Staff Writer

The FDA has granted approval to axicabtagene ciloleucel (Axi-cel;Yescarta) for the treatment of adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy, according to an announcement from the FDA.

Findings from the phase 3 ZUMA-7 clinical trial supported the approval. In adult patients with primary refractory LBCL or relapse within 12 months following completion of first-line therapy, axi-cel led to a 60% improvement in event-free survival (EFS) compared with standard of care (SOC) chemotherapy.

The EFS benefit in the axi-cel arm was significant with a hazard ratio of 0.40 (95% CI: 0.31, 0.51; stratified 

 <0.0001). The estimated 18-month EFS rate was 41.5% (95% CI, 34.2, 48.6) with axi-cel vs 17.0% (95% CI, 11.8, 23.0) with SOC. The estimated median EFS was 8.3 months (95% CI, 4.5, 15.8) with axi-cel vs 2.0 months (95% CI, 1.6, 2.8) with SOC.

The SOC second-line treatment in the curative setting for LBCL is salvage chemotherapy followed by consolidation high-dose therapy (HDT)–autologous stem cell transplant (ASCT). But due to poor prognosis, many patients are ineligible for SOC.

ZUMA-7 is a randomized, open-label, multicenter study of 359 patients with LBCL who had not yet received treatment for relapsed or refractory lymphoma and were potential candidates for autologous hematopoietic stem cell transplantation. Patients were randomized 1:1 to receive axi-cel plus conditioning chemotherapy (n = 180) or SOC with investigator-selected platinum-based chemoimmunotherapy (n = 179). In addition to the primary end point of EFS, the key secondary end points of the study were progression-free survival, safety, and patient-reported outcomes.

Eligible patients for treatment in the study were those with LBCL that was relapsed/refractory within 12 months of frontline therapy and had intentions to proceed to HDT-ASCT. Stratification factors included response to frontline therapy and sAAIPI. Patients were required to be aged 18 years or older.

At baseline, the treatment arms were well balanced. The median patient age was 59 years (range, 21-81), and 30% of patients were 65 years and older. Most patients (79%) had stage III/IV disease, and 45% of patients had a sAAIPI of 2 to 3. Most patients (74%) were primary refractory to their frontline therapy vs 26% who relapsed within 1 year of their prior treatment. Sixteen percent of patients had high-grade BL (double-/triple-hit) vs 33% who had double-expressor lymphoma and 6% who had 

 rearrangement. Fifty-four percent of patients had elevated lactate dehydrogenase levels.

With a data cutoff date of March 18, 2021, for the primary analysis, 94% of the 180 patients randomized received CAR T-cell therapy, and 36% of those randomized to the SOC arm underwent HDT-ASCT.

The objective response rate was 83% with axi-cel vs 50% with SOC (odds ratio, 5.31; 95% CI, 3.1-8.9; 

 < .0001). In the axi-cel arm, the ORR consisted of a 65% complete response rate and an 18% partial response rate; these rates were 32% and 18%, respectively, with SOC.

At the time of the interim analysis, the median overall survival (OS) was not reached (95% CI, 28.3–not evaluable [NE]) with axi-cel compared with 35.1 months (95% CI, 18.5–NE) with SOC (HR, 0.730; 95% CI, 0.530-1.007; 

Grade 3 or higher adverse effects (AEs) were observed in 91% of patients treated with axi-cel compared with 83% of those treated with SOC. The most common grade 3 or higher AEs were neutropenia (69% vs 41%, respectively), anemia (30% vs 39%), and leukopenia (29% vs 22%). Grade 3 or higher serious AEs occurred in 42% of the axi-cel arm compared with 40% of the SOC arm.

There were 55 deaths in the axi-cel arm due to progressive disease (n = 47), grade 5 AE during protocol-specified reporting period (n = 7), and definitive therapy-related mortality (n = 1). In comparison, the SOC arm had 68 deaths.

Cases of grade 3 or higher cytokine release syndrome occurred in 6% of patients in the axi-cel arm. The most common any-grade events were pyrexia (99%), hypotension (43%), and sinus tachycardia (31%). CRS was managed by tocilizumab (Actemra) in 65% of patients, corticosteroids in 24%, and vasopressors in 6%. The median time to onset was 3 days and the median duration of events was 7 days.

Finally, grade 3 or higher neurologic events occurred in 21% of axi-cel arm compared with 1% of SOC-treated patients, of which the most common were tremor, confusional state, and aphasia. All events appeared to be managed by corticosteroids. The median time to onset was 7 days in the axi-cel arm was 9 days compared with 23 days in the SOC arm.

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. News release. FDa website. April 1, 2022. Accessed April 1, 2022. https://bit.ly/3u07jNx

2. Locke F, Miklos DB, Jacobson CA, et al. Primary analysis of ZUMA‑7: a phase 3 randomized trial of axicabtagene ciloleucel (axi-cel) versus standard‑of‑care therapy in patients with relapsed/refractory large B-cell lymphoma. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2.

Articles

The FDA has granted approval to axicabtagene ciloleucel for the treatment of adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or relapses within 12 months of first-line chemoimmunotherapy, according to an announcement from the FDA.

FDA Approves Second-Line Axi-Cel for Adults With LBCL

Targeted therapy with tyrosine kinase inhibitors (TKIs) is necessary after surgery for patients with metastatic gastrointestinal stromal tumors (GIST) with residual disease requiring resection to prevent disease recurrence, according to Carol Swallow, MD, FRCSC.

At the 2022 European Society for Medical Oncology (ESMO) Sarcoma and GIST Symposium, Swallow, a surgical oncologist at Princess Margaret Hospital and a member of the Division of General Surgery at Mount Sinai Hospital in Toronto, Canada, debated the benefit of surgery in metastatic disease and the use of TKIs in the perioperative setting. She maintained that resection alone without continuing TKI therapy is “not adequate treatment” and sought to prove the necessity of both surgery and TKI therapy through various levels of evidence. 

Prior to the standard use of imatinib (Gleevec), data from a Memorial Sloan Kettering Cancer Center study showed very poor survival for patients with metastatic and recurrent GIST who had a resection alone.

Findings from an additional study from Poland of patients with initially inoperable and/or metastatic GIST showed that recurrences were common in patients who did not receive imatinib after surgery.

 Of 32 patients included in the study, 5 patients did not receive further imatinib therapy and 4 had recurrent disease, resulting in a lower progression-free survival (PFS) for this subgroup. “So it has become standard to continue the imatinib,” Swallow said.

She emphasized that upfront cytoreduction is not useful for patients. In a retrospective study of 249 patients with advanced GIST who either did or did not receive cytoreduction prior to the start of imatinib, the investigators found that cytoreduction prior to imatinib did not improve the prognosis of these patients.

 = .164) were similar regardless of surgical resection or not.

“The controversy continues, though, about patients who have responded to TKI therapy and whether they should be offered what we call adjuvant surgery. Does this type of resection in this setting benefit them?” she added.

Swallow highlighted 3 randomized, controlled trials that addressed this controversy.

In a multicenter trial from China, patients with recurrent or metastatic GIST and residual disease were randomized to surgery or imatinib treatment alone. In those who underwent surgery, the 2-year PFS rate was 88.4% compared with 57.7% in the imatinib-alone arm (

 = .089). The median OS was not reached in the surgery arm and was 49 months in the imatinib arm (

 However, the trial had poor accrual and closed early.

An earlier, smaller study of patients with GIST and liver metastases treated with either neoadjuvant therapy, resection, and adjuvant therapy or imatinib alone, showed a significant difference in OS (

Meta-analyses also indicated improved survival for patients with advanced GIST who underwent surgery alone compared with surgery following TKI administration. In one such analysis of more than 650 patients with advanced GIST, surgical resection following TKI was associated with both improved PFS (HR, 2.08; 95% CI, 1.58-2.76;

 < .001) and OS (HR, 2.13; 95% CI, 1.59-2.85; 

A retrospective analysis of the Spanish Group for Research on Sarcoma (GEIS) looked at 171 patients with locally advanced or metastatic GIST. The median survival was 59.9 months for those treated with imatinib alone and 87.6 months for those treated with imatinib and metastasectomy (HR for OS by multivariate analysis, 0.47; 95% CI, 0.24-0.90;

“The baseline features of these patients were not similar, and this is representative of many of these observational studies,” Swallow said.

An analysis of 323 patients with metastatic GIST suggested that certain prognostic factors affected survival outcomes with surgery.

Those who had positive margins from surgery (HR, 1.85; 95% CI, 1.19-2.87; 

 = .006) or multifocal progressive disease (HR, 3.08; 

 = .001) had worse PFS outcomes. Radiographic response to TKI therapy at the time of surgery also influenced PFS. Patients who were responsive to TKI therapy had a median PFS of 31 months, 19 months for stable disease, 10 months in the case of unifocal progression, and 5 months for multifocal progression (

 < .001). Regarding TKI, patients treated with imatinib had improved PFS compared with either sunitinib or other TKI therapy, regardless of radiographic response.

Swallow emphasized that surgery is still necessary to manage residual disease after TKI therapy to eliminate resistant clones and delay the time to next treatment in patients who are considered good candidates for resection. Clinical practice guidelines for GIST also recommend the use of surgery for residual disease following response to imatinib therapy, followed by further imatinib after surgical resection.

However, Swallow reminded the audience that patient selection is critical and should be guided by response status and performance status.

1. Swallow C. The management of residual disease after TKIs in GIST. Presented at: 2022 ESMO Sarcoma and GIST Symposium; January 31-February2, 2022; Virtual.

2. Mudan SS, Conlon KC, Woodruff JM, Lewis JJ, Brennan MF. Salvage surgery for patients with recurrent gastrointestinal sarcoma: prognostic factors to guide patient selection. Cancer. 2000;88(1):66-74. doi:10.1002/(sici)1097-0142(20000101)88:1<66::aid-cncr10>3.0.co;2-0

3. Rutkowski P, Nowecki Z, Nyckowski P, et al. Surgical treatment of patients with initially inoperable and/or metastatic gastrointestinal stromal tumors (GIST) during therapy with imatinib mesylate. J Surg Oncol. 2006;93(4):304-311. doi:10.1002/jso.20466

4. An HJ, Ryu MH, Ryoo BY, et al. The effects of surgical cytoreduction prior to imatinib therapy on the prognosis of patients with advanced GIST. Ann Surg Oncol. 2013;20(13):4212-4218. doi:10.1245/s10434-013-3279-9

5. Du CY, Zhou Y, Song C, et al. Is there a role of surgery in patients with recurrent or metastatic gastrointestinal stromal tumours responding to imatinib: a prospective randomised trial in China. Eur J Cancer. 2014;50(10):1772-1778. doi:10.1016/j.ejca.2014.03.280

6. Xia L, Zhang MM, Ji L, Li X, Wu XT. Resection combined with imatinib therapy for liver metastases of gastrointestinal stromal tumors. Surg Today. 2010;40(10):936-942. doi:10.1007/s00595-009-4171-x

7. Guo Y, Liu J, Wang F, et al. The role of surgical resectionfollowing tyrosine kinase inhibitors treatment in patients with advanced gastrointestinal stromal tumors: a systematic review and meta-analysis. J Cancer. 2019;10(23):5785-5792. doi:10.7150/jca.30040

8. Rubió-Casadevall J, Martinez-Trufero J, Garcia-Albeniz X, et al; Spanish Group for Research on Sarcoma (GEIS). Role of surgery in patients with recurrent, metastatic, or unresectable locally advanced gastrointestinal stromal tumors sensitive to imatinib: a retrospective analysis of the Spanish Group for Research on Sarcoma (GEIS). Ann Surg Oncol. 2015;22(9):2948-2957. doi:10.1245/s10434-014-4360-8

9. Fairweather M, Balachandran VP, Li GZ, et al. Cytoreductive surgery for metastatic gastrointestinal stromal tumors treated with tyrosine kinase inhibitors: a 2-institutional analysis. Ann Surg. 2018;268(2):296-302. doi:10.1097/SLA.0000000000002281

10. Casali PG, Blay JY, Abecassis N, et al; ESMO Guidelines Committee, EURACAN, and GENTURIS. Gastrointestinal stromal tumours: ESMO–EURACAN–GENTURIS clinical practice guidelinesfor diagnosis, treatment and follow-up. Ann Oncol. 2022;33(1):20-33. doi:10.1016/j.annonc.2021.09.005

Targeted therapy with tyrosine kinase inhibitors is necessary after surgery for patients with metastatic gastrointestinal stromal tumors with residual disease requiring resection to prevent disease recurrence.

Targeted Therapy Is Considered a Necessity for Metastatic GIST

In a real-world study, more patients with metastatic castration-sensitive prostate cancer (mCSPC) achieved an early and deep prostate-specific antigen (PSA) reduction from baseline of 90% or more (PSA90 response) when treated with apalutamide (Erleada) versus enzalutamide (Xtandi), according to data presented in a poster at the 2022 Genitourinary Cancers Symposium.

Patients who received apalutamide (n = 174) achieved a PSA90 response at a 70.4% rate compared with 62.5% of patients who received enzalutamide (n = 177) at the end of the 12-month follow-up (HR, 1.49; 95% CI, 1.05-2.11; 

 = .024). The median time to PSA90 response was 3.13 months and 5.20 months in the apalutamide and enzalutamide groups, respectively. Weighted Kaplan-Meier analysis was used to assess the proportion of patients who achieved a PSA90 response and to assess the median to PSA90.

“The clinical implications of these observations warrant further consideration given existing evidence on the association between attainment of rapid, deep, and durable PSA response with survival-related end points in patients treated with these medications,” study authors wrote.

Both apalutamide and enzalutamide are next-generation androgen receptor inhibitors. Enzalutamide was approved by the FDA on December 16, 2019, and apalutamide was approved in this indication on September 17, 2019.

The index date of the study was defined as the first dispensation of apalutamide or enzalutamide following the approval date of enzalutamide. Patients were assigned to mutually exclusive treatment cohorts based on the first dispensation of apalutamide or enzalutamide. The observation period went from the index date to either index treatment discontinuation, initiation of a different next-generation androgen inhibitor, the use of radiopharmaceuticals, the end of clinical activity, or the end of data availability, whichever occurred first.

In terms of statistical analysis methods, inverse probability of treatment weighting based on propensity score (PS) was used to account for the differences in baseline characteristics in the apalutamide and enzalutamide groups. PS was determined by a logistic regression model for apalutamide or enzalutamide treatment assignments with the baseline characteristics of age, race, index year, androgen deprivation therapy (ADT) use of 6 months or more, first-generation antiandrogen use, most recent PSA level, most recent testosterone level, Gleason score, and time between metastasis and the index date.

Investigators wanted to compare the proportion of patients with mCSPC newly treated with apalutamide versus enzalutamide who achieved a PSA90 response at 6 months and beyond. The data used in the study was sourced from Precision Point Specialty Analytics and was collected as part of routine clinical care from 69 United States urology clinics from February 1, 2017, to March 5, 2021. The data was de-identified and was Health Insurance Portability and Accountability Act compliant.

To be included in the study, patients had to be at least 18 on the index date, have at least 1 medication dispensation for apalutamide or enzalutamide, and have at least 12 months of clinical activity prior to the index date. Eligible patients also needed to have evidence of metastatic prostate cancer, defined by the presence of bone, nodal, visceral metastasis prior to or on the index date. A minimum of 1 PSA test during the 13 weeks prior to and including the index date was required.

Patients were excluded from the study if they had prior use of a radiopharmaceutical or a next-generation androgen inhibitor before the index date, or the use of 2 or more next-generation androgen inhibitors. If patients displayed evidence of castration resistance prior to or on the index date, they were not included in the study.

Baseline patient characteristics were evaluated in the 12 months preceding the index date. In the weighted apalutamide group, the median age was 76.0 compared with 75.0 in the enzalutamide cohort. Most patients in both groups were White (71.0% vs 70.5%, respectively), had an index date from 2019-2020 (77.2% vs 77.1%, respectively), and reported prior ADT use (91.4% vs 91.2%, respectively). The mean baseline PSA level was 18.4 ng/mL in the apalutamide cohort compared with 18.3 ng/mL.

PSA testing frequency was similar between the 2 cohorts; 73.6% and 69.5% of patients had a post-index PSA measurement by 6 months in the apalutamide and enzalutamide groups, respectively. A median of 3.8 PSA tests were done per year in the apalutamide cohort compared 3.3 in the enzalutamide cohort. Most patients in both groups had a PSA test every 6 months on average (71.2% vs 67.8%, respectively).

At 6 months follow-up, 69.3% of the apalutamide group achieved a PSA90 response versus 55.6% in the enzalutamide group (HR 1.56; 95% CI, 1.09-2.22; 

 = .014). Apalutamide also outperformed enzalutamide in terms of PSA90 response at the 9-month mark (70.4% vs 62.5%; HR, 1.49; 95% CI, 1.05-2.11; 

The investigators noted that the study was limited because some of the clinical data used could contain inaccuracies or omissions, and the data did not capture any clinical services obtained outside of the urology practice. The study didn’t address if the findings represent a clinically meaningful difference or if they translate into differences in longer-term outcomes. Additionally, the database that was used represented the community urology perspective and may not necessarily be representative of the entire United States population of patients with mCSPC.

Lowentritt B, Pilon D, Khilfeh I, et al. Attainment of early, deep prostate-specific antigen response in metastatic castration-sensitive prostate cancer: A comparison of patients initiated on apalutamide or enzalutamide. J Clin Oncol. 2022;40(suppl 6):43. doi:10.1200/JCO.2022.40.6_suppl.043

According to real-world data, apalutamide may be more likely to offer an early and deep prostate-specific antigen reduction than enzalutamide.

Apalutamide Bests Enzalutamide in Metastatic Castration-Sensitive Prostate Cancer

Allarity Therapeutics, Inc has submitted a new drug application to the FDA for dovitinib as a potential option in the third-line treatment of patients with renal cell carcinoma (RCC), according to a press release by the company.

The application is supported by the company’s prior pre-market approval submission with the regulatory agency for use of the validated companion diagnostic Dovitinib-DRP, to select eligible patients with RCC for treatment with the agent.

“This NDA submission for dovitinib, in connection with the Dovitinib-DRP companion diagnostic, is a historic milestone for our Company and an important step for late-stage RCC patients awaiting new treatment options,” Steve Carchedi, chief executive officer of Allarity Therapeutics, Inc., stated in a press release. “Over the past decade, we have worked diligently to advance our novel oncology therapeutics pipeline together with our unique DRP diagnostic technology to realize the promise of personalized cancer care for patients.”

A pan-TKI that was developed to target FGFR, VEGFR, and other receptor tyrosine kinases (RTKs), dovitinib binds to and inhibits the phosphorylation of type III-V RTKs that encourage tumor cell proliferation and survival in certain cancer cells.

Moreover, the agent inhibits other members of the RTK superfamily, such as FGFR1, FGFR3, FMS-like tyrosine kinase 3, c-KIT, and colony-stimulating factor receptor 1. By doing this, dovitinib can potentially reduce cellular proliferation and angiogenesis, and induce tumor cell apoptosis.

Previously, in the open-label, phase 3 GOLD trial (NCT01223027), investigators set out to compare the safety and efficacy of dovitinib with that of sorafenib (Nexavar) in patients with metastatic RCC.

The trial enrolled those who had a clear cell or a component of clear cell histology and who had previously received 1 VEGF-targeted therapy like sunitinib (Sutent) or bevacizumab (Avastin) plus 1 prior mTOR inhibitor like everolimus (Afinitor) or temsirolimus (Torisel) in either sequence. To be eligible, patients needed to be at least 18 years of age and have had disease progression on, or within 6 months of receiving, their last therapy.

Other inclusion criteria included measurable disease per RECIST v1.1 criteria, a Karnofsky performance status of 70 or higher, and acceptable hematologic, renal, and hepatic functions. Patients were allowed to have received prior anticancer agents, including cytokines and anticancer vaccines.

If patients received prior sorafenib or dovitinib, had brain metastases, clinically significant cardiac disease, or uncontrolled hypertension, they were excluded.

A total of 570 participants were randomized to receive oral dovitinib at a dose of 500 mg on a 5-days-on and 2-days-off schedule (n = 284) or oral sorafenib at a twice-daily dose of 400 mg (n = 286). Treatment was administered until progressive disease, intolerable toxicity, death, or withdrawn consent. Crossover was not permitted.

The primary end point of the trial was progression-free survival (PFS), and the key secondary end point was overall survival (OS). Additional secondary end points comprised overall response, PFS per investigator assessment, time to definitive worsening of Karnofsky performance status, patient-reported outcomes (PROs), and safety. Biomarker analyses served as an exploratory end point of the research.

Patient characteristics were noted to be well balanced between the treatment arms. Among the randomized population, sunitinib was the most used prior VEGF inhibitor; everolimus was the most frequently utilized mTOR inhibitor. Ninety-two percent of patients received a VEGF inhibitor followed by an mTOR inhibitor (n = 259, dovitinib arm; n = 265, sorafenib arm).

Data showed that the median PFS per central radiologist review with dovitinib was 3.7 months (95% CI, 3.5-3.9) vs 3.6 months (95% CI, 3.5-3.7) with sorafenib (HR, 0.86; 95% CI, 0.72-1.04; 

 = .063). The median investigator-assessed PFS in the investigative (95% CI, 3.7-5.1) and control (95% CI, 3.7-5.0) arms was 3.9 months (HR, 1.00; 95% CI, 0.82-1.21).

When assessed by patient demographics and disease characteristics, no subset of patients was found to have a clinically significant PFS benefit with dovitinib.

Moreover, the best overall response per central review was a partial response; this occurred in 4% of those who received dovitinib and 4% who received sorafenib. In both the investigative and control arms, 52% of patients achieved stable disease; 29% and 31% of patients, respectively, experienced disease progression.

The best percentage change from baseline in sum of diameters per central review and by waterfall plot revealed tumor reductions in 51% of those who received dovitinib and 46% of those who were given sorafenib.

Additionally, the median OS with dovitinib was 11.1 months (95% CI, 9.5-13.4) vs 11.0 months (95% CI, 8.6-13.5) with sorafenib (HR, 0.96; 95% CI, 0.75-1.22). The median time to definitive worsening of Karnofsky performance status was 5.1 months (95% CI, 3.8-6.5) and 5.7 months (95% CI, 4.6-7.4) in the investigative and control arms, respectively (HR, 1.12; 95% CI, 0.87-1.45).

PROs proved to be comparable between the 2 treatment arms. For example, the median time to definitive deterioration by 10% in the quality-of-life scores of the EORTC QLQ-C30 in the investigative and control arms was 4.1 months (95% CI, 3.2-5.3) and 4.7 months (95% CI, 3.8-5.6), respectively (HR, 1.08; 95% CI, 0.86-1.36).

The safety analysis included all participants who received at least 1 dose of dovitinib (n = 280) or sorafenib (n = 284). At the time of the data cutoff, which was January 25, 2013, the median follow-up was 11.3 months (range, 7.9-14.6), 440 PFS events and 265 deaths were reported.

Treatment-emergent toxicities that were grade 3 or 4 in severity included hypertriglyceridemia (14%), fatigue (10%), hypertension (8%), diarrhea (7%), dyspnea (6%), anemia (5%), and increase in γ-glutamyltransferase levels (5%) with dovitinib. Eighty-five patients who received dovitinib reported treatment-emergent acne-like rashes vs 66 patients who received sorafenib.

Treatment-emergent serious effects of any grade were experienced by 48% of those who received dovitinib and 39% of those who were given sorafenib, the most common of which was dyspnea (6% vs 5%, respectively).

Fourteen percent of patients on the investigative arm died on the study or within 30 days of their last dose vs 15% of those on the control arm; this was most commonly because of their RCC, at 12% and 13%, respectively. Four deaths were suspected to potentially be associated with study treatment. Three were reported in the dovitinib group, and these patients had large intestine perforation, pulmonary embolism, and death not otherwise specified. The 1 reported in the sorafenib group was because of toxic epidermal necrolysis.

Dovitinib has also demonstrated activity in gastrointestinal stromal tumors, endometrial cancer, breast cancer, and hepatocellular carcinoma.

“We greatly look forward to the approval of dovitinib and to introducing the clinical value of DRP companion diagnostics to oncologists and their patients,” Carchedi said, in the press release.

Allarity Therapeutics submits new drug application (NDA) to the US FDA for dovitinib for third-line treatment of renal cell carcinoma (RCC). News release. Allarity Therapeutics, Inc.; December 22, 2021. Accessed December 22, 2021. https://bit.ly/32qiAeA

Pipeline: dovitinib. Allarity Therapeutics, Inc. website. Accessed December 22, 2021. https://bit.ly/32pMnEb

Motzer RJ, Porta C, Vogelzang NJ, et al. Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. 

. 2014;15(3):286-296. doi:10.1016/S1470-2045(1)70030-0

FDA approval is being sought for dovitinib as a treatment option for patients with renal cell carcinoma. 

NDA for the Dovitinib Submitted to FDA for Approval in RCC

Treatment with datopotamab deruxtecan phase 1 TROPION-PanTumor01 trial (NCT03401385) showed promising activity through overall response rates (ORRs) in patients with advanced or metastatic triple-negative breast cancer (TNBC), according to cohort data presented during the 2021 San Antonio Breast Cancer Symposium (SABCS).

Among all patients in the TNBC cohort of the trial (n = 44), the ORR by blinded independent central review (BICR) was 34% at a median follow-up of 7.6 months (range, 4-13). This included a confirmed complete response (CR) or partial response (PR) in 14 patients (32%), plus 1 patient (2%) with a CR/PR that was pending confirmation. Seventeen patients (39%) had stable disease (SD), 2 patients (5%) were not evaluable (NE), and 8 patients (18%) had progressive disease (PD). Overall, the disease control rate (DCR) was 77%.

Furthermore, at a median follow-up of 8.8 months (range, 4-13), the ORR was 52% in patients with TNBC who did not receive prior treatment with a Topo I inhibitor-based ADC (n = 27), which included 13 patients (48%) with confirmed CRs or PRS, plus 1 patient (4%) with a CR/PR pending confirmation. Nine patients (33%) had SD, 1 patient (4%) was NE, and 4 patients (15%) had PD. The DCR was 81%.

Additional data showed that the median duration of response was not reached (range, 2.7 to 7.4+ months); the majority of responses were ongoing at the data cutoff.

"There are clear responses or clear tumor regressions in those patients who had prior Topo-based ADCs with at least 1 confirmed PR," lead study author Ian E. Krop, MD, PhD, of Dana-Farber Cancer Institute, said in a presentation during the conference. "However, because a full 30% of the patients on this study had a prior Topo I inhibitor(-based) ADC, and that is the same class of payload as (datopotamab deruxtecan), there is a possibility of cross resistance. Therefore, we did want to look at specifically the subset of patients who had not had 1 of these prior ADCs."

There are currently very limited standard treatments for patients with advanced or metastatic TNBC that considered relapsed/refractory. TROP2 is highly expressed in various malignancies, including breast cancer. In the TROPION-PanTumor01 study, investigators are evaluating the safety and efficacy of the TROP2-directed ADC datopotamab deruxtecan in patients with advanced or metastatic breast cancer, non–small cell lung cancer (NSCLC), and other tumor types.

At the 2021 SABCS, Krop, who is an associate chief in the Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, clinical research director of the Breast Oncology Center, and associate professor of medicine at Harvard Medical School, presented on the data from the TNBC cohort.

Patients enrolling in the trial were required to have relapsed/refractory advanced or metastatic solid tumors, an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1. Additionally, patients needed to be at least 18 years old in the United States or 20 years old in Japan, and be unselected for TROP2 expression. Those with stable, treated brain metastases were permitted.

In the TNBC cohort, 42 of 44 patients received datopotamab deruxtecan intravenously (IV) at 6 mg/kg every 3 weeks, and the other 2 patients received the ADC IV 8 mg/kg every 3 weeks. The decision to use the 6-mg/kg dose, which was selected for expansion across other tumors, as well as in the phase 3 TROPION-Lung01 (NCT04656652) and TROPION-Breast01 (

) studies, was based on clinical results and exposure-response analyses for safety and efficacy.

The primary end points of the trial were safety and tolerability; secondary end points included efficacy, pharmacokinetics, and anti-drug antibodies.

In the TNBC cohort, the median age was 53 years (range, 32-82), and 31 patients (70%) were based in the United States vs 13 patients (30%) in Japan. The majority of patients had an ECOG performance status of 1 (59%) and did not have de novo metastatic disease (68%). Eleven percent of patients had brain metastases.

Furthermore, the median number of prior therapies in the metastatic setting was 3 (range, 1-10), and 68% of patients had at least 2 prior lines of therapy. Previous treatments included taxanes (91%), platinum-based chemotherapy (52%), immunotherapy (43%), PARP inhibitors (16%), and Topo I inhibitor-based ADC (30%).

At the data cutoff date of July 30, 2021, 31 patients (70%) discontinued treatment, including 30 due to disease progression, and 1 patient due to an adverse event (AE). Thirteen patients (30%) remained on treatment at the time of the presentation.

Furthermore, datopotamab deruxtecan showed a manageable safety profile with no new safety signals. The most frequent treatment-emergent adverse events (TEAEs) included nausea, stomatitis, vomiting, and fatigue. However, neutropenia and diarrhea were both uncommon. No cases adjudicated as treatment-related interstitial lung disease were observed.

Ninety-eight percent of patients had at least 1 TEAE, 45% of which were considered to be of grade 3 or higher; 23% experienced grade 3 or higher treatment-related TEAEs. Dose reductions due to AEs were required in 18% of patients, and 14% of patients experienced treatment interruption due to AE. One patient discontinued treatment due to AEs, and no fatal AEs were reported.

Krop added that the HR-positive, HER2-negative cohort of TROPION-PanTumor01 is now fully enrolled and data are forthcoming. Datopotamab deruxtecan is also being explored in the phase 1b/2 BEGONIA trial (NCT03742102), which is testing the agent in combination with durvalumab (Imfinzi) as a first-line treatment for patients with metastatic TNBC.

Additionally, the phase 3 TROPION-Breast01 trial is investigating datopotamab deruxtecan in HR-positive, HER2-negative breast cancer. A phase 3 trial of datopotamab deruxtecan in patients with TNBC is being planned, Krop said.

"We have come a long way in TNBC when we're talking about comparing different targeted therapies, when up until a few years ago, there were no targeted therapies at all," Krop said. "This is good progress. There is potential room for looking at this drug both in pretreated patients, like what was seen here, as well as earlier lines of therapy."

1. Krop I, Juric D, Shimizu T, et al. Datopotamab deruxtecan (Dato-DXd) in advanced/metastatic HER2 negative breast cancer: triple negative breast cancer results from the phase 1 TROPION-PanTumor01 study. Presented at: 2021 San Antonio Breast Cancer Symposium; December 7-10, 2021; San Antonio, TX. Abstract GS1-05.

2. Schmid P, Nunes AT, Dry H, et al. BEGONIA: phase 1b/2, open-label, platform study of the safety and efficacy of durvalumab (D) ± paclitaxel (P) with novel oncology therapies for first-line metastatic triple-negative breast cancer (mTNBC): Addition of arm 7, D + datopotamab deruxtecan (Dato-DXd; DS-1062).

. 2021;39(15_suppl). doi:10.1200/JCO.2021.39.15_suppl.TPS1105

Early results from a phase 1 study show promise for datopotamab deruxtecan for patients with advanced or metastatic triple-negative breast cancer. 

Datopotamab Deruxtecan Demonstrates Highly Promising Efficacy in Advanced or Metastatic TNBC

Clinicians are eagerly awaiting  overall survival (OS) data from the phase 3 KEYNOTE-564 trial (NCT03142334) to confirm adjuvant pembrolizumab’s (Keytruda) role as a potential new standard treatment for patients with renal cell carcinoma (RCC).

Results shared in a webinar during the 2021 European Association of Urology (EAU) Congress showed that at a median follow-up of approximately 24 months, adjuvant pembrolizumab induced a 32% reduction in the risk of disease recurrence or death compared with placebo (HR, 0.68; 

 Per investigator assessment, the median disease-free survival (DFS) was not yet reached in either the pembrolizumab arm (n = 496) or the placebo arm (n = 498).

The OS data are still immature, with 3.6% (n = 18) and 6.6% (n = 33) of events occurring in the pembrolizumab and placebo arms, respectively. The median OS has not yet been reached in either arm but is trending favorably toward the PD-1 inhibitor (HR, 0.54; 

 = .0164); however, this has not crossed the prespecified boundary of statistical significance. The estimated 2-year OS rates are 96.6% with pembrolizumab and 93.5% with placebo.

“These early data from the trial are very promising, with a clear reduction in the disease recurring in patients on pembrolizumab. There are signs as well that the drug may improve survival rates, but we can’t be sure of that for another few years. We’re hopeful that this trial, when complete, will provide a strong case for this drug to be approved for use by the medicines regulator,” said coinvestigator Thomas Powles, MBBS, MRCP, MD, in a press release.

 Powles is a professor of genitourinary oncology and group lead for solid tumor research at Barts Cancer Institute, and director of the Barts Cancer Centre in London, United Kingdom.

The standard-of-care treatment for patients with locoregional RCC is surgery; however, nearly half of patients eventually experience disease recurrence. Currently, no standard adjuvant systemic therapy exists that is supported by high levels of evidence worldwide.

In the double-blind, multicenter KEYNOTE-564 study, investigators explored pembrolizumab vs placebo following nephrectomy in patients with clear cell RCC. Specifically, patients’ disease had to meet criteria that categorized them as high risk for recurrence, which included: pT2, grade 4 or sarcomatoid, N0, M0; pT3, any grade, N0, M0; pT4, any grade, N0, M0; any pT, any grade, N-positive, M0; or M1 with no evidence of disease after surgery.

Patients had to have undergone nephrectomy within 12 weeks prior to randomization, could not have previously received systemic treatment, and had to have an ECOG performance status of 0 or 1. In addition, a tissue sample had to have been obtainable for PD-L1 assessment.

All patients were randomized 1:1 to receive pembrolizumab at 200 mg every 3 weeks or placebo every 3 weeks, both for approximately 1 year.

At 1 year, the estimated DFS rates were 85.7% with pembrolizumab and 76.2% with placebo. At 2 years, these rates were 77.3% and 68.1%, respectively.

Regarding safety, all-grade adverse events (AEs) with pembrolizumab occurred in 96.3% of patients and in 91.1% of those receiving placebo; grade 3 to 5 AEs occurred in 32.4% and 17.7%, respectively. AEs led to death in 2 patients treated with pembrolizumab and in 1 patient receiving placebo.

1. Powles T. Pembrolizumab (pembro) vs. placebo as post nephrectomy adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): randomized, double-blind, phase 3 KEYNOTE-564 study. Presented at: 36th Annual EAU Congress; July 8-12, 2021; Virtual.

2. New use of old drug reduces risk of kidney cancer returning. News release. European Association of Urology. July 10, 2021. Accessed August 17, 2021. https://bit.ly/3ldbQ9A

Results shared in a webinar during the 2021 European Association of Urology Congress show the potential of adjuvant pembrolizumab for the treatment of renal cell carcinoma.