Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Prof Winnie Yeo, 03 Aug 2020
Despite the availability of antiemetics, a substantial proportion of patients receiving chemotherapy experience chemotherapy-induced nausea and vomiting (CINV), significantly impacting treatment compliance and quality of life (QoL). At the 24th Annual Scientific Symposium of the Hong Kong Cancer Institute, Professor Winnie Yeo of the Department of Clinical Oncology, Chinese University of Hong Kong, presented results of a local study showing superior efficacy of the fixed-dose netupitant/palonosetron (NEPA) combination regimen vs aprepitant-based regimen in controlling CINV in breast cancer patients receiving highly emetogenic anthracycline-cyclophosphamide (AC) chemotherapy.
Christina Lau, 14 Jul 2020

Flat-dose nivolumab, administered as a 30-minute infusion, is well tolerated and active in Asian patients with previously treated advanced non-small-cell lung cancer (NSCLC), according to results of the phase IIIb CheckMate 870 study.

Dr. Michael Tsz-Yeung Kam, 04 Jun 2020

Third-generation EGFR tyrosine kinase inhibitors (TKIs) targeting the EGFRT790M mutation, such as osimertinib, have brought significant improvements to the management of EGFR-positive non-small-cell lung cancer (NSCLC). However, optimization of EGFRT790M mutation testing remains challenging in clinics. At a symposium organized by the Hong Kong Cancer Therapy Society, Dr Michael Tsz-Yeung Kam, Specialist in Clinical Oncology in Hong Kong, discussed real-world challenges in EGFRT790M testing and the current workflow at his centre.

CASTOR and POLLUX: 4-year follow-up of daratumumab in R/R MM

14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  

Daratumumab is a human immunoglobulin Gκ (IgGκ) monoclonal antibody targeting CD38, which induces programmed cell death, that also has an immunomodulatory mechanism of action confirmed by high-parameter mass cytometry. [J Immunol 2016;197:807-813; Cytometry A 2019;95:279-289]

In the phase III CASTOR and POLLUX studies, daratumumab in combination with SoC regimens (Vd or Rd) induced rapid, deep and durable responses, reduced the risk of disease progression or death by >60 percent, and increased the rates of minimal residual disease (MRD) negativity. [N Engl J Med 2016;375:754-766; N Engl J Med 2016;375:1319-1331; Haematologica 2018;103:2079-2087; Haematologica 2018;103:2088-2096]

 CASTOR trial update

At a median follow-up of 40.0 months, the CASTOR study demonstrated that DVd significantly improved clinical outcomes vs Vd alone in patients with R/R MM. DVd significantly reduced the risk of disease progression or death by 69 percent (median progression-free survival [PFS], 16.7 months vs 7.1 months; hazard ratio [HR], 0.31; 95 percent confidence interval [CI], 0.25 to 0.40; p<0.0001), and tripled rates of complete response or better vs Vd (≥CR) (30 percent vs 10 percent; p<0.0001). [Mateos MV, et al, ASH 2018, abstract 3270]

Sustained PFS benefit with DVd

The benefit of adding daratumumab to Vd was sustained after a median follow-up of 50.2 months (3.6 years after CASTOR interim analysis). This benefit was particularly prominent in patients who had received one previous line of treatment, who constituted approximately half of the intention-to-treat (ITT) population. [Weisel K, et al, ASH 2019, poster 3192]

With the extended follow-up, DVd was found to reduce the risk of disease progression or death by 69 percent vs Vd in the ITT population (median PFS, 16.7 months vs 7.1 months; HR, 0.31; 95 percent CI, 0.24 to 0.39; p<0.0001), and by 79 percent among first-time relapsed patients (median PFS, 27.0 months vs 7.9 months; HR, 0.21; 95 percent CI, 0.15 to 0.31; p<0.0001). The 48-months PFS rates among DVd-treated patients were 21 percent in the ITT population and 32 percent among those who had received one prior line of treatment, which is in stark contrast with no Vd-treated patients surviving 48 months without progression. (Figure 1) [Weisel K, et al, ASH 2019, poster 3192]

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Of note, PFS was also improved with the addition of daratumumab among poor-prognosis patients who were refractory to lenalidomide, who constituted 24 percent of the DVd arm and 33 percent of the Vd arm (median, 7.8 months vs 4.9 months; HR, 0.44; 95 percent CI, 0.28 to 0.68; p=0.0002). Similarly, adding daratumumab to Vd reduced the risk of disease progression or death by 59 percent in patients with high cytogenic risk (ie, positive for t(4;14), t(14;16), and/or del17p cytogenetic abnormalities) (median PFS for DVd vs Vd, 12.6 months vs 6.2 months; HR, 0.41; 95 percent CI, 0.21 to 0.83; p=0.0106) and by 75 percent in those with standard risk (median PFS, 16.6 months vs 6.6 months; HR, 0.25; 95 percent CI, 0.18 to 0.35; p<0.0001).

DVd induces deeper and more durable responses

In the same updated analysis, DVd demonstrated a significantly higher overall response rate (ORR) vs Vd (85 percent vs 63 percent; p<0.0001), with higher rates of response-evaluable patients achieving very good partial response or better (≥VGPR) (63 percent vs 29 percent; p<0.0001) and ≥CR (30 percent vs 10 percent; p<0.0001). Among first-time relapsed patients, DVd also demonstrated a higher ORR vs Vd (92 percent vs 74 percent; p=0.0007) as well as higher rates of ≥VGPR (77 percent vs 42 percent; p<0.0001) and ≥CR (43 percent vs 15 percent; p<0.0001). Similarly, ORRs were more than 20 percent higher for DVd vs Vd in both standard and high cytogenetic risk groups (standard risk: 84 percent vs 62 percent, p<0.0001; high risk: 85 percent vs 56 percent, p=0.0512).

DVd prolonged the time to next subsequent therapy vs Vd (median, 25.4 vs 9.7 months; HR, 0.27; 95 percent CI, 0.21 to 0.34; p<0.0001) and extended PFS on the next subsequent line of therapy (PFS2) (median, 34.2 months vs 20.3 months; HR, 0.47; 95 percent CI, 0.37 to 0.58; p<0.0001). Among patients who received one prior line of treatment, the PFS2 benefit of DVd was maintained, with a >2-year improvement vs Vd (median, 49.9 vs 23.1 months; HR, 0.37; 95 percent CI, 0.26 to 0.53; p<0.0001).

Higher MRD negativity rate with DVd

The MRD-negativity rate was defined as the proportion of patients who achieved

MRD-negative status at any time following the first treatment dose and was calculated using the entire ITT population to allow for a stringent and unbiased evaluation of MRD. Patients were considered to be MRD-positive if they had an MRD-positive test result or had no MRD assessment.

Rates of MRD negativity (defined as <1 myeloma cell in 100,000 cells or 10-5) were higher for DVd vs Vd in the ITT population (15 percent vs 2 percent; p<0.000001) and among patients who were receiving DVd as their second-line therapy (21 percent vs 3 percent; p=0.000013). MRD negativity rates were also higher for DVd vs Vd in both cytogenetic risk groups (standard risk: 13 percent vs 3 percent; p=0.0013; high risk: 15 percent vs 0 percent; p=0.0047). A greater proportion of patients treated with DVd were able to sustain MRD negativity for ≥6 months and ≥12 months vs those treated with Vd (≥6 months: 10 percent vs 1 percent; p<0.0001; ≥12 months: 7 percent vs 0 percent).

POLLUX trial update

In a previously reported analysis of the POLLUX study, conducted at a median follow-up of 44.3 months, daratumumab added to Rd extended the median PFS of R/R MM patients to over 3.5 years (44.5 months), compared with just under 1.5 years (17.7 months) afforded by Rd alone (HR, 0.44; 95 percent CI, 0.35 to 0.55; p<0.0001). [Bahlis N, et al, ASH 2018, abstract 1996]

DRd provides sustained PFS benefit

After 4.5 years (54.8 months) of median follow-up, DRd continued to demonstrate significant efficacy benefits vs Rd in R/R MM patients. In the ITT population, the median PFS was 45.0 months with DRd vs 17.5 months with Rd (HR, 0.44; 95 percent CI, 0.35 to 0.54; p<0.0001). The PFS benefit was even more pronounced in patients who had received only one prior line of treatment and who accounted for 52 percent of the overall ITT cohort. Among these patients, the PFS attained with DRd lasted more than 2.5 years longer than that in Rd-treated patients (median, 53.3 months vs 19.6 months; HR, 0.42; 95 percent CI, 0.31 to 0.58; p<0.0001). (Figure 2) [Kaufman JL, et al, ASH 2019, poster 1866]  

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Notably, PFS was also prolonged with DRd vs Rd in the poorer prognosis groups of patients with high cytogenic risk or bortezomib-refractory disease. Patients with high cytogenic risk (ie, those with t(4;14), t(14;16), and/or del17p cytogenetic abnormalities) had their risk of disease progression or death reduced by 63 percent with VRd vs Rd and achieved a median PFS of 26.8 months on DRd vs 8.3 months on Rd (HR, 0.37; 95 percent CI, 0.18 to 0.76; p=0.0056). Standard-risk patients treated with DRd had a median PFS of 52.0 months vs 18.6 months in the Rd arm (HR, 0.42; 95 percent CI, 0.32 to 0.56; p<0.0001). Bortezomib-refractory patients receiving DRd had a median PFS of 34.3 months, which was nearly 2 years longer than that of patients treated with Rd (11.3 months; HR, 0.42; 95 percent CI, 0.25 to 0.71; p=0.0008).

Higher ORR and MRD negativity rates with DRd

In addition to extending PFS, adding daratumumab to Rd increased the ORR and rates of ≥VGPR and ≥CR in the response-evaluable population (DRd vs Rd: ORR, 93 percent vs 76 percent; VGPR, 81 percent vs 49 percent; ≥CR: 58 percent vs 24 percent; p<0.0001 for all). The differences in response rates were also apparent among patients who had received one prior line of treatment (DRd vs Rd: ORR, 93 percent vs 80 percent, p=0.0003; VGPR, 80 percent vs 56 percent, p<0.0001; ≥CR, 59 percent vs 29 percent, p<0.0001).

­MRD negativity (10-5) rate was higher for DRd vs Rd in the ITT population (33 percent vs 7 percent; p<0.0001) as well as among first-time relapsed patients (32 percent vs 10 percent; p=0.000005). The improvement in MRD negativity associated with DRd vs Rd was sustained in patients with high or standard cytogenic risk (high risk: 29 percent vs 3 percent, p=0.0016; standard risk: 35 percent vs 9 percent, p<0.0001). Furthermore, MRD negativity was sustained for 6 months by 20 percent of DRd-treated patients vs only 2 percent of patients in the Rd arm; rates of sustained MRD negativity for ≥12 months were 16 percent vs 1 percent, respectively.

Time to next subsequent therapy was prolonged with DRd vs Rd (median, not reached vs 22.8 months; HR, 0.38; 95 percent CI, 0.30 to 0.48; p<0.0001). In addition, DRd prolonged PFS2 vs Rd by over 20 months (median, 53.3 vs 31.6 months; HR, 0.53; 95 percent CI, 0.42 to 0.66; p<0.0001).

Updated safety results

In the CASTOR trial, the most common grade 3/4 treatment-emergent adverse events (TEAEs) that occurred more frequently in the DVd vs Vd group were thrombocytopenia (46 percent vs 33 percent), neutropenia (14 percent vs 5 percent), lymphopenia (10 percent vs 3 percent), and hypertension (7 percent vs 1 percent). Despite these differences, the discontinuation rate due to TEAEs was similar for DVd and Vd (10 percent vs 9 percent).

During the longer follow-up period, invasive secondary primary malignancies were reported in 6 percent of patients who received DVd vs 2 percent of those who received Vd. This was consistent with previously reported CASTOR results, while other phase III studies of daratumumab combination therapy reported balanced rates of secondary primary malignancies in both the daratumumab and control groups. [Weisel K, et al, ASH 2019, poster 3192; Mateos MV, et al, ASH 2018, abstract 3270; Bahlis N, et al, ASH 2018, abstract 1996]

The most common grade 3/4 TEAEs that were more prevalent with DRd vs Rd in the POLLUX trial were neutropenia (57 percent vs 42 percent), pneumonia (16 percent vs 10 percent), diarrhoea (10 percent vs 4 percent), and fatigue (7 percent vs 4 percent). As in the CASTOR trial, the rate of discontinuation due to TEAEs was not substantially affected by the addition of daratumumab to Rd (DRd vs Rd, 17 percent vs 15 percent).

Invasive secondary primary malignancies occurred in 6 percent of patients in both the DRd and Rd groups. [Kaufman JL, et al, ASH 2019, poster 1866]

Conclusion

The most recent data from the CASTOR and POLLUX trials, reported after more than 4 years of median follow-up, continued to demonstrate the significant efficacy benefits achieved by the addition of daratumumab to Vd or Rd, such as deeper (as reflected by higher ORRs) and more durable (as reflected by PFS and PFS2) responses and improved MRD negativity rates. Most prominent benefits were observed among patients who had received only one prior line of treatment. The benefit of adding daratumumab to Vd or Rd was evident in the high cytogenic risk groups and in patients with lenalidomide- and bortezomib-refractory disease as well as in the ITT population.   


 


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Most Read Articles
14 Feb 2020
The phase III CASTOR and POLLUX studies previously demonstrated benefit of daratumumab plus bortezomib and dexamethasone (DVd) or lenalidomide and dexamethasone (DRd) vs standard-of-care (SoC) Vd or Rd regimen in relapsed or refractory multiple myeloma (R/R MM). The latest efficacy and safety results after 4 years of follow-up from CASTOR and POLLUX were presented at the American Society of Hematology (ASH) 61st Meeting & Exposition 2019 held in Orlando, Florida, US.  
Prof Winnie Yeo, 03 Aug 2020
Despite the availability of antiemetics, a substantial proportion of patients receiving chemotherapy experience chemotherapy-induced nausea and vomiting (CINV), significantly impacting treatment compliance and quality of life (QoL). At the 24th Annual Scientific Symposium of the Hong Kong Cancer Institute, Professor Winnie Yeo of the Department of Clinical Oncology, Chinese University of Hong Kong, presented results of a local study showing superior efficacy of the fixed-dose netupitant/palonosetron (NEPA) combination regimen vs aprepitant-based regimen in controlling CINV in breast cancer patients receiving highly emetogenic anthracycline-cyclophosphamide (AC) chemotherapy.
Christina Lau, 14 Jul 2020

Flat-dose nivolumab, administered as a 30-minute infusion, is well tolerated and active in Asian patients with previously treated advanced non-small-cell lung cancer (NSCLC), according to results of the phase IIIb CheckMate 870 study.

Dr. Michael Tsz-Yeung Kam, 04 Jun 2020

Third-generation EGFR tyrosine kinase inhibitors (TKIs) targeting the EGFRT790M mutation, such as osimertinib, have brought significant improvements to the management of EGFR-positive non-small-cell lung cancer (NSCLC). However, optimization of EGFRT790M mutation testing remains challenging in clinics. At a symposium organized by the Hong Kong Cancer Therapy Society, Dr Michael Tsz-Yeung Kam, Specialist in Clinical Oncology in Hong Kong, discussed real-world challenges in EGFRT790M testing and the current workflow at his centre.