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Key Studies in Genitourinary, Gastrointestinal, Breast, and Lung Cancers: CCO Independent Conference Highlights of the 2021 Virtual ESMO Annual Meeting

Eva M. Ciruelos, MD, PhD
Karim Fizazi, MD, PhD
Eric Van Cutsem, MD, PhD
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Vamsidhar Velcheti, MD
Released: December 15, 2021

Studies in Breast Cancers From ESMO 2021

DESTINY-Breast03: Background

Eva M. Ciruelos, MD, PhD:
I will review the 3 most important BC trials presented at ESMO 2021. The first study is DESTINY‑Breast03, which is the first randomized trial comparing the ADCs, T-DXd, and T-DM1 head to head in previously treated HER2‑positive mBC.32

ADCs have shown promising activity in previously treated HER2‑positive mBC. T‑DM1 was established as the second-line SoC based on the EMILIA trial, with median PFS outcomes from 6-10 months.33,34 T-DXd has a higher drug to antibody ratio (~8:1) than T-DM1 (~3.5:1.0).35

T‑DXd is approved by the FDA the treatment of adults with unresectable or metastatic HER2‑BC who have received ≥2 previous anti‑HER2­–based regimens in the metastatic setting based on results of the single-arm phase II DESTINY‑Breast01 study.17,36

DESTINY-Breast03: Study Design

Eva M. Ciruelos, MD, PhD:
The ongoing DESTINY‑Breast03 trial enrolled 524 patients with unresectable or metastatic HER2-positive BC who were previously treated with trastuzumab plus a taxane in the advanced/metastatic setting. Patients were stratified by hormone receptor status, prior treatment with pertuzumab, and history of visceral disease and randomized 1:1 to receive T‑DXd or T‑DM1. At the time of this analysis, the median follow-up for the T-DXd arm is 16.2 months vs 15.3 months for T-DM1.

The primary endpoint is PFS by BICR and secondary endpoints include OS, ORR, and safety.

DESTINY-Breast03: Baseline Characteristics and Prior Therapies

Eva M. Ciruelos, MD, PhD:
Patients in both arms were a median age of 54 years. Visceral disease was present in 70% of patients and brain metastases in 19.8% to 23.8%. Approximately 70% of patients had received 0-2 prior lines of therapy in the metastatic setting. Pertuzumab had been used as a prior therapy in approximately 60% of patients in each arm, and anti‑HER2 TKIs were given to 13.7% to 16.1% of patients.

DESTINY-Breast03: PFS by BICR (Primary Endpoint)

Eva M. Ciruelos, MD, PhD:
The primary endpoint of PFS by BICR was achieved (HR: 0.28; 95% CI: 0.22-0.37; P = 7.8 x 10-22). The median PFS has not been reached for T‑DXd arm vs 6.8 months in the T‑DM1 arm, and the 12-month PFS is 75.8% vs 34.1%. This trial is impressively positive, clinically relevant, and statistically significant.

DESTINY-Breast03: PFS by Investigator Assessment, OS (Secondary Endpoints)

Eva M. Ciruelos, MD, PhD:
PFS by investigator assessment was also significant (HR: 0.26; 95% CI: 0.20-0.35; P = 6.5 x 10-24). Although the OS data are still immature, they currently favor T‑DXd treatment (HR: 0.56; 95% CI: 0.36-0.86; P = .007172).

DESTINY-Breast03: Response

Eva M. Ciruelos, MD, PhD:
T‑DXd improved patient responses, with a DCR of 96.6% vs 76.8% and an ORR of 79.7% vs 34.2% (P <.0001). There was also an impressive reduction in tumor volume and disease progression (1.1% vs 17.5%).

DESTINY-Breast03: Safety Summary and Adverse Events of Special Interest

Eva M. Ciruelos, MD, PhD:
Grade ≥3 TEAEs affected a similar number of patients receiving T-DXd and T-DM1 (45.1% vs 39.8%), but treatment discontinuation because of drug-related TEAE was higher in the T-DXd arm (12.8% vs 5.0%).

Drug-related ILD/pneumonitis affected more patients receiving T-DXd (10.5% vs 1.9%) and was grade 3 in 2 patients (0.8%). A decrease in left ventricular ejection fraction affected 2.7% of patients receiving T-DXd vs 0.4% of patients receiving T-DM1, but all events were grade 1 or 2.

DESTINY-Breast-3: Drug-Related TEAEs

Eva M. Ciruelos, MD, PhD:
The most common grade ≥3 drug‑related TEAE affecting the blood/lymphatic system in patients receiving T-DXd was neutropenia (19.1%). Grade ≥3 thrombocytopenia affected 24.9% of patients treated with T‑DM1.

Nausea was more common with T-DXd treatment (72.8% vs 27.6%), as was vomiting (44.0% vs 5.7%) and diarrhea (23.7% vs 3.8%).

DESTINY-Breast-3 Conclusions

Eva M. Ciruelos, MD, PhD:
The DESTINY‑Breast03 trial is the first phase III study to directly compare T-DXd with T‑DM1 in the second‑line setting of advanced HER2‑positive BC. The most important message from this trial is that T‑DXd showed statistically and clinically significant PFS benefit with a 72% reduction in the risk of progression or death vs T‑DM1 in patients who were previously treated with a taxane and trastuzumab. This benefit was consistent across patient subgroups and efficacy endpoints, with a confirmed ORR of 79.7% with T-DXd vs 34.2% with T-DM1. OS data are not mature at this time but showed numerically longer OS with T‑DXd. The safety profile was comparable between the 2 arms, and the most important AEs were lower than previously reported in the DESTINY‑Breast01 trial.

T‑DXd should be considered the new standard second‑line treatment in HER2‑positive advanced BC because of the significant improvement in PFS, ORR, and DCR with a very well-known safety profile.

TULIP: Background

Eva M. Ciruelos, MD, PhD:
The second trial that I will discuss is the phase III TULIP trial.37 Trastuzumab duocarmazine is a new HER2-targeting ADC based on trastuzumab with a cleavable linker and a duocarmazine payload that alkylates DNA and has a drug-to-antibody ratio of 2.4 to 2.8.38 Trastuzumab duocarmazine has a 3-way mechanism of action that includes the uptake of the ADC by internalization and intracellular release of the payload, proteolytic cleave and subsequent release of the payload in the tumor microenvironment, and diffusion of the active payload to neighboring tumor cells

TULIP was the first phase III trial to compare efficacy of this drug with physician’s choice of CT in patients with previously treated HER2‑positive advanced BC.

TULIP: Study Design

Eva M. Ciruelos, MD, PhD:
All 437 patients enrolled in the trial had locally advanced or metastatic HER2-positive BC and received ≥2 prior therapies for metastatic disease or T-DM1 for metastatic disease. Patients were randomized 2:1 to receive trastuzumab, duocarmazine, or physician’s choice of CT: lapatinib plus capecitabine, trastuzumab plus capecitabine, trastuzumab plus vinorelbine, or trastuzumab plus eribulin. Treatment was continued until disease progression or unacceptable toxicity. Stratification was based on geographic region (European Union plus Singapore vs North America), the number of prior therapies (1-2 vs >2), and prior exposure to pertuzumab (yes or no).

The primary endpoint was PFS by BICR, and secondary endpoints were PFS by investigator, OS, ORR, and HRQoL.

TULIP: Baseline Characteristics and Prior Therapies

Eva M. Ciruelos, MD, PhD:
This patient population was heavily pretreated with a median of 4 to 5 prior lines of therapy in the metastatic setting. Trastuzumab was previously received by approximately 90% of patients in both arms, T‑DM1 by 87%, pertuzumab by 60%, and lapatinib by 30%. Far fewer patients had received neratinib, tucatinib, or margetuximab.

TULIP: PFS by BICR (Primary Endpoint)

Eva M. Ciruelos, MD, PhD:
Trastuzumab duocarmazine significantly improved median PFS (by BICR) to 7.0 months vs 4.9 months, (HR: 0.64; 95% CI: 0.49-0.84; P = .002). The PFS benefit was consistent across analyzed subgroups, including age, hormone receptor status, and prior therapy. These results are both statistically significant and clinically relevant.

TULIP: PFS by Investigator Assessment, OS (Secondary Endpoints)

Eva M. Ciruelos, MD, PhD:
There was also a benefit in PFS by investigator assessment, with a median PFS of 6.9 months with trastuzumab duocarmazine and 4.6 months with CT (HR: 0.60, 95% CI: 0.47-0.77; P <.001). A benefit in OS was not achieved, however, as the median OS was 20.4 months with trastuzumab duocarmazine vs 16.3 months with CT (HR: 0.83, 95% CI: 0.62-1.09; P = .153).

TULIP: Responses (Central Review)

Eva M. Ciruelos, MD, PhD:
Responses were nearly the same between the arms, with an ORR of 27.8% with trastuzumab duocarmazine vs 29.5% with CT, and a clinical benefit rate of 38.5% vs 32.2%.


Eva M. Ciruelos, MD, PhD:
The most important TEAEs related to trastuzumab duocarmazine were eye toxicity: conjunctivitis, keratitis and dry eye of grade ≥3 affected 22.0% of patients.

TULIP: AEs of Special Interest and HRQoL

Eva M. Ciruelos, MD, PhD:
Eye toxicity led to discontinuation of trastuzumab duocarmazine in 20.8% of patients and dose modification in 22.9% of patients. ILD affected 7.6% of patients receiving trastuzumab duocarmazine and was grade ≥3 in 2.4%. ILD led to discontinuation in 5.2% and dose modification in 2.1%.

Six patients (2.1%) who received trastuzumab duocarmazine had fatal AEs. Four of the deaths were judged to be treatment related and were caused by respiratory failure (n = 1), pneumonia (n = 1), and pneumonitis (n = 2). HRQoL showed no changes from baseline or differences between treatment arms.

TULIP: Conclusions

Eva M. Ciruelos, MD, PhD:
TULIP was the first phase III trial to compare the new ADC trastuzumab duocarmazine with physician’s choice of CT in patients heavily pretreated for advanced HER2‑positive BC. Median PFS (by BICR) was significantly improved from 4.9 months with CT to 7.0 months with trastuzumab duocarmazine (HR: 0.64; P = .002).

Apart from investigator-assessed PFS, the rest of the secondary endpoints were not met, as OS and ORR were nearly the same between the arms. Eye toxicity was the most common AE but can be mitigated with prophylactic eye drops, regular eye examinations, and treatment discontinuation or delay.

Based on TULIP, I think trastuzumab duocarmazine could be a new option for patients with pretreated HER2‑positive locally advanced or mBC and could be better than the SoC in patients who are heavily pretreated with 3, 4, or even 5 prior lines of therapy. Of note, very few patients on this study had received the newer therapies neratinib, tucatinib, T-DXd, or margetuximab.

KEYNOTE-355 Final Analysis: Background

Eva M. Ciruelos, MD, PhD:
The last trial that I will review is KEYNOTE‑355, a randomized placebo‑controlled phase III trial of pembrolizumab plus CT in previously untreated advanced triple‑negative BC.39

A prespecified interim analysis showed a significant PFS improvement with the addition of pembrolizumab to CT vs CT alone in patients whose tumors expressed PD‑L1 with a combined positive score (CPS) ≥10.40 Based on these results, pembrolizumab plus CT received FDA approval in PD‑L1–positive (CPS ≥10), locally recurrent unresectable or advanced triple‑negative BC.41

What was presented at ESMO this year was the final analysis of OS outcomes in the KEYNOTE-355 trial.

KEYNOTE-355: Study Design

Eva M. Ciruelos, MD, PhD:
KEYNOTE-355 was a double-blind multicenter phase III trial that randomized 847 patients to receive CT plus pembrolizumab or placebo plus CT. All patients had locally recurrent inoperable or metastatic triple‑negative BC and had completed curative intent treatment ≥6 months before first recurrence. Patients continued therapy until progression, toxicity, or completion of 35 cycles.

The primary endpoints were PFS and OS in the PD‑L1 CPS ≥10, PD‑L1 CPS ≥1, and the intention to treat (ITT) patient populations. Secondary endpoints included ORR, DoR, DCR, and safety.

KEYNOTE-355: Baseline Characteristics (ITT)

Eva M. Ciruelos, MD, PhD:
Between 36.7% and 38.9% of patients had a CPS ≥10, with 75.1% having a CPS ≥1. Taxane was chosen as the preferred treatment option for 45% of all patients and carboplatin plus gemcitabine was chosen for 55%. The disease-free interval in all patients was less than 12 months in 22.1% of the patients in the pembrolizumab plus CT arm vs 17.8% with CT alone.

KEYNOTE-355 Final Analysis: OS (Coprimary Endpoint)

Eva M. Ciruelos, MD, PhD:
Median OS was improved in patients with a PD-L1 CPS ≥10 with the addition of pembrolizumab to CT at 23.0 months vs 16.1 months (HR: 0.73, 95% CI: 0.55-0.95; 1-sided P = .0093). The percentage of patients who were alive at 24 months was also improved in the arm receiving pembrolizumab (48.2% vs 34.0%). These differences were not statistically significant in the PD-L1 CPS ≥1 or ITT patient populations.

KEYNOTE-355 Final Analysis: OS in PD-L1 CPS Subgroups

Eva M. Ciruelos, MD, PhD:
Patients with a PD-L1 CPS of ≥20 had similar OS outcomes to patients with CPS ≥10 with a median OS of 24.0 months with pembrolizumab plus CT vs 15.6 months for placebo plus CT (HR: 0.72; 95% CI: 0.51-1.01). OS outcomes were similar across demographic and disease subgroups within the CPS ≥10 and CPS ≥1 patient populations.

KEYNOTE-355 Final Analysis: PFS (Coprimary Endpoint)

Eva M. Ciruelos, MD, PhD:
Pembrolizumab plus CT was previously reported to show a PFS benefit in the prespecified interim analysis, which was maintained in the final analysis. In patients with a CPS ≥10, the median PFS was 9.7 months vs 5.6 months (HR: 0.66, 95% CI: 0.50-0.88). There was also a PFS benefit for the addition of pembrolizumab in the CPS ≥1 and ITT populations.

KEYNOTE-355 Final Analysis: Other Efficacy Outcomes

Eva M. Ciruelos, MD, PhD:
The ORR was 52.7% with pembrolizumab plus CT in the PD-L1 CPS ≥10 population vs 40.8% with CT alone. Other efficacy endpoints also favored the addition of pembrolizumab in the PD-L1 CPS ≥10 patient population, including the DCR (65.0% vs 54.4%) and the 12-month DoR (55.5% vs 37.9%).

KEYNOTE-355 Final Analysis: Safety

Eva M. Ciruelos, MD, PhD:
Grade ≥3 AEs occurred in approximately 67% of the patients in both treatment arms. The most frequent immune‑mediated AEs of any grade in the pembrolizumab plus CT arm were hypothyroidism (15.8%), hyperthyroidism (4.3%), pneumonitis (2.5%), colitis (1.8%), and severe skin reactions (1.8%).

KEYNOTE-355 Final Analysis: Conclusions

Eva M. Ciruelos, MD, PhD:
The KEYNOTE‑355 trial is the first phase III study to show that the addition of pembrolizumab to CT significantly improves both PFS and OS in patients with previously untreated PD‑L1 CPS ≥10 locally advanced unresectable or metastatic triple‑negative BC.

In patients with a PD-L1 CPS ≥10, the median OS improved from 16.1 months to 23.0 months with the addition of pembrolizumab, and median PFS improved from 5.6 months to 9.7 months. The safety outcomes were consistent with the profiles of each regimen and no new safety concerns emerged.

The key message that healthcare professionals should take away from this trial is that the combination of pembrolizumab plus CT is a new SoC for patients with locally recurrent or advanced triple‑negative BC whose tumors have a PD‑L1 CPS ≥10. PD‑L1 testing should be routinely done in all patients with BC to identify patients that will benefit from pembrolizumab plus CT.

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Supported by educational grants from
Daiichi Sankyo, Inc.
Exelixis, Inc.
Ipsen Biopharmaceuticals, Inc.

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