Greatest benefit with Trastuzumab Deruxtecan Vs T-DM1 seen in previously treated HER2 + breast cancer


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“These data support that trastuzumab deruxtecan is becoming the standard of care for the second-line treatment of HER2-positive metastatic breast cancer,” said Javier Cortés, MD, in a data presentation. Cortés is responsible for breast cancer and gynecological cancers at Ramón y Cajal University Hospital in Madrid, Spain, and clinical researcher for the Breast Cancer Research Program at the Vall d’Hebron Institute of Oncology in Barcelona, ​​Spain.

Referring to the Kaplan-Meier curves for PFS, Cortés said that there is a “clear and early separation of the curves starting at the time of the first scan after treatment and continuing throughout treatment.”

In a discussion of the summary, Shanu Modi, MD, also drew attention to the early separation, saying, “If the waterfall chart from DESTINY-Breast01 was dramatic, I think these PFS curves from DESTINY-Breast03 are surprising. , just like the risk ratio. of 0.28 and the P value of 10-22. Modi is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

Median overall survival (OS) was NE in both arms (RR: 0.56; 95% CI: 0.36-0.86; P = 0.007172). 12 month bone rates. were 94.1% (95% CI, 90.3% to 96.4%) versus 85.9% (95% CI, 80.9% to 89.7%).

The operating system data has not exceeded the preset limit of P

DESTINY-Breast03 randomized 524 patients with HER2 positive metastatic breast cancer, previously treated with trastuzumab and taxane, to receive either trastuzumab deruxtecan 5.4 mg / kg every 3 weeks or T-DM1 3.6 mg / kg every 3 weeks. Patients with clinically stable and treated brain metastases were eligible for recruitment.

The primary endpoint was PFS by independent central blinded examination. A key secondary endpoint was overall survival and other secondary endpoints included objective response rate (ORR) by BICR and investigator assessment, duration of response by BICR, PFS by investigator and security.

Stratification factors for analysis included hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease. The median follow-up was 16.2 months for the trastuzumab deruxtecan group and 15.3 months for the T-DM1 group.

Baseline characteristics were well balanced between treatment arms: 50.2% vs. 51% had hormone receptor positive, 23.8% vs. 19.8% had brain metastases, and 70.5% vs. 70.3% had visceral disease, respectively. The median age was 54.3 years (range, 27.9-83.1) versus 54.2 years (range, 20.2-83), respectively.

Almost half of the patients included in the study had only one line of prior treatment in the metastatic setting (49.8% vs. 46.8%, respectively). The percentage of patients who received 2 prior treatments was 21.5% in the trastuzumab deruxtecan arm vs. 24.7% in the T-DM1 arm. Of note, both groups included a handful of patients who had received at least 5 prior lines of treatment (8.8% vs. 6.8%, respectively).

In the trastuzumab deruxtecan arm, 62.1% of patients had previously received pertuzumab and 16.1% received another anti-HER2 tyrosine kinase inhibitor; these rates were 60.1% and 13.7%, respectively, in the T-DM1 arm.

The data cut-off date for the interim PFS analysis was May 21, 2021.1 It should be noted that on July 30, 2021, the independent drug monitoring committee recommended that investigators unblind the study.2

“At the time of this analysis, more than 50% of patients remain on trastuzumab deruxtecan [n = 132] against 18% of patients on T-DM1 [n = 47]”Cortés said.

In an investigator-rated analysis of PFS, the median PFS was 25.1 months (95% CI, 22.1-NE) in the trastuzumab deruxtecan arm vs. 7.2 months (95% CI, 6 , 8-8.3) in the T-DM1 arm (RR: 0.26 95% CI: 0.20-0.35; P = 6.5 x 10-24). The 12-month PFS rates were 76.3% (95% CI, 70.4% -81.2%) versus 34.9% (95% CI, 28.8% -41.2%) , respectively.

“Improved efficacy with trastuzumab deruxtecan exists in all predefined subgroups, including hormone receptor status, previous pertuzumab treatment, presence of visceral disease, number of prior lines of treatment, and presence of ‘absence of brain metastases,’ Cortés said.

During the discussion, Modi drew attention to the PFS data from patients with treated and stable brain metastases, the median PFS was almost 3 times longer with trastuzumab deruxtecan (n = 62) compared to T -DM1 (n = 52). The median PFS was 15.0 months (95% CI, 12.6-22.2) vs 5.7 months (95% CI, 2.9-7.1) with T-DM1 (RR, 0.3796; 95% CI 0.2267-0.6357). “This is a very important clinical difference to highlight between these 2 agents,” said Modi.

The ORR and the best overall response data were also in favor of trastuzumab deruxtecan. Specifically, the confirmed ORR in the trastuzumab deruxtecan arm was 79.7% (95% CI, 74.3% -84.4%) versus 34.2% (95% CI, 28.5% -40 , 3%) in the T-DM1 arm (P <.0001>

Among the responders in the trastuzumab deruxtecan arm, 16.1% had a complete response (CR) and 63.6% had a partial response (PR). Among the responders in the T-DM1 arm, 8.7% had CR and 25.5% had PR. Stable disease was reported in 16.9% and 42.6% of patients, respectively. The disease control rate (CR plus RP plus stable disease) was 96.6% with trastuzumab deruxtecan vs 76.8% with T-DM1.

Modi noted that the ORR with trastuzumab deruxtecan was comparable to that observed with pertuzumab / trastuzumab / docetaxel (80.2%) in the first line in the results of the phase 3 CLEOPATRA study (NCT00567190).3 “It’s exciting to see that 16% of patients on trastuzumab deruxtecan have had CR,” said Modi. “We recall in CLEOPATRA that this number was 5.5%, so it is interesting to speculate whether we will see a greater proportion of patients with long-term disease remission in the trastuzumab deruxtecan arm. “

In terms of safety, the incidence of grade 3/4 treatment-related adverse reactions (TREs) was 45.5% with trastuzumab deruxtecan vs. 39.8% with T-DM1. This difference extended to the incidence of severe drug-related TSEs (10.9% vs. 6.1%, respectively), drug-related TSEs associated with discontinuation (21.4% vs. 12.6%) and drug-related TEEs associated with dose reductions (21.4% vs. 12.6%).1

The median duration of treatment was 14.3 months (range: 0.7-29.8) for patients who received trastuzumab deruxtecan versus 6.8 months (range: 0.7-25.1) for those who received T-DM1.

Interstitial lung disease (ILD) / pneumonitis was the most common EIT associated with discontinuation of treatment with trastuzumab deruxtecan (8.2%); thrombocytopenia was the most common AEI leading to discontinuation of T-DM1 (2.7%).

Adverse reactions associated with dose reduction of trastuzumab deruxtecan were nausea (6.2%) and neutropenia (3.5%) and for T-DM1 were thrombocytopenia (4.2%), alanine aminotransferase (2.7%) and the increase in aspartate aminotransferase (2.7%).

No drug-related deaths occurred in either arm.

Most drug-related ADEs were gastrointestinal or hematologic. The most common grade 3 or higher adverse reactions with trastuzumab deruxtecan were neutropenia (19.1%), thrombocytopenia (7.0%), nausea (6.6%), leukopenia (6.6%) ) and anemia (5.8%). For T-DM1, the most common grade 3 or higher AEIs were thrombocytopenia (24.9%), increase in aspartate aminotransferase (5.0%), increase in alanine aminotransferase ( 4.6%) and anemia (4.2%).

“If the efficiency was impressive, I would say that the safety [data] of DESTINY-Breast 03 was reassuring, ”said Modi, adding that“ there were no nasty surprises in this essay. T-DM1 certainly sets the bar high for antibody-drug conjugate safety, and I think that’s one of its great strengths. “

The lower rates of LTD are encouraging

Modi stated that in terms of discontinuation of treatment due to EIT, pulmonary toxicity with trastuzumab deruxtecan is expected. “Pulmonary toxicity was one of the eagerly awaited results of this trial and T-DM1 [had an approximate] 2% incidence of low grade events, ”Modi said. “In comparison, trastuzumab deruxtecan presented a risk of [10.5%], so 5 times higher than T-DM1, but lower than that seen inn DESTINY-Breast01 [NCT03248492]. “

More importantly, Modi added, no Grade 4 or 5 ILD / pneumonitis events were observed, “a major difference from DESTINY-Breast01 and major relief.”

As to why less pulmonary toxicity was observed in DESTINY-Breast03, this may be due to the fact that the trial included a less heavily pretreated patient population and therefore exposed to a few lines of cancer treatment and a stricter selection of patients; However, Modi said this rationale is only a guess at the moment.

“Of course there was also a greater awareness [concerning ILD]”Modi said.” There has been a big education campaign around the pulmonary toxicity of trastuzumab deruxtecan. If you look at the rates of LTD, the rates were consistent until 2019, when management guidelines were put in place. updates were implemented and incidence rates began to decline.

Specifically, Modi presented pooled data demonstrating that the incidence of LTD overtime of any grade was 24.3% (n = 18/74) in 2016; 19.6% (n = 33/168) in 2017; 15.3% (n = 87/569) in 2018; 15.6% (n = 28/179); and 6.9% (n = 11/160) in 2020.4

Based on what is known about trastuzumab deruxtecan, Cortés and Modi both stated that the unmatched efficacy and reduced risk of pulmonary toxicity supported the use of trastuzumab deruxtecan as second-line.1.2

Trastuzumab deruxtecan is approved for patients with unresectable metastatic HER2-positive breast cancer who have already received at least 2 lines of anti-HER2-based regimens in a metastatic setting.5

The references

  1. Cortés J, Kim SB, Chung WP et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM) in patients (Pts) with HER2 + metastatic breast cancer (mBC): results from the randomized phase III study DESTINY-Breast03. Presented at: European Society of Medical Oncology 2021 Annual Congress. September 16-21, 2021; virtual. Summary LBA1.
  2. Enhertu significantly improved progression-free survival in the DESTINY-Breast03 versus trastuzumab emtansine (T-DM1) controlled trial in patients with HER2-positive metastatic breast cancer. Press release. AstraZeneca and Daiichi Sankyo Company; August 9, 2021. Accessed September 18, 2021. bit.ly/3tRh5zG
  3. Baselga J, Cortés J, Kim SB, et al; CLEOPATRA investigators. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N English J Med. 2012; 366 (2): 109-119. doi: 10.1056 / NEJMoa1113216
  4. Powell CA, Modi S, Iwata H, et al. Study review of drug-related interstitial lung disease (ILD) in patients (pts) with metastatic breast cancer (mBC) HER + treated with trastuzumab deruxtecan (T-DXd). Anne Oncol. 2021; 32 (suppl 2): ​​S61-S62. doi: 10.1016 / j.annonc.2021.03.106
  5. Enhertu. Prescribing information. Daiichi Sankyo; 2021. Accessed September 18, 2021. bit.ly/3CtlWKm

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