, Deepu Madduri, MD, assistant professor of Medicine (Hematology and Medical Oncology), associate director of Cellular Therapy Service, and director of Clinical Operations with the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai, discussed the most influential multiple myeloma research that came out of 2020.

At the ASH [Annual Meeting & Exposition] this year, the most influential research, as you saw, were [about] bispecific [agents] or CAR T-cell therapies, right? We’re seeing a lot of changes in immune regulation [regarding] how the immune cells are working and understanding how to use those to target and attack the myeloma cells. There’s going to be a combination of trials and combination therapies that are really going to come up [to the front-line setting to determine] if that will benefit the patients.

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The expert in multiple myeloma spoke about the research that she believes will be most influential for patients with multiple myeloma.

Deepu Madduri, MD, on Research in Multiple Myeloma This Past Year

The FDA has granted approval to the supplemental biologics license application for the combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) as therapy for patients with advanced renal cell carcinoma (RCC) in the frontline setting, according to Exelixis, the developer of cabozantinib.

 that was granted in October, and comes ahead of the assigned a Prescription Drug User Fee Act (PDUFA) goal date of February 20, 2021.

Efficacy of the combination was verified in the pivotal phase 3 CheckMate 9ER trial (NCT03141177), which compared the combination versus standard-of-care therapy with sunitinib (Sutent) in patients with previously untreated RCC

“This combination of cabozantinib and nivolumab significantly improved key efficacy measures compared to sunitinib–progression-free survival [PFS], overall survival [OS], and objective response rate [ORR]–while showing a low rate of treatment discontinuations due to side effects. The therapeutic benefit demonstrated in CheckMate 9ER and quality-of-life measures explored emphasize the role of this combination for patients with advanced kidney cancer,” Toni Choueiri, MD, Director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute and the Jerome and Nancy Kohlberg Professor of Medicine at Harvard Medical School, said in a press release. “With this important FDA approval, the combination is poised to become a standard in newly diagnosed metastatic kidney cancer.”

Data from the trial presented at the European Society for Medical Oncology 2020 Virtual Congress demonstrated statistically significant improvement in OS with the experimental combination versus sunitinib, with medians not reached in either arm (HR, 0.60; 98.89% CI, 0.40-0.89; 

 = .001). The median PFS was also improved, at 16.6 months in the cabozantinib and nivolumab arm versus 8.3 months with sunitinib, and this association was found to be statistically significant (HR, 0.51; 95% CI, 0.41-0.64; 

 <.0001). ORR was almost doubled in the experimental arm, at 56% versus 27% with sunitinib.

The combination was generally well tolerated and mimicked the known safety profiles of both agents. The most common adverse reactions that were noted in 20% of patients or more in the cabozantinib/nivolumab arm included diarrhea, fatigue, hepatotoxicity, palmar-plantar erythrodysesthesia, stomatitis, rash, hypertension, hypothyroidism, musculoskeletal pain, decreased appetite, nausea, dysgeusia, abdominal pain, cough and upper respiratory tract infection. The discontinuation rate from all causes was around 20%.

“While significant progress has been made in the treatment landscape for advanced kidney cancer over the last several years, patients still need more therapeutic options to treat this disease as we search for a possible cure,” Bryan Lewis, President and Co-founder of KidneyCAN, said in a press release. “As patients are living longer with advanced kidney cancer, focusing on the safety and effectiveness of new treatments has become even more important. The findings for the combination of cabozantinib and nivolumab in the CheckMate 9ER trial make the FDA approval of this combination a notable development for the patient community.”

In total, 651 patients with untreated advanced or metastatic RCC with a clear cell component were randomized to cabozantinib at 4 mg daily plus nivolumab at 240 mg intravenously every 2 weeks (n = 323) or oral sunitinib administered at 50 mg daily on a 4-weeks-on/2-weeks-off cycle (n = 328). PFS was the primary end point with secondary end points of OS, ORR, and safety.

Both nivolumab and cabozantinib are already approved for separate indications in RCC. This combination is currently under review for approval by other global agencies.

Exelixis Announces U.S. FDA approval of Cabometyx (cabozantinib) in Combination with Opdivo (nivolumab) as a First-Line Treatment for Patients with Advanced Renal Cell Carcinoma. News release. January 22, 2021. Accessed January 22, 2021. 

https://ir.exelixis.com/news-releases/news-release-details/exelixis-announces-us-fda-approval-cabometyxr-cabozantinib-2

Articles

The FDA granted approval to the combination use of cabozantinib plus nivolumab ahead of its February PDUFA date as therapy for the first-line treatment of patients with advanced renal cell carcinoma.

Cabozantinib Plus Nivolumab Is Granted Full Approval for Frontline RCC Indication

Data from the phase 1/2 TRANSCEND-CLL-004 study (NCT03331198) established feasibility for the combination of the investigational CD-19–directed chimeric antigen receptor (CAR) T-cell product lisocabtagene maraleucel (liso-cel) with ibrutinib (Imbruvica) for patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The phase 1, dose-escalation portion of the trial examining the CAR T-cell product plus a BTK inhibitor in patients with relapsed/refractory disease were presented at the American Society of Hematology Annual (ASH) Meeting & Exposition and showed that the combination was well tolerated and achieved high rates of response and undetectable minimal residual disease (MRD).

“Despite highly active targeted therapy, most patients with high-risk CLL will eventually relapse or progress on treatment and many develop refractory disease,” William G. Wierda, MD, PhD, executive medical director of The University of Texas MD Anderson Cancer Center, said in a presentation of the data. “Notably responses [to ibrutinib and liso-cel therapy] were seen among these heavily pretreated patients. Liso-cel expansion and function were seen in vivo in the presence of concurrent ibrutinib therapy.”

Liso-cel—a CD-19­–targeting, defined composition, 4-1BB CAR T-cell product administered at equal doses of CD8+ and CD4+ CAR-positive T cells—was examined at 2 dose levels of 50 or 100 × 106 CAR T-cells with or without ibrutinib at 420 mg daily. Eligible patients had progressed on prior ibrutinib therapy at enrollment, high-risk features and received ibrutinib for 6 months or more with less than a complete remission (CR), 

 mutations, or prior ibrutinib with no contraindications to reinitiating therapy.

Patients in the current analysis (n = 19) were either restarted or continued on ibrutinib therapy at initiation, then underwent leukapheresis for T-cell collection and production. Bridging therapy was allowed. Lymphodepletion with fludarabine 30 mg/m2 and cyclophosphamide 30 mg/m2 was followed by liso-cel administration. Patients remained on daily ibrutinib at least 90 days after receiving liso-cel and could be continued beyond the 90 days per investigator preference. The primary end point of the phase 1 combination therapy arm was safety and laboratory abnormalities with exploratory objectives of antitumor activity.

Among all treated patients, 12 (63%) had a CR or CR with incomplete blood count recovery (CRi) and 6 had a partial response (PR), resulting in an overall response rate (ORR) of 95% (95% CI, 74.0%-99.9%). For those treated at the lower liso-cel dose (n = 4), those rates were 50% and 25%, respectively, with an ORR of 75% (95% CI, 19.4%-99.9%). With the highest dose level of liso-cel (n = 15), the ORR was 100% (95% CI, 78.2%-100.0%), with a 67% CR/Cri rate and a 33% PR rate.

Among all patients, 89% had undetectable MRD (≤10-4 at 10-month follow-up) in the blood and 79% on the bone marrow. In the lower-dose group, undetectable MRD occurred at a rate of 75% in both the blood and marrow. For the higher-dose group, rates of undetectable MRD were 93% and 80%, respectively.

“There was a high undetectable MRD concordance between blood and bone marrow,” Wierda said. “Complete remission and undetectable MRD rates were high, demonstrating therapeutic activity for this combination.”

Most patients remained in remission at follow-up and most responses occurred by day 30. Liso-cel peak expansion occurred by day 11 and long-term persistence was noted in 38% of patients at 6 months and 20% at 12 months.

Grade 3/4 treatment-emergent adverse events (AEs) occurred in 95% of patients, with neutropenia/decreased neutrophil count (89%), anemia (47%), and febrile neutropenia (26%) occurring most frequently. Notably, cytokine release syndrome was observed in three-quarters of patients (74%), but only 1 experienced a grade 3 event and none had grade 4 complications. Neurological events were observed in 32%, with 16% being grade 3 and none at grade 4. Managements of CRS and neurological events included tocilizumab alone (11%), corticosteroids alone (16%), or a combination of both therapies (16%).

Baseline characteristics revealed that patients were mostly men (63%) with a median age of 61 years (range, 50-77). About a third (32%) had bulky disease, defined as at least 1 lesion measuring 5 cm or more, and most had high risk features including deletion 17 p (42%), a 

 mutation (32%), and/or a complex karyotype (42%).

“Research continues with this combination at dose level 2 [100 × 106 CAR-positive T-cells] in a cohort expansion,” Weirda concluded.

Wierda WG, Dorritie KA, Munoz J, et al. Transcend CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). 

. 2020;136(suppl 1):39-40. Abstract 644. doi:10.1182/blood-2020-14062.

Findings from a phase 1/2 trial indicate that lisocabtagene maraleucel plus ibrutinib may represent a viable treatment option for patients with heavily pretreated chronic lymphocytic leukemia or small lymphocytic lymphoma and high-risk disease features.

Promising Efficacy Data for Heavily Pretreated CLL/SLL Indicate Potential Benefit for Liso-cel Combination With Ibrutinib

Compared with concurrent chemoradiotherapy followed by surgery and adjuvant chemotherapy (CRT plus A), total neoadjuvant therapy for patients with locally advanced rectal cancer was associated with better pathological complete response (PCR) rates and a potential advantage for disease-free survival (DFS), according to data published in 

While the data suggest total neoadjuvant therapy is a promising strategy, the long-term effects this treatment has on disease recurrence and overall survival rates need further exploration.

“Total neoadjuvant therapy appears to be a promising treatment strategy that has been reported in several trials,” wrote the investigators who were led by Anup Kasi, MD, MPH. “Total neoadjuvant therapy enhances one’s chances of attaining a PCR, which traditionally has been shown to correspond to higher overall and disease-free survival. Our meta-analysis suggests an improved disease-free survival, although the true effect of (total neoadjuvant therapy) on overall and disease-free survival is unclear and requires further evaluation in a prospective randomized manner.”

Overall, the use of total neoadjuvant therapy was associated with an increased chance of achieving PCR (odds ratio [OR], 2.44; 95% CI, 1.99-2.98) for patients with locally advanced rectal cancer. Pooled prevalence of PCR was recorded at 29.9% (range, 17.2%-38.5%) for patients in the total neoadjuvant therapy group and 14.9% (range, 4.2%-21.3%) for those in the CRT-plus-A group.

The investigators did not find a statistically significant difference for the proportion of sphincter-preserving surgery (OR, 1.06; 95% CI, 0.73-1.54) or ileostomy (OR, 1.05; 95% CI, 0.76-1.46) between the total neoadjuvant therapy and CRT-plus-A groups.

Only 3 out of 7 total studies examined data on DFS. A pooled analysis of these results showed that patients undergoing total neoadjuvant therapy saw significantly higher odds of improved DFS (OR, 2.07; 95% CI, 1.20-3.56; I2 = 49%).

This systematic review and meta-analysis examined 2416 patients from 7 unique studies in which 1206 patients received total neoadjuvant therapy. Median age for patients receiving total neoadjuvant therapy ranged from 57 to 69 years, with 58% to 73% of patients being male.

“The pooled analysis demonstrated a significantly higher chance of achieving a PCR as well as improved disease-free survival [with total neoadjuvant therapy],” wrote the investigators. “Surgical outcomes, including rates of sphincter-preserving surgery and ileostomy, did not significantly differ among the 2 populations.”

The investigators explained that a significant limitation of the data is that none of the end points were consistently reported across the 7 unique studies analyzed. Specifically, while all 7 included PCR, only 4 studies reported the rates of sphincter-preserving surgery, 2 reported specific ileostomy requirements, and 3 reported DFS.

Moreover, there was not enough data to accurately calculate a pooled overall survival rate for patients across the 7 studies. Therefore, the investigators were limited by the data they could report in their systematic review and meta-analysis.

“Total neoadjuvant therapy theoretically offers multiple surgical advantages, such as improved odds of receiving a sphincter-sparing surgery and lower odds of requiring an ileostomy; however, neither of these outcomes was evident in our meta-analysis, suggesting that the benefit is primarily in disease control and decreased recurrence rates,” the investigators concluded.

Kasi A, Abbasi S, Handa S, et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer. 

. 2020;3(12):e2030097. doi:10.1001/jamanetworkopen.2020.30097.

Research published in JAMA Network Open found that total neoadjuvant therapy enhanced pathological complete response rates for patients with locally advanced rectal cancer.

Total Neoadjuvant Therapy Improves Rates of Pathological Complete Response in Rectal Cancer

The FDA has accepted and granted priority review to the biologics license application (BLA) for the intravenous PD-1 inhibitor retifanlimab as a possible treatment for adult patients with locally advanced or metastatic squamous cell carcinoma of the anal canal (SCAC) who have progressed on, or who are refractory to, platinum-based chemotherapy, according to the drugs developer, Incyte.

A prescription drug user fee act (PDUFA) target action was set by the FDA for July 25, 2021.

“Patients with SCAC who have progressed after first-line chemotherapy treatment currently have no approved treatments available, and we are encouraged that the FDA’s acceptance of this BLA for priority review brings us one step closer to addressing this historically neglected, yet important, tumor,” Lance Leopold, MD, group vice president of Immuno-Oncology Clinical Development at Incyte, said in a press release. “Despite SCAC being a rare disease, its incidence is increasing, and its impact is profound. We look forward to working with the FDA to potentially fill an unmet need and advance progress in SCAC for patients.”

The BLA submission is based on data observed in the open-label, single-arm, multicenter, phase 2 POD1UM-202 (NCT03597295) trial, which evaluated retifanlimab in the indicated patient population. Results from this trial were presented at the European Society for Medical Oncology (ESMO) Virtual Congress 2020.

Patients enrolled in the trial were given retifanlimab intravenously at a dose of 500 mg every 4 weeks. The trial enrolled a total of 94 patients, including several with well-controlled HIV infection.

The primary end point of the study is objective response rate (ORR) as determined by independent central review using RECIST v1.1. Key secondary end points include duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS), safety, and pharmacokinetics.

The study results presented at ESMO 2020 showed an ORR of 13.8% with retifanlimab monotherapy, including 1 complete response and 12 partial responses; 33 patients (35.1%) had stable disease. Responses were observed regardless of PD-L1 status, presence of liver metastases, age, or HIV-positive status and were also durable, with a median DOR of 9.5 months (5.6-not estimable).

Median PFS and OS were 2.3 (95% CI, 1.9-3.6) and 10.1 (95% CI, 7.9-NE) months, respectively. Importantly, responses were associated correlated with longer PFS and OS.

Treatment-related adverse events (AEs) of grade 3 or higher were reported in 11.7% of patients. Moreover, immune-related AEs of grade 3 or higher occurred in 6.4% of patients and treatment discontinuation due to immune-related AEs occurred in 2.1% of patients. The most common AEs observed (incidence ≥20%) were fatigue and diarrhea.

Retifanlimab was previously granted orphan drug designation by the FDA for the treatment of anal cancer. The investigational intravenous anti-PD1 agent is currently under evaluation in registration-directed trials as a monotherapy for patients with microsatellite instability–-high endometrial cancer, Merkel cell carcinoma, and SCAC as well as part of a combination regimen with platinum-based chemotherapy for patients with non–-small cell lung cancer and SCAC.

The phase 3 POD1UM-303/InterAACT 2 (NCT04472429) trial of retifanlimab in combination with carboplatin and paclitaxel in patients with inoperable locally recurrent or metastatic SCAC is now open and actively recruiting patients.

1. Incyte announces acceptance and priority review of BLA for retifanlimab as a potential treatment for patients with squamous cell carcinoma of the anal canal (SCAC). News release. Incyte. Published January 21, 2021. Accessed January 22, 2021. https://investor.incyte.com/press-releases/press-releases/2021/Incyte-Announces-Acceptance-and-Priority-Review-of-BLA-for-Retifanlimab-as-a-Potential-Treatment-for-Patients-with-Squamous-Cell-Carcinoma-of-the-Anal-Canal-SCAC/default.aspx

2. Rao S, Capdevila J, Gilbert D, et al. POD1UM-202: Phase II study of retifanlimab in patients (pts) with squamous carcinoma of the anal canal (SCAC) who progressed following platinum-based chemotherapy. 

. 2020;31(suppl 4):S1142-S1215. doi: 10.1016/annonc/annonc325

The BLA submission is based on data observed in the phase 2 POD1UM-202 trial of retifanlimab in previously treated patients with locally advanced or metastatic squamous cell carcinoma of the anal canal who had progressed on, or were intolerant of, standard platinum-based chemotherapy.

FDA Grants Priority Review to BLA for Retifanlimab as Possible Treatment for SCAC

The FDA has granted orphan drug designation to the novel viral immunotherapy PVSRIPO for the treatment of patients with advanced stage IIB through IV melanoma, according to Istari Oncology, the developer of the agent.

PVSRIPO is designed to stimulate a patient’s innate and adaptive immune system to promote an anti-tumor response and establish long-term immunologic memory to help prevent the cancer’s return.

Istari is currently recruiting for the open-label, randomized, phase 2 LUMINOS-102 (NCT04577807) trial of PVSRIPO in patients with PD-1 refractory melanoma. The study plans to characterize the safety, tolerability, and initial efficacy of PVSRIPO intratumoral injection alone and in combination with a PD-1 inhibitor.

The company plans to dose the first patient this quarter.

“We are happy to kick off the new year with the announcement that our request for an orphan drug designation has been granted to PVSRIPO for the treatment of advanced melanoma,” Matt Stober, president and chief executive officer at Istari Oncology, said in a press release. “This is just one of many milestones to come in 2021 as we continue to drive the clinical development of PVSRIPO across multiple indications.”

LUMINOS-102 will follow the successful phase 1 monotherapy study (NCT03712358) of PVSRIPO in anti–-PD-1 refractory advanced melanoma, results of which were previously presented at the 2020 Society for Immunotherapy of Cancer (SITC) Annual Meeting.

In this study, PVSRIPO injections were well tolerated with no serious adverse events (AEs) or dose-limiting toxicities reported. Moreover, all treatment-emergent AEs were grade 1 or 2, with grade 1 pruritus being the most common at 58%. All but 2 PVSRIPO-related, treatment-emergent AEs were localized to the injected or adjacent lesions (1 event each of grade 1 hot flash and grade 1 fatigue).

In spite of the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients >5 lesions), 4 of 12 patients (33%) achieved an objective response per independent radiologic review committee, including 4 of 6 (66%) who received the maximum administered dose of 3 injections. Pathologic complete response was also reported in 2 of 4 (50%) patients with in-transit disease.

Following treatment with PVSRIPO therapy, 10 of 12 patients (83%) again received immune checkpoint inhibitor (ICI)–-based therapy and 6 of 12 patients (50%) remained progression-free at the data cutoff.

“We are encouraged by the data from our phase 1 trial presented at last year’s Society for Immunotherapy of Cancer (SITC) 2020 Annual Meeting” Garrett Nichols, MD, MS, chief medical officer at Istari Oncology, said in the release. “We plan to build upon that success with LUMINOS-102. As those data and the data from our other solid tumor trials emerge, we will continue to work closely with the FDA toward the goal of bringing PVSRIPO to market.”

1. Istari Oncology announces FDA grants orphan drug designation for PVSRIPO for the treatment of advanced melanoma. News release. Durham, NC. Published January 10, 2021. Accessed January 19, 2021. https://istarioncology.com/press-release-fda-grants-orphan-drug-designation-for-pvsripo-for-the-treatment-of-advanced-melanoma/

2. Beasley G, Farrow N, Landa K, et al. A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma.

 2020;8(suppl 2):A185. Abstract 302. doi:10.1136/jitc-2020-SITC2020.0302

The novel viral immunotherapy PVSRIPO is designed to stimulate a patient’s innate and adaptive immune system to promote an antitumor response and establish long-term immunologic memory to help keep their cancer at bay.

FDA Grants Orphan Drug Designation to PVSRIPO for Treatment of Advanced Melanoma

 suggest that assays determining intratumor heterogeneity (ITH) could be helpful in determining which patients with renal cell carcinoma (RCC) are more likely to respond to PD-1 blockade.

Moving forward, the investigators suggested that understanding the mechanism by which ITH impacts response to PD-1 inhibitors may provide insights into how ITH could affect cancer therapy and patient survival, and aid in the development of predictive biomarkers for response to immune checkpoint therapy (ICT).

“A key unanswered question in RCC is whether and which genomic metrics are correlated with clinical benefit of ICT,” wrote the study authors who were led by Xia Ran. “Our results suggest that low ITH is associated with increased response to anti–PD-1 immunotherapy in RCC through increased immune activity involving more neoantigens and less frequent immune evasion.”

Among patients with clear cell RCC (ccRCC; n = 336) and papillary RCC (pRCC; n = 280) taken from The Cancer Genome Atlas, investigators quantified ITH using mutant-allele tumor heterogeneity (MATH). An independent cohort of 152 patients with ccRCC was used to validate the findings. Additionally, to assess the relationship between ITH and response to anti–PD-1 immunotherapy, 35 patients with metastatic ccRCC from a clinical trial of anti­–PD-1 therapy were evaluated with results validated across 3 equal-size simulated data sets (n = 60) generated by random sampling with replacement based on the trial cohort.

Of those with ccRCC, low ITH was found to be associated with response to anti­–PD-1 immunotherapy through increased immune activity involving more neoantigens, elevated expression of human lymphocyte antigen class 1 genes, and greater abundance of dendritic cells. Moreover, the investigators also revealed that among patients with ccRCC, the association between the level of ITH and response to PD-1 blockade was independent of 

 mutation status and that taking both factors into consideration resulted in better performance when compared with the individual predictors in determining prognosis with anti–PD-1 immunotherapy.

In patients with pRCC, increased immune activity was greater in patient with low-ITH status, which included greater neoantigen counts, increased amounts of monocytes, and decreased expression of PD-L1 and PD-L2.

“In this study, we quantified ITH using MATH based on the allele frequencies of somatic mutations,” the authors noted. “Admittedly, there are other well-designed tools (eg PyClone, EXPANDS, and ABSOLUTE) quantifying ITH based on not only somatic mutations, but also other metrics such as copy number estimates and loss of heterozygosity. While taking more parameters into account may improve the accuracy of ITH quantification, it also means more complex analyses and longer run time, which is not conducive to large-scale clinical application.”

Ultimately, based on their findings, the investigators indicated MATH may be a quick and accurate measurement of ITH in RCC. However, it was also suggested that the cutpoint of MATH scores for ccRCC and pRCC will need further preclinical and prospective clinical validation in order to be used for large-scale clinical application.

Ran X, Xiao J, Zhang Y, et al. Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma. 

. 2020;12:1-17. doi:10.1177/1758835920977117

“Our results suggest that low [intertumoral heterogeneity] is associated with increased response to anti–PD-1 immunotherapy in renal cell carcinoma through increased immune activity involving more neoantigens and less frequent immune evasion,” wrote the study authors, led by Xia Ran.

Assays of Intratumoral Heterogeneity May Predict RCCs Likely to Respond to PD-1 Blockade

According to a presentation at the 2020 American Society for Hematology Annual Meeting & Exposition, the combination of venetoclax (Venclexta) and azacitidine (Vidaza) showed impressive efficacy for patients with acute myeloid leukemia with 

 mutations who were treatment naïve and ineligible for chemotherapy, achieving high response rates, with a longer duration of response and increased median overall survival when compared with treatment with azacitidine alone.

, Dan Pollyea, MD, MS, of the University of Colorado Cancer Center, talked about the impact of this study and its potential to help patients with 

When it when it comes to venetoclax, I don’t think there were any real preconceived notions that patients with these mutations would respond better or worse [to treatment]. But that was certainly the observation that we began seeing in the very first clinical trials, and that’s been an ongoing observation, all the way up to this latest phase 3 study that was [published] in the 

 As to why this is the case? That’s a fascinating question. Some of my colleagues have made really great attempts to answer that question, but I think, for the most part, a lot of it still remains to be understood. I think in the coming years, this question will get worked out. And I think that the excitement around that is that it could potentially lead to us allowing for 

 wild-type [disease] to maybe have the same responses, if we can understand why 

1. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and Venetoclax in Previously Untreated Acute Myeloid Leukemia. 

. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971

The leukemia expert talks about how current findings may hold promise for a larger group of patients in the future.

Dan Pollyea, MD, MS, on Venetoclax and IDH Mutations in Patients With AML

Results from the phase 3 IMbrave150 trial (NCT03434379) show sustained survival benefits with atezolizumab (Tecentriq) and bevacizumab (Avastin) versus sorafenib (Nexavar) in previously untreated patients with advanced hepatocellular carcinoma (HCC), according to a presentation at the 2021 Gastrointestinal Cancers Symposium.

At a median follow-up of 15.6 months, the median overall survival (OS) was 19.2 months with the combination versus 13.4 months with sorafenib (HR, 0.66; 95% CI, 0.52-0.85; 

 = .0009). The median progression-free survival (PFS) was 6.9 months versus 4.3 months, respectively (HR, 0.65; 95% CI, 0.53-0.81; 

“The median survival for atezolizumab/bevacizumab is now over 19 months. This is the longest survival seen in a phase 3 study of advanced liver cancer,” lead study author, Richard S. Finn, MD, professor of clinical medicine, Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine, University of California, Los Angeles (UCLA), and director of the Signal Transduction and Therapeutics Program at the UCLA Jonsson Comprehensive Cancer Center, said in a virtual presentation of the data during the meeting.

In May 2020, the FDA approved the combination for patients with unresectable or metastatic HCC who have not received prior systemic therapy based on findings from the primary analysis of the IMbrave150 study in which both coprimary end points of PFS (HR, 0.59) and OS (HR, 0.58) were met.

The global, multicenter, randomized, open-label study enrolled 501 treatment-naive patients with locally advanced or metastatic and/or unresectable HCC and randomized them 2:1 to 1200 mg of intravenous (IV) atezolizumab every 3 weeks plus 15 mg/kg of IV bevacizumab every 3 weeks (n = 336) or 400 mg of sorafenib twice daily (n = 165) until unacceptable toxicity or loss of clinical benefit.

Eligible patients had 1 or more measurable untreated lesions per RECIST 1.1 criteria, Child-Pugh class A liver function and an ECOG performance status of 0 or 1.

Updated patient disposition indicated that 40% of patients in the combination arm remain on study versus 26% in the sorafenib arm; 18% and 3% of patients remain on treatment, respectively. Sixty percent of patients in the combination arm have discontinued the study versus 74% in the sorafenib arm, primarily because of death (53% and 60%, respectively).

“The baseline characteristics have not changed from the primary analysis. The majority of patients came from outside of Asia and had high-risk features, such as an elevated alpha-fetoprotein, macrovascular invasion, or extrahepatic spread,” said Finn.

With an additional 12 months of follow-up, the updated results also demonstrated an 18-month OS rate of 52% with the combination versus 40% with sorafenib. The 18-month PFS rates were 24% and 12%, respectively.

“We see with longer follow-up that we have more responses with atezolizumab/bevacizumab than initially reported,” said Finn.

The confirmed objective response rate by RECIST v1.1 criteria was 30% with the combination versus 11% with sorafenib, with complete response rates of 8% and less than 1%, respectively. The disease-control rate was 74% with the combination versus 55% with sorafenib.

The median duration of response was 18.1 months with the combination versus 14.9 months with sorafenib. Fifty-six percent of patients in the combination arm had an ongoing response at the clinical cutoff versus 28% of patients in the sorafenib arm.

Regarding follow-up systemic therapy for HCC, 36% of patients in the combination arm had at least 1 subsequent systemic therapy versus 52% of patients in the sorafenib arm. Types of follow-up therapies included TKIs (32% versus 33%, respectively), immunotherapy (3% versus 26%, respectively), chemotherapy (3% versus 9%, respectively), angiogenesis inhibitors (2% versus 6%, respectively), among others (2% versus 4%, respectively).

In the Chinese cohort (n = 194), the median OS was 24.0 months in the combination arm versus 11.4 months in the sorafenib arm (stratified HR, 0.53; 95% CI, 0.35-0.80). The 18-month OS rates were 56% and 33%, respectively.

In terms of safety, all-grade treatment-related adverse effects (TRAEs) occurred in 86% of patients in the combination arm versus 95% of patients in the sorafenib arm. The rates of grade 3/4 TRAEs were 43% and 46%, respectively. Grade 5 TRAEs occurred in 2% of patients in the combination arm versus less than 1% in the sorafenib arm.

AEs leading to withdrawal from any component of treatment occurred in 22% of patients in the combination arm versus 12% in the sorafenib arm. AEs leading to dose interruption of any study treatment occurred in 59% and 44% of patients, respectively.

“The safety and tolerability of the combination remains consistent with what we saw in the primary analysis,” concluded Finn.

Finn RS, Qin S, Ikeda M, et al. IMbrave150: updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). 

 2021;39(suppl 3):267. http://bit.ly/2LVd9Mu.

Compared with previous standard-of-care therapy with sorafenib, the IMbrave150 combination maintains overall survival superiority in treatment-naive advanced hepatocellular carcinoma.


Updated Data Show Survival Benefit Continues in Advanced HCC With Atezolizumab/Bevacizumab Combo

Chemotherapy-refractory cholangiocarcinomas harboring 

 fusions responded well to infigratinib treatment and revealed an acceptable safety profile for the agent, according to final results from cohort 1 of a phase 2 trial (NCT02150967) presented during the 2021 Gastrointestinal Cancers Symposium.

The TKI elicited an objective response rate (ORR) per blinded independent review (BIR) of 23.1% (95% CI, 15.6%-32.2%) in a total of 108 patients with advanced/metastatic cholangiocarcinoma. The ORR was comprised of 1 complete response and 24 partial responses; 66 participants achieved stable disease with the agent, while 11 experienced disease progression. The median duration of response (DOR) was 5.0 months (95% CI, 0.9-19.1).

“Infigratinib is an oral, FGFR1-3 selective TKI that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing 

 fusions,” lead study author Milind Javle, MD, professor in the Department of Gastrointestinal Medical Oncology of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, said during an oral presentation of the data. “Infigratinib, administered as second- and later-line treatment, represents a new therapeutic option for [these] patients.”

Approximately 14% of patients with intrahepatic cholangiocarcinoma have tumors that harbor FGFR fusions, and second-line chemotherapy appears to have limited efficacy in these patients. Previously, however, infigratinib has been shown to have preliminary activity in tumors that harbor these aberrations.

 For example, results from a phase 2 trial (NCT02150967) showed that the agent elicited an ORR of 14.8% in patients with 

-altered advanced disease, with a disease control rate (DCR) of 75.4%.

 fusions only, these rates were 18.8% and 83.3%, respectively.

The open-label, phase 2 trial enrolled 140 patients with unresectable locally advanced or metastatic cholangiocarcinoma who had either progressed on or were intolerant to gemcitabine-based chemotherapy. To be eligible for enrollment, all participants had to have either 

Patients were assigned to 1 of the 3 cohorts: patients with 

 gene fusions or rearrangements comprised cohort 1 (n = 120), those with 

 mutations comprised cohort 2 (n = 20), and those with 

 gene fusions who had progressed after previous treatment with a selective FGFR inhibitor beyond infigratinib were included in cohort 3 (n = 20).

Patients received single-agent infigratinib at a daily dose of 125 mg for 21 days in 28-day treatment cycles. The co-primary end points of the trial were ORR and DOR, while key secondary end points included progression-free survival (PFS), DCR, best overall response (BOR), overall survival (OS), safety, and pharmacokinetics.

Results presented during the 2021 Gastrointestinal Cancers Symposium were focused on cohort 1, which enrolled a total of 122 patients; 14 patients were excluded from the analysis because they had other genetic alterations such as 

 fusions or rearrangements were included in the protocol-defined analysis population. Of these patients, 107 received previous gemcitabine-based treatment, 88 had 

At the time of data cutoff, 96 patients had discontinued treatment with the study drug. The majority (n = 67), discontinued due to disease progression, while 15 did so because of toxicity, and 9 because of clinical progression. Moreover, 3 discontinuations were due to patient decision, 1 was due to death, and 1 patient was lost to follow-up. A total of 12 patients were still receiving treatment with infigratinib at the time of data cutoff.

 fusion partner was BICC1, which was observed in 25% (n = 27) of patients, followed by AHCYL1, which was noted in 3.7% (n = 4) of patients. “Interestingly, 35% of patients had novel fusion partners,” noted Javle.

The median age of study participants “was relatively low,” according to Javle, at 53 years. The majority of patients, or 62%, were female. Moreover, 72.2% of patients were white, 10.2% were Asian, 3.7% were Black or African American, and 13.9% were other or unknown. The majority of patients had an ECOG performance status of 1 (57.4%; n = 62) and stage IV disease at the time of study entry (99.1%; n = 107). Just under 70% of patients had metastases in the lung, while 57.4% had them in the lymph nodes, and 25.9% had them in the bone.

“This was an extensively pretreated population, with a median of 2 prior lines of therapy,” noted Javle. “In fact, [approximately] 46% of patients had 1 or less lines of therapy, and the rest had 2 or more prior lines of therapy.”

Additional results revealed that the BOR was 34.3% (95% CI, 25.4-44.0) and median time to response with infigratinib was 3.6 months (range, 1.4-7.4); the DCR with infigratinib was 84.3% (95% CI, 76.0-90.6). Per investigator assessment, the confirmed ORR was 30.6% and the median duration of response was 6.0 months (range, 5.2-9.0).

Additionally, the median PFS in these patients per BIR was 7.3 months (95% CI, 5.6 -7.6), with a 4-month PFS rate of 75.2% (95% CI, 65.2-82.7). The median OS was 12.2 months (95% CI, 10.7-14.9) in this population.

“Interestingly, the clinical activity with infigratinib may depend on prior lines of chemotherapy,” said Javle.

The ORR in patients who received 1 or less prior lines of therapy was 34.0% (95% CI, 21.2-48.8) versus just 13.8% (95% CI, 6.1-25.4) in those who received 2 or more prior lines of treatment; this translated to a BOR that was superior in the subgroup who received 1 or fewer prior lines of treatment, at 42.0% (95%, 28.2-56.8) versus 27.6% (95% CI, 16.7-40.9), respectively. Additionally, the DCR in the patients who received fewer prior lines of treatment was 88.0% (95% CI, 75.7-95.5) versus 81.0% (95% CI, 68.6-90.1) in those who received 2 or more prior lines.

“However, there was no [significant] difference in terms of DOR or median PFS,” added Javle. The DOR in those who received 1 or fewer lines of previous treatment was 5.6 months (range, 3.7 months-9.5 months) versus 4.9 months (95% CI, 3.7 months–not evaluable). The median PFS in these subgroups was 7.3 months (95% CI, 5.6-9.3) versus 7.4 months (95% CI, 5.6-7.7), respectively.

“The vast majority of patients experienced benefit in terms of either stable disease or partial response,” added Javle. All subgroups of patients appeared to benefit with infigratinib, irrespective of gender, age, baseline ECOG performance status, disease stage at time of study entry, and region; those who received fewer lines of therapy achieved the most benefit.

The majority of toxicities reported with infigratinib were grade 1 or 2 in severity; these adverse effects (AEs) were found to be both reversible and easily managed. The most frequently reported AEs were mechanism based; they included calcium phosphate homeostasis (85.2%), tissue calcification (2.8%), pathological fracture (0.9%), vascular calcification/mineralization (0.9%), and eye disorders (70.4%). Central serous retinopathy/retinal pigment epithelial detachment–like events occurred in 16.7% of patients.

Infigratinib is now under exploration in a phase 3 trial (NCT03773302), which is evaluating its safety and efficacy compared with standard-of-care gemcitabine or cisplatin in the frontline treatment of patients with unresectable locally advanced or metastatic cholangiocarcinoma with 

Javle M, Roychowdhury S, Kelley RK, et al. Final results from a phase 2 study of infigratinib (BGJ398), a FGFR-selective tyrosine kinase inhibitor, in patients with previously-treated advanced cholangiocarcinoma containing FGFR2 fusions/rearrangements. 

. 2021;39(suppl 3):265. http://bit.ly/3oX1njs.

Guagnano V, Kauffmann A, Wöhrle S, et al. FGFR genetic alterations predict for sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. 

. 2012;2(12):1118-1133. doi:10.1158/2159-8290.CD-12-0210

Javle M, Lowery M, Shroff RT, et al. Phase II study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma. 

. 2018;36(3):276-282. doi:10.1200/JCO.2017.75.5009

Phase 3 study of BGJ398 (oral infigratinib) in first line cholangiocarcinoma with FGFR2 gene fusions/translocations. ClinicalTrials.gov. Updated December 22, 2020. Accessed January 17, 2021. https://clinicaltrials.gov/ct2/show/NCT03773302.

Encouraging efficacy and safety outcomes were reported at the 2021 Gastrointestinal Cancers Symposium when infigratinib was used to treat FGFR2 fusion–positive cholangiocarcinomas that are refractory to chemotherapy. 
