenary session, the OUTBACK trial was presented. This study looked at adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone. It was a collaborative trial between the Australian New Zealand Gynecologic Oncology Group, the Radiation Therapy Oncology Group and NRG Oncology. At the time the study was developed, I was the chair of the NRG Cervical Cancer Committee, a position that I held for 11 years.

In 1999, the National Cancer Institute had a clinical alert, saying that chemotherapy of weekly cisplatin should be added to radiation in the treatment of locally advanced cervical cancer and in 1999, became the clinical standard. In the recurrent setting, cervical cancer had historically been considered chemotherapy resistant. Working again through the Historical Gynecologic Oncology Group, now NRG Oncology Group, we have shown that chemotherapy is very sensitive and on behalf of NRG Oncology, I published in 2009, in the 

 a study called Protocol 204 (NCT03438396), which established a global systemic therapy for cervical cancer in the recurrence setting as platinum taxane of either cisplatin or carboplatin with paclitaxel.

With this new discovery, we decided to launch a very ambitious randomized phase 3 trial taking patients with locally advanced cervical cancer being treated with radiation and randomizing them in a 1:1 basis to 4 additional cycles of carboplatin, paclitaxel, delivered at an area under the curve of 5 and paclitaxel at 155 milligrams per square meter. It was a little bit of an unusual dose because these patients had all received prior radiation, which increases the toxicity from cytotoxic chemotherapy. It was a very ambitious trial. The study was initially slated to enroll 780 patients and was increased to 900 and had an 80% power with a 2-sided alpha of 5% for an absolute improvement of 8% in OS.

While this trial was going on, in 2013, a study was presented at ASCO and we got FDA approval for the addition of bevacizumab (Avastin) to the use of platinum taxane chemotherapy in recurrent cervical cancer. It changed the standard of care while the standard was ongoing. Recently, we also had 2 phase 3 trials of checkpoint inhibitors that have further evolved the standard of care.

Having said that, this trial reported at ASCO 2021, showed that there was no difference when 4 additional cycles of carboplatin and paclitaxel was added to chemotherapy. There was no difference in the 5-year OS, which in the chemotherapy radiation alone group was 71%.

When there were 4 additional cycles of carboplatin and paclitaxel after chemotherapy and radiation, the 5-year survival was 1% greater with a hazard ratio of .90 and confidence interval of .70 overlapping 1 with an upper boundary of 1.17.

Interestingly, there was also no improvement in PFS. The 5-year PFS was 61% versus 63%. There was also no improvement in local regional control. There was a slight improvement numerically in local control, but not substantially. If anything, as we looked at the subset analysis, which was hypothesis generating, the patients greater than 60 did better without the additions of chemotherapy. So, in looking at the important prognostic factors, not only could we not identify subset where it worked, we actually identified a subset in which it appeared not to work.

Can you talk about the reasoning behind adding these additional cycles of chemotherapy to this treatment plan?

The OUTBACK trial identified a group of patients who were at high risk for recurrence, meaning that the tumors were too large for radical surgery with the hypothesis being that chemotherapy could improve the OS and perhaps the cure rate by cytotoxic destruction of micro-metastatic disease.

What impact do you believe these results will have on the clinical or community oncology setting?

We've seen the evolution that cervical cancer is indeed sensitive to chemotherapy. NRG Oncology and the Historical Gynecologic Oncology Group has been very impactful in defining the role of radiation in systemic therapy and treating cervical cancer, particularly locally advanced cervical cancer. This is a wonderful opportunity to improve on that outcome, particularly with the discovery over the last decade or so that cervical cancer is actually a chemotherapy-sensitive disease, rather than a chemotherapy-resistant disease. Because of that, these date were impactful because they show that it doesn't.

There are well intentioned providers who are giving additional cycles of chemotherapy after chemotherapy and radiation in locally advanced cervical cancer without evidence. It needs to stop because it doesn't provide any benefit. That's the impact of this research.

There are 4 lessons learned from the OUTBACK trial. And we should utilize these lessons to improve the quality of our ongoing and future clinical trials and locally advanced cervical cancer. Number 1, when post-progression survival is long, and crossover is common, or switching as we call it, the end point should never be OS. It should be PFS. Now as it turns out, it probably wouldn't have been positive anyways.

The second lesson is you have to use right agents at the time. The right agents at the time were carboplatin/paclitaxel, but as I mentioned in 2014, bevacizumab and carboplatin/paclitaxel became the global standard. And today, we have 2 randomized phase 3 trials of checkpoint inhibitors.

Third, we need to enroll the right patients. These patients that were enrolled, were actually not at high risk for recurrence, most of them were cured. So, we need to identify patients at the highest unmet medical need, enroll those patients with the right end point, and treat the with the right agents.

Finally, patients who receive radiation and chemotherapy are pretty beat up at the end of their treatment. Twenty percent of the patients, in fact, didn't even complete their chemotherapy and radiation. If you don't complete it, you're certainly not going to transition to a maintenance phase. Even when they finished it, another 20% or so didn't transition to a maintenance phase. So, if we want to change the impact of chemotherapy and radiation, this idea of a switch maintenance strategy after chemotherapy and radiation, is probably not wise. It may be better to start the systemic therapy during the radiation which after all, is when the systemic therapy cisplatin is started.

Mileskin LR, Moore KN, Barnes E, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). 

. 39(18):L8A3. doi: 10.1200/JCO.2021.39.15_suppl.LBA3.

In an interview with Targeted Oncology, Bradley Monk, MD, FACCOG, FACS, discusses the OUTBACK trial, including the results, strengths, and challenges.









Survival Improvement Not Shown With Adjuvant Chemotherapy in Locally Adnvaced Cervical Cancer

The UriFind test that utilizes DNA methylation detection for the diagnosis of bladder cancer has been granted a breakthrough device designation by the FDA, according to a press release by AnchorDx.

UriFind is a non-invasive test that allows for bladder cancer detection using a urine sample. Cancer is detected using methylation detection of exfoliated cell DNA in the patient’s urine. The test has been shown to be as strong as a cystoscopy and more accurate than exfoliative cytology and fluorescence in situ hybridization (FISH) for the detection of early, non-muscle invasive bladder cancer.

The designation was granted based on real-world data published in 

. The diagnostic model was trained using 313 samples and validated by 175 samples in a multicenter, prospective, independent cohort. Samples were collected from across China. The modeling cohort enrolled 142 patients with urothelial carcinoma, 12 healthy participants, and 159 non-cancer controls between June 2017 and May 2019. In the blinded cohort, 109 patients with bladder cancer and 66 non-cancer controls were included. The surveillance cohort enrolled 38 patients with tumor recurrence and 43 patients without recurrence.

The device had a 90% specificity for CpG biomarker cg21472506 and an 83.1% specificity for cg11437784. Compared with the similar device EpiCheck, UriFind was also more sensitive to recurrent bladder-cancer. UriFind has a sensitivity of 75% to low-grade recurrent bladder cancer and 93% for high-grade recurrent bladder cancer. For EpiCheck, the low-grade sensitivity rate if 40% and a high-grade sensitivity rate of 89%.

“The early-stage, minimal, residual, and recurrent tumors of BCa were very difficult to diagnose, which was usually missed by urine cytology and FISH. However, this method achieved a great improvement in sensitivity over cytology and FISH, serving as a promising solution in these conditions. Importantly, the UD score positively correlated with the grade, stage, size, and the presence of residual and recurrent tumors of BCa. These results make this method attractive for use in clinical decision-making across a variety of patients and situations, and could in turn reduce the current burden of repeated cystoscopy and blind Re-TURBT,” study authors wrote.

1.AnchorDx's Non-invasive Bladder Cancer Early Detection Test, UriFind, Earns "Breakthrough Device Designation" from FDA. News release. AnchorDx. July 21, 2021. Accessed July 21, 2021. 

2.Chen X, Zhang J, Rian W, et al. Urine DNA methylation assay enables early detection and recurrence monitoring for bladder cancer. 

The UriFind test that utilizes DNA methylation detection for the diagnosis of bladder cancer has been granted a breakthrough device designation by the FDA. 

Sara Karlovitch | Authors

Articles

Chinese Study Finds That Sintilimab and Biosimilar Bevacizumab Prolong HCC PFS

Oral MDM2 Inhibitor Milademetan Enters Phase 3 Study for Patients with De-Differentiated Liposarcoma

Survival Improvement Not Shown With Adjuvant Chemotherapy in Locally Adnvaced Cervical Cancer

UriFind Test for Bladder Cancer Granted FDA Breakthrough Device Designation