CE / CME
Physician Assistants/Physician Associates: 1.25 AAPA Category 1 CME credits
Nurses: 1.25 Nursing contact hours
Physicians: maximum of 1.25 AMA PRA Category 1 Credits™
Pharmacists: 1.25 contact hours (0.125 CEUs)
Released: February 23, 2024
Expiration: February 22, 2025
HER2CLIMB-02: T-DM1 Plus Tucatinib in Previously Treated HER2-Positive MBC
Sara A. Hurvitz, MD:
Next, we will explore several studies in the setting of HER2-positive MBC.
First is the placebo-controlled phase III HER2CLIMB-02 trial evaluating tucatinib, a HER2-directed tyrosine kinase inhibitor, in combination with T-DM1.26 An earlier phase Ib trial reported that this regimen was tolerable and active in patients with heavily pretreated HER2-positive MBC, with intracranial activity observed among those with brain metastases at study entry.27
Like HER2CLIMB, HER2CLIMB-02 allowed enrollment of patients with active brain metastases.26 This study also allowed enrollment of patients who were less heavily treated than those eligible for HER2CLIMB, the randomized phase II trial that led to FDA approval of tucatinib plus trastuzumab and capecitabine for adults with advanced unresectable/metastatic HER2-positive brain cancer, including those with brain metastases, after ≥1 prior anti–HER2-based regimen for metastatic disease.28 HER2CLIMB-02 required patients to have prior treatment with trastuzumab and a taxane but did not permit those previously treated with trastuzumab deruxtecan (T-DXd) or tucatinib. Participants were then randomized to receive tucatinib plus T-DM1 vs placebo plus T-DM1. The primary endpoint is investigator-assessed PFS.
It is important to note that the design of HER2CLIMB-02 does not address important questions regarding how well a tucatinib-based regimen works after T-DXd or how this regimen compares with the approved regimen of tucatinib plus trastuzumab and capecitabine.
HER2CLIMB-02: Baseline Characteristics
Sara A. Hurvitz, MD:
At baseline, approximately 44% of patients had a presence or history of brain metastases.26 Of note, 88.6% to 91.1% had received prior pertuzumab.
HER2CLIMB-02: PFS (Primary Endpoint)
Sara A. Hurvitz, MD:
The trial met its primary endpoint: The addition of tucatinib to T-DM1 significantly improved PFS vs placebo plus T-DM1 (HR: 0.76; 95% CI: 0.61-0.95; P = .0163).26 The median PFS was 9.5 months with tucatinib plus T-DM1 vs 7.4 months with placebo plus T-DM1, yielding a 2-month improvement.
HER2CLIMB-02: OS
Sara A. Hurvitz, MD:
This positive result in PFS triggered the first interim OS analysis.26 Only 53% of OS events have occurred, meaning these data are immature, but no significant difference was observed between the treatment arms. The median OS was not reached with tucatinib plus T-DM1 vs 38.0 months with placebo plus T-DM1.
HER2CLIMB-02: PFS in Patients With Brain Metastases
Sara A. Hurvitz, MD:
With the caveat that this could not be formally tested because of the hierarchical testing strategy, PFS was also analyzed in patients with brain metastases.26 There was an interesting numerical improvement of 2 months in median PFS among patients with brain metastases who received tucatinib plus T-DM1 vs placebo plus T-DM1 (median PFS: 7.8 vs 5.7 months, respectively; HR: 0.64; 95% CI: 0.46-0.89).
These data are consistent with the findings of HER2CLIMB, such that adding tucatinib to a standard chemotherapy-based regimen improves outcomes in patients with brain metastases.27,29,30
HER2CLIMB-02: Safety
Sara A. Hurvitz, MD:
Tucatinib plus T-DM1 was associated with an increased risk of elevated transaminases.26 Grade ≥3 elevations in alanine aminotransferase or aspartate aminotransferase occurred in 16.5% of patients who received tucatinib plus T-DM1 vs 2.6% of patients who received placebo plus T-DM1. Increased alanine aminotransferase was the most common toxicity leading to discontinuation of tucatinib or placebo (2.6% vs 0%, respectively).
HER2CLIMB-02: TEAEs of Interest
Sara A. Hurvitz, MD:
No Hy’s law cases were observed in this study.26 That being said, a substantial number of patients needed to have doses held or reduced because of hepatotoxicity. If this regimen enters clinical practice, we will have to pay careful attention to liver function testing as patients are being treated.
HER2CLIMB-02: Clinical Implications
Sara A. Hurvitz, MD:
These data further emphasize the role of tucatinib for treating HER2-positive MBC, especially among those with brain metastases. That being said, I do not consider these results to be practice changing or moving us away from the current standard. The standard of care in this setting would be to offer second-line T-DXd to patients who have already received treatment with trastuzumab and a taxane, based on the significantly prolonged OS reported in DESTINY-Breast03.31
Taken together, these data show that tucatinib should play an important role in treatment for patients with brain metastases. However, tucatinib plus T-DM1 is not approved by the FDA, and I am not sure that this regimen will replace tucatinib plus trastuzumab and capecitabine, which is already approved.
Joyce O’Shaughnessy, MD:
I agree, especially because tucatinib plus trastuzumab and capecitabine significantly improved OS vs placebo plus trastuzumab and capecitabine in patients with heavily pretreated HER2-positive MBC.30 We cannot say yet whether tucatinib plus T-DM1 significantly improves OS. Thus, I anticipate healthcare professionals continuing to prefer the approved regimen that significantly improves OS in HER2-positive MBC.
That being said, some patients with a history of gastrointestinal toxicity are unable to tolerate oral medications. They may not be able to tolerate capecitabine, so it is good to have the potential alternative of tucatinib plus T-DM1. In addition, I found the intracranial efficacy to be very encouraging with the HER2CLIMB-02 regimen. If the OS results are positive, then we may have another option that can be combined with tucatinib.
I do want to note that this regimen is under clinical investigation in the curative setting. The phase III CompassHER2 RD trial (NCT04457596) is comparing tucatinib plus T-DM1 vs placebo plus T-DM1 in patients with HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy and surgery.
DEBBRAH: T-DXd in Cohort With HER2-Positive/HER2-Low MBC and Leptomeningeal Carcinomatosis
Joyce O’Shaughnessy, MD:
The next study involves patients with HER2-positive or HER2-low ABC and leptomeningeal carcinomatosis (LMC). LMC develops in approximately 5% of patients with ABC and unfortunately has limited treatment options and a poor prognosis.32,33
This study is an interim analysis of cohort 5 of the multicohort phase II DEBBRAH trial.34 Cohort 5 enrolled adults with HER2-positive or HER2-low MBC and LMC and administered T-DXd at the standard dose every 3 weeks. This report presents data from 7 patients, of whom 3 had HER2-positive disease and 4 had HER2-low disease. All had cerebrospinal fluid‒positive cytology. None had received whole-brain radiation or stereotactic radiosurgery/stereotactic radiotherapy.
DEBBRAH, Cohort 5 With LMC: OS and PFS
Joyce O’Shaughnessy, MD:
We saw promising results from this small cohort. This interim analysis reported a median OS of 13.3 months, a notable improvement from the historical median of 3-6 months with treatment.32-34 The median PFS was 8.9 months, with 71% of patients alive and without progression at 6 months. These data are clearly encouraging.
DEBBRAH, Cohort 5 With LMC: Best Response for Intracranial, Extracranial, and Overall Lesions
Joyce O’Shaughnessy, MD:
T-DXd was associated with intracranial activity in these patients with LMC, with an intracranial clinical benefit rate of 80% and prolonged stabilization (≥24 weeks) observed in 5 of 7 patients.34 Although 5 patients experienced progressive disease, none had worsening LMC or progression of intracranial lesions.
These results are consistent with the data from the TUXEDO trial demonstrating that T-DXd can penetrate the blood–brain barrier and cause major cytoreduction of brain metastasis.35
DEBBRAH, Cohort 5 With LMC: Clinical Implications
Joyce O’Shaughnessy, MD:
These data were very encouraging and suggest a new use of T-DXd for patients with HER2-positive/HER2-low MBC and LMC. The intracranial and extracranial clinical benefit rates were approximately 80%, although it is too early to compare efficacy for HER2-positive vs HER2-low disease.
Sara A. Hurvitz, MD:
I was very glad to see a study with cohorts specifically for patients with LMC. As we gain more data on drugs showing activity in the brain, I hope that additional studies will include these patients with LMC, who typically have very poor prognoses.
DESTINY-Breast08: T-DXd Plus Endocrine Therapy in Hormone Receptor–Positive/HER2-Low MBC
Sara A. Hurvitz, MD:
Continuing our discussion of new data on T-DXd, Jhaveri and colleagues36 presented data from 2 cohorts in the multicohort phase Ib DESTINY-Breast08 trial. This trial enrolled patients with hormone receptor–positive/HER2-low ABC who had no prior chemotherapy in the metastatic setting. The patients received T-DXd with either anastrozole (n = 21) or fulvestrant (n = 20).
These were not heavily pretreated patients, with 30.0% to 33.3% having received no prior treatment for metastatic disease.
DESTINY-Breast08: Results
Sara A. Hurvitz, MD:
Bearing in mind that this was a parallel-cohort study not meant to compare the 2 arms, it is interesting that the ORRs were markedly different. The confirmed ORR was 71.4% with T-DXd plus anastrozole and 40.0% with T-DXd plus fulvestrant.36 The median PFS was 13.5 months and not reached, respectively.
I was particularly interested in seeing these data because this study nicely complements the TRIO-US B-12 TALENT trial (NCT04553770), in which neoadjuvant T-DXd is combined with or without anastrozole in patients with hormone receptor–positive/HER2-low EBC.
DESTINY-Breast08: Clinical Implications
Sara A. Hurvitz, MD:
In DESTINY-Breast08, responses look more promising for T-DXd in combination with anastrozole, but these results are certainly not conclusive given the small cohort sizes and noncomparative design of this study. The lack of stratification means there could have been differences in baseline characteristics that led to these differences in response.
Based on the safety profile, I believe that combining T-DXd with concurrent endocrine therapy is unlikely to harm patients, but I am not sure that the combination will lead to a benefit over T-DXd alone. The TALENT trial—which combined T-DXd with anastrozole in the neoadjuvant setting—reported slightly worse responses when T-DXd was combined with endocrine therapy vs T-DXd alone. Of the patients who have completed imaging at the end of treatment, 68% who received T-DXd alone had an objective response vs 58% in the combination arm.37
Based on the results from TALENT and DESTINY-Breast08, I would not implement this combination outside of a clinical trial setting. When treating hormone receptor–positive/HER2-positive MBC, I sequence T-DXd with endocrine therapy as a separate line of therapy, rather than using them in combination.
Joyce O’Shaughnessy, MD:
I completely agree with that assessment. These data suggest that the combination of T-DXd plus anastrozole is well tolerated, but the PFS and ORR results are limited by small cohort sizes. It will be very interesting to see additional follow-up from the TALENT trial on this combination in the curative setting.
I also look forward to data from the ongoing phase III DESTINY-Breast05 trial (NCT04622319), which is comparing adjuvant T-DXd vs T-DM1 in patients with HER2-positive EBC and residual disease following neoadjuvant therapy.
Phase II Trial of Zanidatamab in Combination With Palbociclib and Fulvestrant in Hormone Receptor–Positive/HER2-Negative MBC
Joyce O’Shaughnessy, MD:
I am very interested in our next study in the setting of HER2-positive disease. This study evaluated zanidatamab, a biparatopic antibody in which one arm of the variable region binds to HER2 at domain 2 and the other arm at domain 4.38 Zanidatamab inhibits HER2 heterodimerization and homodimerization and mediates HER2 internalization. This biparatopic targeting makes zanidatamab unique compared with trastuzumab, which binds only to domain 4, as well as pertuzumab, which binds only to domain 2. Essentially, zanidatamab is like trastuzumab and pertuzumab combined into a single agent.
Zanidatamab was evaluated in this single-arm phase IIa trial, which enrolled 51 patients with hormone receptor–positive/HER2-positive breast cancer that was unresectable, locally advanced, or metastatic.39 HER2 status was determined locally and then reassessed centrally. Patients had been previously treated with trastuzumab, pertuzumab, and T-DM1; those with previously treated, stable brain metastases were permitted to enroll. Zanidatamab was administered intravenously every 2 weeks in combination with full-dose palbociclib and fulvestrant.
The primary endpoints were safety, which was previously reported for part 1 of the study, and PFS at 6 months, which is the focus of the current analysis.39,40
Of the 51 patients identified as having HER2-positive disease by local testing, central testing confirmed 32 as having HER2-positive disease. However, central testing identified 18 as having HER2-negative disease, with missing data for 1 patient.
Phase II Trial of Zanidatamab: Results
Joyce O’Shaughnessy, MD:
At 6 months, 67% of all patients were progression free, with a median PFS of 12 months.39 The median PFS was longer for the subset with HER2-positive disease confirmed centrally (15 months) than for those with discordant testing results (8 months). Among all patients, the confirmed ORR was 35%.
This regimen was well tolerated. Grade 3/4 neutropenia occurred in 53% of patients, consistent with the myelosuppressive effects of palbociclib. Another common treatment-related AE (TRAE) was diarrhea, which occurred at any grade in 80% of patients and at grade 3/4 in 14% of patients. Diarrhea is also part of the safety profiles for pertuzumab and trastuzumab.41,42 However, unlike pertuzumab and trastuzumab, zanidatamab was not associated with skin irritation.
Cardiotoxicity also is established as part of the safety profile for trastuzumab. In this trial, the zanidatamab-based regimen was associated with decreased ejection fraction in 12% of patients, with 2% experiencing a grade 3/4 event.39
Phase II Trial of Zanidatamab: Clinical Implications
Joyce O’Shaughnessy, MD:
I find these results quite promising and supportive for the strategy of combining a HER2-directed agent with a CDK4/6 inhibitor and endocrine therapy for our patients with ER-positive/HER2-positive disease.
At SABCS 2023, Patel and colleagues43 presented results from the phase I/II ASPIRE trial, which is evaluating a chemotherapy-free regimen for first-line treatment of hormone receptor–positive/HER2-postive MBC. The investigators reported that combining anastrozole with full-dose palbociclib, trastuzumab, and pertuzumab was associated with a median PFS of 21.2 months in 30 patients. This is close to the results from the large phase III CLEOPATRA trial, which reported a median PFS of 18.7 months with first-line pertuzumab, trastuzumab, and docetaxel in HER2-positive MBC.44 Taken together, these results suggest that blocking the ER, inhibiting CDK4/6, and targeting HER2 with trastuzumab and pertuzumab could be effective for patients earlier in the metastatic setting.
CDK4/6 inhibitors do not have FDA approval in HER2-positive breast cancer, but that may change soon. The phase III PATINA trial (NCT02947685) is comparing the combination of an anti-HER2 therapy and endocrine therapy with or without palbociclib in patients with hormone receptor–positive/HER2-positive MBC and recently finished enrollment. If PATINA shows that the addition of palbociclib significantly improves PFS, those results could bring the CDK4/6 inhibitor into the first-line setting. That would be practice changing.
Sara A. Hurvitz, MD:
I agree. I am very interested in the development of zanidatamab, and I like that this phase II trial is evaluating a chemotherapy-free regimen that targets multiple pathways.45
We should note that this study reported a sizable proportion of patients with HER2 testing results that were discordant by central vs local testing.39 The median PFS of 15 months in those with centrally confirmed HER2-positive disease was notable for this heavily pretreated population. However, this discordance does call into question how much we can rely on our HER2 testing.
TROPiCS-02 Subgroup Analysis by Age: Sacituzumab Govitecan vs Treatment of Physician’s Choice in Hormone Receptor–Positive/HER2-Negative MBC
Sara A. Hurvitz, MD:
Moving into the setting of HER2-negative disease, we will now discuss a post hoc analysis of the TROPiCS-02 trial.46 This is the registrational phase III trial that led to FDA approval of sacituzumab govitecan for adults with hormone receptor–positive/HER2-negative breast cancer that is unresectable, locally advanced, or metastatic and who have received endocrine-based therapy and ≥2 additional systemic therapies for metastatic disease.47 Sacituzumab govitecan is a TROP-2–directed antibody–drug conjugate (ADC) with a topoisomerase I inhibitor payload (SN-38).
The current report presented a subgroup analysis by age, which I consider to be very important because older patients are historically underrepresented in clinical trials.48
TROPiCS-02 Subgroup Analysis by Age: Baseline Characteristics
Sara A. Hurvitz, MD:
Approximately one third of patients were aged 65 years and older.46 Older patients had a greater burden of preexisting comorbidities, with 81% to 89% of those aged 65 years and older having ≥4 comorbidities vs 74% to 75% of those younger than 65 years. That being said, the older patients who were eligible for this clinical trial had good organ function and acceptable Eastern Cooperative Oncology Group performance status. This underscores the highly selective nature of clinical trials, even in older patients.
TROPiCS-02 Subgroup Analysis by Age: Efficacy
Sara A. Hurvitz, MD:
In both age subgroups, sacituzumab govitecan was associated with improved PFS, OS, and ORR vs standard chemotherapy.46 I was reassured to see that sacituzumab govitecan was associated with improved efficacy regardless of age category.
TROPiCS-02 Subgroup Analysis by Age: Efficacy by RDI
Sara A. Hurvitz, MD:
When the investigators stratified each age group by relative dose intensity (RDI), they observed that regardless of age, those who had an RDI >90% generally had better efficacy outcomes.46 This dose-response relationship was more pronounced in the younger patients.
These results may suggest that RDI may be a surrogate indicator for a patient’s general health and how well they are tolerating treatment. This does not mean that we must compel patients to take a higher dose of sacituzumab govitecan, but rather that RDI could simply be a prognostic factor indicating that patients who are able to take more drug are doing better overall.
TROPiCS-02 Subgroup Analysis by Age: Safety
Sara A. Hurvitz, MD:
Safety is an important concern for our older patients, who may be more frail or have more comorbidities. In this analysis, older patients had higher rates of dose reduction and discontinuation due to TEAEs.46 TEAEs leading to dose discontinuation of sacituzumab govitecan occurred in 17% of older patients vs 3% of younger patients.
This suggests that older patients need to be monitored more closely to ensure that they are tolerating treatment well.
TROPiCS-02 Subgroup Analysis by Age: Time to Deterioration
Sara A. Hurvitz, MD:
The investigators reported that sacituzumab govitecan generally prolonged the median time to deterioration of patient-reported outcomes in both younger and older patients.46
TROPiCS-02 Subgroup Analysis by Age: Clinical Implications
Joyce O’Shaughnessy, MD:
I find these data reassuring: Sacituzumab govitecan demonstrated very similar efficacy in older and younger women. There were more discontinuations in the older age group, of course. However, in terms of patient-reported outcomes in the older subgroup, sacituzumab govitecan increased the median time to deterioration of patient-reported quality of life and overall health status.
TROPION-Breast01: Dato-DXd vs Chemotherapy for Patients With Previously Treated Hormone Receptor–Positive/HER2-Negative ABC
Joyce O’Shaughnessy, MD:
At SABCS 2023, we saw a second presentation of results from the ongoing phase III TROPION-Breast01 trial, which initially were presented at ESMO 2023.49,50 TROPION-Breast01 is evaluating another TROP-2–directed ADC, Dato-DXd, which also has a topoisomerase 1 inhibitor payload (deruxtecan).
The TROPION-Breast01 trial is comparing Dato-DXd vs chemotherapy of physician’s choice in patients with ER-positive/HER2-negative ABC who had previously received 1-2 prior lines of chemotherapy and either progressed on or were unsuitable for endocrine therapy. Dato-DXd was administered intravenously every 3 weeks.
The coprimary endpoints are PFS per blinded independent central review (BICR) and OS.
TROPION-Breast01: Efficacy
Joyce O’Shaughnessy, MD:
Dato-DXd significantly improved median PFS by 2 months vs chemotherapy (6.9 vs 4.9 months, respectively), yielding an HR of 0.63 (95% CI: 0.52-0.76; P <.0001).50 The Dato-DXd arm also had a higher ORR of 36.4% vs 22.9% in the chemotherapy arm.
The OS data remain immature but suggest that Dato-DXd prolongs survival vs chemotherapy (HR: 0.84; 95% CI: 0.62-1.14).49
TROPION-Breast01: PFS in Patient Subgroups (BICR)
Joyce O’Shaughnessy, MD:
The subgroup analyses showed that Dato-DXd was associated with consistent PFS benefit, regardless of whether the patient had previously received a CDK4/6 inhibitor, the duration of treatment with a CDK4/6 inhibitor, or the presence of brain metastases at baseline.50
TROPION-Breast01: Safety
Joyce O’Shaughnessy, MD:
Overall, Dato-DXd was well tolerated compared with chemotherapy. Dato-DXd has a safety profile very different from sacituzumab govitecan.46,50 For example, neutropenia is an important part of the safety profile with sacituzumab govitecan, but any-grade neutropenia occurred in only 11% of patients who received Dato-DXd. Unlike sacituzumab govitecan, Dato-DXd can cause stomatitis, which occurred at any grade in 50% of patients vs 13% with chemotherapy. Fortunately, the risk of stomatitis can be reduced with a prophylactic steroid mouth rinse.
In the Dato-DXd arm, the most common TRAEs leading to dose interruptions were stomatitis, fatigue, infusion-related reactions, and interstitial lung disease, at rates of approximately 1% each.
Sara A. Hurvitz, MD:
It is important to note that ADCs with the deruxtecan payload (ie, T-DXd and Dato-DXd) convey more risk of interstitial lung disease than sacituzumab govitecan, which has the SN-38 payload.51
TROPION-Breast01: Clinical Implications
Joyce O’Shaughnessy, MD:
I anticipate that the FDA will issue an approval for Dato-DXd in this setting and that we will then have both Dato-DXd and sacituzumab govitecan as options for our patients. Currently, we do not have mature OS data for TROPION-Breast01, and the positive OS data from TROPiCS-02 makes sacituzumab govitecan the more compelling option. If TROPION-Breast01 also reports positive OS data, then choosing between these options would largely depend on the patient’s individual risk for the toxicities most associated with each agent.
Sara A. Hurvitz, MD:
I completely agree. If Dato-DXd becomes available, an important question will be how to sequence Dato-DXd and sacituzumab govitecan. I am wary of the potential for cross-resistance to develop, given that both agents target TROP-2 and have a topoisomerase I inhibitor payload. I hope we will have prospective studies investigating the question of sequencing and looking for biomarkers indicative of resistance.
KEYLYNK-009: Maintenance Pembrolizumab Plus Olaparib vs Pembrolizumab Plus Chemotherapy in Untreated Metastatic or Locally Recurrent Inoperable TNBC
Sara A. Hurvitz, MD:
Our final study is addressing a long-standing question: Can we switch from an induction regimen to a different maintenance regimen in TNBC, similar to the approach used in ovarian cancer?
The randomized phase II KEYLYNK-009 trial enrolled 460 patients with TNBC that was recurrent and inoperable or metastatic; PD-L1 status had to be confirmed.52 All patients received induction treatment with carboplatin plus gemcitabine and pembrolizumab for 4-6 cycles. The patients were then randomized to receive maintenance with olaparib plus pembrolizumab vs continuing the induction regimen. It is notable that this study is evaluating olaparib, a PARP inhibitor, in patients who were not required to have germline BRCA mutations.
The coprimary endpoints were PFS per BICR and OS.
KEYLYNK-009: Primary Endpoints
Sara A. Hurvitz, MD:
Median PFS was very similar between the treatment arms at 5.5 months with pembrolizumab plus olaparib vs 5.6 months with pembrolizumab plus chemotherapy, yielding an HR of 0.98 (95% CI: 0.72-1.33; P = .4556).52 The median OS also was quite similar between arms at 25.1 vs 23.4 months, respectively.
KEYLYNK-009: Secondary Endpoints
Sara A. Hurvitz, MD:
Shown here are the results for the secondary endpoints, which looked at efficacy among patients with PD-L1 CPS ≥10 and those with tumors harboring a BRCA (tBRCA) mutation.52
At baseline, 47.8% to 48.1% of patients had a PD-L1 CPS ≥10. Both PFS and OS were similar between treatment arms, even in this subpopulation of patients with PD-L1 CPS ≥10.
At baseline, tBRCA mutation was present in 21.5% to 22.1% of patients. The median PFS was longer for patients with tBRCA mutation who received pembrolizumab plus olaparib vs pembrolizumab plus chemotherapy (12.4 vs 8.4 months, respectively). The median OS was not reached vs 23.4 months, respectively.
Altogether, these data suggest that maintenance therapy with pembrolizumab plus olaparib could provide greater benefit in patients with tBRCA mutation.
KEYLYNK-009: Safety
Sara A. Hurvitz, MD:
It is critical to consider the safety profiles of these regimens. Unsurprisingly, grade 3-5 TRAEs were more common with pembrolizumab plus chemotherapy vs pembrolizumab plus olaparib (68.4% vs 32.6%, respectively).52
Treatment discontinuation due to AEs also occurred more often with pembrolizumab plus chemotherapy (19.5% vs 8.9% with pembrolizumab plus olaparib). Although the rates of immune-mediated AEs were similar between arms, no patients in the pembrolizumab plus olaparib arm experienced an immune-mediated AE leading to treatment discontinuation.
KEYLYNK-009: Clinical Implications
Sara A. Hurvitz, MD:
These negative results are not practice changing but do have a more optimistic interpretation: Pembrolizumab plus olaparib may offer comparable efficacy and improved tolerability vs pembrolizumab plus chemotherapy.
Joyce O’Shaughnessy, MD:
I agree. However, this study was designed to test for superiority, not inferiority, and cannot support approval of the pembrolizumab plus olaparib as maintenance therapy in TNBC.
Sara A. Hurvitz, MD:
Yes. These results do provide support for continued clinical investigation into maintenance strategies after induction chemotherapy in this setting. I hope that we will see more studies evaluating PARP inhibitors outside of the strictly defined population with germline BRCA mutations, such as patients with somatic BRCA mutations or PALB2 mutations.
Joyce O’Shaughnessy, MD:
I anticipate these data could be applied to some uncommon clinical scenarios, such as for patients with a germline BRCA mutation who need to continue cytotoxic therapy but whose bone marrow is not tolerating chemotherapy. Olaparib would then be an option. In the future, I hope to be able to administer less chemotherapy as maintenance and offer olaparib instead in selected patients with TNBC.
Conclusions
Joyce O’Shaughnessy, MD:
SABCS 2023 featured numerous important studies in both the early and advanced settings.
In the setting of hormone receptor–positive/HER2-negative EBC, biomarker analyses of KEYNOTE-756 and CheckMate 7FL identified patients more likely to benefit from adding an ICI to neoadjuvant chemotherapy followed by adjuvant endocrine therapy. The final iDFS data from NATALEE further supported use of adjuvant ribociclib, and molecular profiling data from monarchE support further study into the role of MYC amplification in resistance to CDK4/6 inhibition.
Turning to early TNBC, Neo-N observed no pCR benefit from starting nivolumab before a neoadjuvant anthracycline-free chemotherapy regimen, and ALEXANDRA/IMpassion030 found no benefit from ICI in the adjuvant setting alone.
Results from the long-awaited NRG Oncology/NSABP B-51/RTOG 1304 trial suggest that we may be able de-escalate radiation therapy in patients with relatively minimal baseline node positivity and/or ER-negative/HER2-positive disease who converted to axillary lymph node negativity after neoadjuvant chemotherapy.
We saw multiple studies in HER2-positive/HER2-low MBC. The HER2CLIMB-02 trial further supports using a tucatinib-based regimen, particularly in those with brain metastases, but does not support moving away from the standard of care. Data from a small DEBBRAH cohort encourage using T-DXd to treat those with LMC.
In the setting of hormone receptor–positive/HER2-low MBC, results from the DESTINY-Breast08 trial and earlier TALENT trial suggest no meaningful benefit from giving T-DXd with concurrent endocrine therapy.
A phase II trial reported encouraging efficacy and supports further investigation into the strategy of combining zanidatamab or another HER2-directed agent with a CDK4/6 inhibitor and endocrine therapy for patients with ER-positive/HER2-positive disease.
Turning to hormone receptor–positive/HER2-negative MBC, a subgroup analysis of TROPiCS-02 reported consistent benefits with sacituzumab govitecan regardless of age, albeit with more discontinuations among older patients. The TROPION-Breast01 trial met its coprimary endpoint of PFS with Dato-DXd, but we await mature OS data. Finally, in the setting of advanced TNBC, results from KEYLYNK-009 suggest that switching to maintenance pembrolizumab plus olaparib after induction with pembrolizumab plus chemotherapy may offer comparable efficacy and improved tolerability vs continuing induction therapy; further study of maintenance strategies is needed in this setting.
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