Jason Harris

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Articles

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

Frontline Venetoclax and Obinutuzumab Maintains Delay of Progression in CLL

Sustained efficacy and durable responses was seen with Ciltacabtagene autoleucel (cilta-cel), an investigational B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, in heavily pretreated patients with relapsed/refractory multiple myeloma, according to updated findings of the phase 1b/2 CARTITUDE-1 trial (NCT03548207) presented during the 2021 ASCO Annual Meeting.

In new data from the phase 1b/2 CARTITUDE-1 study, cilta-cel induced an overall response rate (ORR) of 97.9% with an 80.4% rate of stringent complete response (sCR), at a median follow-up of 18 months (range, 1.5-30.5).

These data include results from 97 patients (median age, 61 years; 58.8% men) who received a median of 6 prior treatment regimens (range, 3-18). All patients had been exposed to an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody; 42.3% were penta-drug refractory, and 99% were refractory to their most recent line of therapy. All received a single infusion of cilta-cel (target dose: 0.75×106 CAR+ viable T cells/kg) 5 to 7 days following lymphodepletion.

“The efficacy results observed in heavily pretreated patients with multiple myeloma receiving cilta-cel are remarkable,” principal investigator Saad Z. Usmani, MD, said in a news release. He is Division Chief of Plasma Cell Disorders at Levine Cancer Institute, Atrium Health. “With the possibility of achieving the progression-free-survival reported and responses deepening as observed in the longer-term follow-up, I’m hopeful that cilta-cel will be part of the armamentarium in the future for patients in need of an additional treatment option.”

At 18 months, 66% of patients were alive and progression free (95% CI, 54.9-75.0) with an sCR of 75.9% (95% CI, 63.6-84.5). The rate of overall survival at 18 months was 80.9% (95% CI, 71.4-87.6). Investigators found that response rates were comparable across prespecified subgroups and lines of treatment (range, 95%-100%).

The rate of very good partial response was 14%. Three percent of patients had a partial response (PR). Median time to first response was 1 month (range, 0.9–10.7 months), and the median time to best response was 2.6 months (range, 0.9-15.2 months).Investigators found the results deepened over time, with a median duration of response of 21.8 months (95% CI, 21.8-NE). An estimated 73% of patients who responded to treatment have not progressed or died at 12 months. The median duration of response was not reached in patients with sCR.

Sixty-one patients were evaluable for minimal residual disease (MRD). Of those, 91.8% achieved MRD negativity status at 10-5 at a median of 1 month (range, 0.8-7.7 months) following infusion.

Investigators did not observe any new safety signals with the longer follow-up. The most common any-gradehematologic adverse events (AEs) were neutropenia (95.9%), anemia (81.4%), thrombocytopenia (79.4%), leukopenia (61.9%); and lymphopenia (52.6%).Most patients (n = 92) experienced any-grade cytokine release syndrome (CRS). The median duration of CRS was 4 days (range, 1-97) and 99% resolved within 14 days of onset. Most (95%) were grade 1/2 events.

“Cilta-cel has a manageable safety profile consistent with its mechanism of action,” Usmani said during the presentation.

Janssen filed a marketing authorization application to the European Medicines Agency in April 2021 based on these findings. Additionally, in May 2021, the FDA granted a priority review designation to a biologics license application for cilta-cel in this indication, based on data from CARTITUDE-1. The regulatory agency is expected to make a decision on the application by November 29, 2021, under the Prescription Drug User Fee Act.

Results from cohort A (n = 20) of the phase 2 CARTITUDE-2 study (NCT04133636) of patients with multiple myeloma who progressed following 1 to 3 prior lines of therapy and who were refractory to lenalidomide (Revlimid) were presented at the 2021 ASCO Annual Meeting and will subsequently be presented at the 2021 European Hematology Association Congress. Here, investigators observed early and deep responses at a median follow-up of 5.8 months (range, 2.5-9.8).

At the February 21 data cutoff, the ORR was 95% with 45% patients achieving a sCR and 30% with a CR. Ten percent of patients had a VGPR and 10% had a PR. The overall safety profile, including incidence of CRS and most common hematologic AEs, was consistent previous results.

1.Usmani SZ, Berdeja JG, Madduri D, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed/refractory multiple myeloma (R/R MM): Updated results from CARTITUDE-1. 

. 2021,39(suppl 15; abstr 8005). doi:10.1200/JCO.2021.39.15_suppl.8005

2.Janssen reports new data for BCMA CAR-T, cilta-cel, showing deep and durable responses in patients with relapsed or refractory multiple myeloma. News release. Janssen. June 1, 2021. Accessed June 2, 2021. bwnews.pr/3vLIDGW

3.Madduri D, Berdeja JG, Usmani SZ, et al. Cartitude-1: phase 1b/2 study of ciltacabtagene autoleucel, a b-cell maturation antigen–directed chimeric antigen receptor t cell therapy, in relapsed/refractory multiple myeloma. 

. 2020;136(suppl 1):22-25. doi:10.1182/blood-2020-136307

4.Agha ME, Cohen AD, Madduri D, et al. CARTITUDE-2: Efficacy and safety of ciltacabtagene autoleucel (cilta-cel), a BCMA-directed CAR T-cell therapy, in patients with progressive multiple myeloma (MM) after one to three prior lines of therapy. 

. 2021,39(suppl 15; abstr 8013). doi:10.1200/JCO.2021.39.15_suppl.8013

Sustained efficacy and durable responses was seen with Ciltacabtagene autoleucel, an investigational B-cell maturation antigen-directed CAR T-cell therapy, in heavily pretreated patients with relapsed/refractory multiple myeloma. 

Durable Responses Seen with Cilta-Cel at 18 Months in Relapsed/Refractory Multiple Myeloma

At a median follow-up of 73.3 months, investigators in the PALOMA-3 trial have concluded that palbociclib (Ibrance) plus fulvestrant maintains a clinically meaningful improvement in overall survival (OS) compared with placebo plus fulvestrant for patients with HR-positive, HER2-negative advanced breast cancer, according to data presented at the 

Principal investigator Massimo Cristofanilli, MD, associate director for Translational Research at the Lurie Cancer Center and a professor of medicine in the Division of Hematology/Oncology at Northwestern University Feinberg School of Medicine, presented the findings during the 2021 ASCO Annual Meeting.

“An improvement in OS with palbociclib plus fulvestrant continues to be observed with more than 6 years of median follow up in patients with HR-positive advanced breast cancer who progressed on prior endocrine therapy,” Cristofanilli said. “This prolonged OS benefit is particularly evident in patients with endocrine-sensitive disease and those with prior exposure to chemotherapy in the advanced setting.”

The updated median OS in the experimental arm was 34.8 months versus 28.0 months in the placebo arm (stratified HR, 0.81; 95% CI, 0.65-0.99; 1-sided 

 = .0221). In findings reported after a median follow up of 44.8 months, the median OS was 34.9 months for palbociclib/fulvestrant compared with 28.0 months for placebo/fulvestrant (stratified HR, 0.81; 95% CI, 0.64-1.03; 1-sided 

“Remarkable in this metastatic setting is that the 5-year OS rate is 23.3% in the palbociclib arm compared with 16.8% in the placebo arm,” he added.

Cristofanilli noted that 34% of patients had received prior chemotherapy for advanced breast cancer and 35% received more than 2 lines of prior treatment. He said that these types of patients had been excluded from other phase 3 studies testing CDK4/6 inhibitors with fulvestrant.

In patients who had not received prior chemotherapy for advanced disease, the median OS was 39.3 months in the experimental arm versus 29.7 months in the placebo arm (HR, 0.72; 95% CI, 0.55-0.94; 

= .008). In contrast, there was no survival benefit for the combination in patients who did receive chemotherapy previously (24.6 vs 24.3 months; HR, 0.97; 95% CI, 0.69-1.36; 

Among those who were sensitive to prior hormonal therapy, 202 (73.7%) patients in the combination arm and 104 (76.5%) in the placebo group compared with 76.7% and 81.6%, respectively, among those who were not sensitive to hormone therapy. Cristofanilli said the largest group of patients were sensitive to endocrine therapy.

Investigators in the double-blind, phase 3 PALOMA-3 trial (NCT01942135) randomly assigned 521 patients with metastatic breast cancer whose disease progressed on or following endocrine treatment to fulvestrant plus palbociclib (n = 347) or fulvestrant plus placebo (n = 174). The median age was 57 and 56 years in the palbociclib and placebo arms, respectively. Patients were stratified by menopausal status, sensitivity to prior hormonal therapy, and visceral metastases.

Palbociclib conferred an OS benefit regardless of 

mutation status, Cristofanilli said. Mutation status was prognostic for OS and highly associated with shorter OS in patients with 

mutations were also associated with shorter OS, but the connection was weak.

The FDA approved palbociclib plus fulvestrant in February 2016 for women with pretreated HR-positive/HER2-negative metastatic breast cancer. The median progression-free survival was 9.5 months with palbociclib/fulvestrant compared with 4.6 months for placebo/fulvestrant (HR, 0.46; 95% CI, 0.36-0.59; 

In June 2018, drugmaker Pfizer announced that palbociclib/fulvestrant combination failed to improve OS versus fulvestrant/placebo in PALOMA-3 for patients with HR-positive, HER2-negative metastatic breast cancer who received prior endocrine therapy. However, data presented at the 2018 ESMO Congress in October and simultaneously reported in the 

 showed that the combination conferred a statistically significant 10.0-month OS improvement patients who were sensitive to previous endocrine therapy.

More recently, findings presented during the AACR Annual Meeting 2021 in April showed that adding SDX-7320, a novel inhibitor of methionine aminopeptidase 2 (MetAP2), to palbociclib inhibited MCF-7 tumor growth and reduced the expression of proteins associated with resistance to palbociclib in orthotopic MCF-7 xenografts. The combination produced a greater tumor growth inhibition (TGI) rate than either agent alone.

TGI was 49% with 8 mg/kg SDX-7320 and 65% for 40 mg/kg of palbociclib. The combination of 8 mg/kg SDX-7320 and 20 mg/kg palbociclib induced a TGI rate of 70%. When investigators increased the palbociblib dose to 40 mg/kg, the combination induced a TGI rate of 80%.

Furthermore, the addition of SDX-7320 to palbociclib reversed suppression of neutrophils seen with either agent alone. Palboclibib is associated with severe neutropenia and investigators hope the combination reduces incidence of the adverse event.

Cristofanilli M, Rugo HS, Im S, et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. 

. 2021;39(suppl 15):1000. doi:10.1200/JCO.2021.39.15_suppl.1000

Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. 

. 2016;17(4):425-439. doi:10.1016/S1470-2045(15)00613-0

Cristofanilli M, Slamon DJ, Ro J, et al. Overall survival with palbociclib plus fulvestrant in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): analyses from PALOMA-3. Presented at: 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA2_PR. cslide.ctimeetingtech.com/library/esmo/browse/search/2Bxf#2Ea3t02Bh.

Turner NC, Slamon DJ, Ro, I, et al. Overall survival with palbociclib and fulvestrant in advanced breast cancer [published online October 20, 2018].N Engl J Med. doi: 10.1056/NEJMoa1810527. Cornelius P, Mayers B, Dufour P, et al. SDX-7320, a novel inhibitor of methionine aminopeptidase 2 (MetAP2), inhibits MCF-7 tumor growth in combination with palbociclib (Ibrance). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Poster 1068.

Investigators in the PALOMA-3 trial have concluded that Palbociclib plus fulvestrant maintains a clinically meaningful long-term overall survival benefit for patients with either HR+ or HER2 negative breast cancer. 

Palbociclib/Fulvestrant Maintains OS Benefit Long-Term for Patients with Either HR+ or HER2- Breast Cancer 

The combination of tafasitamab-cxix (Monjuvi) and lenalidomide (Revlimid) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) showed sustainable responses at 3-year follow-up of the phase 2 L-MIND trial (NCT02399085).

As of the October 30, 2020, data cutoff, the best objective response rate (ORR) was 57.5% (95% CI, 45.9-68.5) at a median follow up of at least 35 months. Overall, 40% of patients experienced a complete response (CR) and 17.5% had partial response (PR).

Median duration of response (DOR) was 43.9 months (95% CI, 26.1-NR).

“The results of this long-term analysis of the L-MIND study demonstrate that tafasitamab plus lenalidomide followed by extended tafasitamab monotherapy provided durable responses in transplant-ineligible patients with relapsed or refractory DLBCL,” said coauthor Johannes Düll, MD, with Germany’s University Hospital Wurzburg. He presented the findings in a poster during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“These data suggest that this chemotherapy-free combination treatment may have the potential to achieve prolonged remission and survival benefit in this patient population, especially at first relapse.”

In the open-label, multinational, single-arm phase 2 L-MIND study, investigators assigned 81 patients with relapsed/refractory DLBCL to 12 mg/kg IV tafasitamab plus and 25 mg daily oral lenalidomide for up to 12 28-day cycles. Patients with stable disease or better then received the same dose of tafasitamab, an FC-modified humanized anti-CD19 monoclonal antibody, as monotherapy until disease progression.

Düll said that the best ORR was 67.5%, with a CR rate of 47.5% in patients who received 1 prior treatment. The ORR was 47.5% with a CR rate of 32.5% in patients who received 2 or more prior treatments.

The median progression-free survival (PFS) was 11.6 months and the overall survival (OS) of 33.5 months.

Düll noted that patients who had CR had better outcomes. The median DOR was not reached in this subgroup. Similarly, PFS (95% CI, 45.7-NR) and OS (95% CI, 45.7-NR) were not reached.

“Concerning safety, long-term follow up in the L-MIND study shows that tafasitamab plus lenalidomide was tolerated with no unexpected toxicities or new safety signals,” Düll said. “Similar to the primary analysis, the most common treatment emergent adverse events of grade 3 or higher severity during the extended follow-up phase were neutropenia, thrombocytopenia, and febrile neutropenia.”

Forty (49.4%) patients had grade 3 treatment-emergent neutropenia. Fourteen (17.3%) had grade 3 thrombocytopenia, while 10 (12.3%) had grade 3 febrile neutropenia.

“The 3-year efficacy data, combined with the safety and tolerability profile of tafasitamab, further support a therapeutic option for patients with relapsed or refractory DLBCL who are ineligible for transplant—a traditionally difficult-to-treat population,” lead investigator Gilles Salles, MD, PhD, chief of the lymphoma service at Memorial Sloan Kettering Cancer Center, said in a news release.

“I am encouraged to see the confirmed favorable outcome of patients in the L-MIND study, which suggest that this combination treatment regimen could potentially offer a paradigm shift and long-term disease control,” he added.

The FDA approved the tafasitamab/lenalidomide combination in July 2020 for the treatment of adult patients with relapsed/refractory DLBCL, including DLBCL arising from low-grade lymphoma, and who are not eligible for autologous stem cell transplant. The approval was based on previous data from L-MIND, which showed an ORR of 55%. The CR rate was 37% with a PR rate of 18%. The median DOR was 21.7 months.

 demonstrated even greater efficacy. At a median follow-up of 13.2 months 60% (48/80; 95% CI, 48-71) of 80 patients who received the combination had an objective response with 34 (43%) CRs and 14 (18%) PRs.

1. Düll J, Maddocks KJ, Gonzalez-Barca E, et al.Long-term analyses from L-MIND, a phase II study of tafasitamab (MOR208) combined with lenalidomide (LEN) in patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

. 2021;39(suppl 15):7513. doi:10.1200/JCO.2021.39.15_suppl.7513

2. Incyte and MorphoSys announce 3-year results from phase 2 L-MIND study of tafasitamab in combination with lenalidomide for the treatment of relapsed or refractory DLBCL. News release. Incyte. June 4, 2021. Accessed June 5, 2021. https://bwnews.pr/3pnCVsi

3. FDA grants accelerated approval to tafasitamab-cxix for diffuse large B-cell lymphoma. FDA. Updated August 3, 2020. Accessed June 5, 2021. https://bit.ly/34Emq2z

4. Salles G, Duell J, González Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. 

 2020 Jul;21(7):978-988. doi:10.1016/S1470-2045(20)30225-4

The combination of tafasitamab-cxix and lenalidomide in patients with relapsed/refractory diffuse large B-cell lymphoma showed sustainable responses at 3-year follow-up of the phase 2 L-MIND trial.

Jason Harris | Authors

Articles

Frontline Venetoclax and Obinutuzumab Maintains Delay of Progression in CLL

Durable Responses Seen with Cilta-Cel at 18 Months in Relapsed/Refractory Multiple Myeloma

Palbociclib/Fulvestrant Maintains OS Benefit Long-Term for Patients with Either HR+ or HER2- Breast Cancer

Durable Responses Seen With Tafasitamab/Lenalidomide Combo in DLBCL