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Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2021 ASCO Annual Meeting

Joyce O'Shaughnessy, MD
Angeles Alvarez Secord, MD, MHSc
Released: August 12, 2021

Breast Cancer

GeparNUEVO: Survival Outcomes With Durvalumab Plus Neoadjuvant Chemotherapy vs Placebo Plus Neoadjuvant Chemotherapy in Early TNBC

Joyce A. O’Shaughnessy, MD:
I will start by considering the neoadjuvant setting in triple-negative breast cancer (TNBC). Two recent phase III trials have shown that adding anti–programmed cell death-1 (PD-1) or its ligand PD-L1 therapy to neoadjuvant chemotherapy improved complete response rates in early TNBC, even in patients with PD-L1–negative disease.1,2 Some of that effect may be related to tumor-infiltrating lymphocytes (TILs), which correlate with PD-L1 expression levels and are prognostic in early TNBC.3-6

GeparNUEVO is a relatively small, randomized phase II trial that compared the addition of durvalumab, a PD-L1 inhibitor, vs placebo to neoadjuvant chemotherapy in 174 patients with untreated early TNBC.7 Patients were stratified by TIL level (low, medium, or high) and randomized between the durvalumab and placebo arms. At first, the study included an initial 2-week window of opportunity during which patients received durvalumab or placebo monotherapy prior to beginning chemotherapy. That window was closed after the first 117 patients enrolled, due to concerns from the independent data monitoring committee about delaying treatment for patients in the placebo arm. After the monotherapy lead-in, patients received either durvalumab at 1.5 g or placebo every 28 days with weekly nab-paclitaxel at 125 mg/m2 for 12 weeks. The nab-paclitaxel was then switched for epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 14 days for 8 weeks. Patients then proceeded to surgery.

The primary endpoint was pathologic complete response (pCR) rate at surgery, defined as no invasive and no noninvasive tumor residuals in breast and axillary lymph nodes (ypT0, ypN0). Secondary endpoints were invasive DFS, distant DFS, and OS.

The primary analysis was published in 2019 and showed a trend toward improved pCR rate with durvalumab vs placebo (53.4% vs 44.2%, respectively; odds ratio [OR]: 1.45; 95% CI: 0.80-2.63; unadjusted Wald P = .224).7 In the cohort who had gone through the window-of-opportunity lead-in, however, the addition of durvalumab reached statistical significance with a pCR rate of 61.0% vs 41.4% with placebo (OR: 2.22; 95% CI: 1.06-4.64; P = .035). What was interesting is that in both arms, a higher pCR rate was associated with higher TILs. Of note, thyroid dysfunction was the most common immune-related AE and occurred more frequently in the durvalumab arm, with 50% of patients experiencing any-grade thyroid dysfunction vs 43.9% in the placebo arm.

At ASCO 2021, Loibl and colleagues8 presented longer-term survival outcomes after a median follow-up of approximately 3.5 years for the GeparNUEVO trial.

GeparNUEVO: Invasive DFS

Joyce A. O’Shaughnessy, MD:
The addition of durvalumab to neoadjuvant chemotherapy significantly prolonged invasive DFS, with a 3-year invasive DFS rate of 85.6% in the durvalumab arm vs 77.2% in the placebo arm (stratified HR: 0.48; 95% CI: 0.24-0.97; P = .0398).8 In both arms, patients who achieved a pCR were also more likely to be free of invasive disease at 3 years (HR for pCR vs no pCR: 0.34; 95% CI: 0.16-0.73; log-rank P = .004).

GeparNUEVO: Distant DFS

Joyce A. O’Shaughnessy, MD:
Similar outcomes were seen for distant DFS, with a 3-year distant DFS rate of 91.7% in the durvalumab arm vs 78.4% in the placebo arm (stratified HR: 0.31; 95% CI: 0.13-0.74; P = .0078).8 Here again, we see that patients who achieved a pCR were less likely to experience distant disease (HR for pCR vs no pCR: 0.28; 95% CI: 0.11-0.69; log-rank P = .003). In fact, none of the patients with pCR in the durvalumab arm had any distant disease events.

GeparNUEVO: Overall Survival

Joyce A. O’Shaughnessy, MD:
We also saw a beneficial OS effect with durvalumab.8 The 3-year OS rate was 95.2% in the durvalumab arm vs 83.5% in the placebo arm (stratified HR: 0.24; 95% CI: 0.08-0.72; P = .0108). Patients who achieved a pCR had a lower overall risk of death (HR for pCR vs no pCR: 0.27; 95% CI: 0.09-0.81; log-rank P = .012), and all patients who achieved a pCR on durvalumab were still alive at the time of analysis.

GeparNUEVO: Conclusions

Joyce A. O’Shaughnessy, MD:
I found these results very encouraging, although it is a bit surprising to see improvements in invasive DFS, distant DFS, and OS with durvalumab in the context of a relatively modest 9% improvement in pCR rate. Overall, these results with durvalumab support the outcomes we have been seeing with neoadjuvant pembrolizumab in the phase III KEYNOTE‑522 trial and neoadjuvant atezolizumab in the phase III IMpassion031 trial.1,2 The number of events in the IMpassion031 study is small, but the invasive DFS and event-free survival outcomes look promising. I am looking forward to seeing the invasive DFS and event‑free survival data for KEYNOTE-522.

GeparNUEVO is now the third study showing that the addition of a preoperative immune checkpoint inhibitor to neoadjuvant chemotherapy in patients with aggressive, high‑risk TNBC can make a positive difference in the outcomes. We always have to balance efficacy with toxicity, of course, and unfortunately, checkpoint inhibitors have a low risk of very serious, potentially even fatal toxicity. In my mind, that restricts the use of immune checkpoint inhibitors to patients at the highest risk (ie, node-positive disease). As we begin to see more mature data from these trials, we may be able to consider using these agents in node-negative patients.

In my practice, I am now using preoperative pembrolizumab in my high‑risk patients. I was happy to see this presentation at ASCO 2021 because it is confirming the leap of faith I have taken for these very high‑risk patients. They cannot afford to wait for regulatory approval and need effective therapy today.

ADAPT HR-/HER2+: Survival Outcomes With De-escalated Neoadjuvant Trastuzumab Plus Pertuzumab With vs Without Paclitaxel in HER2-Positive, Hormone Receptor–Negative Early-Stage Breast Cancer

Joyce A. O’Shaughnessy, MD:
Continuing to our next study in the neoadjuvant setting, the phase II ADAPT HR-/HER2+ trial evaluated de-escalated neoadjuvant trastuzumab plus pertuzumab with vs without weekly paclitaxel in patients with HER2‑positive, ER‑negative early-stage breast cancer.9,10 This was a small study with only 134 patients who were randomized at an intended 5:2 ratio to trastuzumab plus pertuzumab only vs trastuzumab plus pertuzumab plus weekly paclitaxel for 12 weeks before surgery. Most patients were clinical tumor stage T1 or T2, with just 8% stage T3 or T4. The baseline characteristics were generally balanced across both arms, with 57% overall having node-negative and 88% having grade 3 disease.

ADAPT HR-/HER2+: Efficacy Outcomes

Joyce A. O’Shaughnessy, MD:
The rate of pCR (ypT0/is ypN0; ypT0 ypN0) was 90.5% in those who received trastuzumab plus pertuzumab plus weekly paclitaxel vs 34.4% with trastuzumab plus pertuzumab only.10 The 5‑year invasive DFS rates were 98% vs 87%, respectively (HR: 0.32; 95% CI: 0.07-1.47; P = .144). These are remarkable outcomes.

ADAPT HR-/HER2+: Clinical Implications

Joyce A. O’Shaughnessy, MD:
We need a much larger study to confirm these data, but it is remarkable to see that we may be able to de‑escalate chemotherapy in a patient population that is largely T1 and T2 and not all node-negative disease.10 At this point, we do not know how to identify the approximately 1 out of 3 patients who might achieve a response without chemotherapy, so that approach is less useful. But for a patient who has T1 or T2 clinical node-negative disease, 12 weeks of paclitaxel with trastuzumab plus pertuzumab may be a manageable chemotherapy option. For patients with T2 or T3, node-positive disease, or who have other comorbidities, I think we would still use a regimen of docetaxel, carboplatin, trastuzumab, and pertuzumab. But these are impressive results with de-escalation.

The CompassHER2-pCR trial is evaluating outcomes in patients with HER2-positive early-stage breast cancer who receive up to 4 cycles of preoperative taxane plus trastuzumab and pertuzumab followed by surgery.11 Patients who achieve a pCR will then receive trastuzumab plus pertuzumab; those without a pCR will receive standard trastuzumab emtansine. This is a much larger de-escalation trial with planned enrollment of 1250 patients and is now underway.

Title: Phase III OlympiA: Interim Analysis of
Adjuvant Olaparib vs Placebo in BRCA-Mutated, HER2-Negative, High-Risk Early-Stage Breast Cancer

Joyce A. O’Shaughnessy, MD:
Moving on to the adjuvant setting, we will next review an interim analysis of the phase III OlympiA trial.12,13 This trial is evaluating the safety and efficacy of the PARP inhibitor olaparib vs placebo in patients with germline BRCA1/2-mutated, HER2-negative early-stage breast cancer who are considered at high risk of recurrent disease. Olaparib is currently FDA approved for multiple indications, including the treatment of adults with (suspected) deleterious germline BRCA-mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy (neo)adjuvant/metastatic setting; those with hormone receptor–positive disease must have been previously treated with or ineligible for endocrine therapy.14 

To be eligible for OlympiA, patients had to have completed definitive local treatment and ≥6 cycles of neoadjuvant or adjuvant chemotherapy with anthracyclines and/or taxanes.13 The trial enrolled 1836 patients, who were divided into 2 subgroups. The first subgroup comprised 1509 patients with TNBC; if they had received adjuvant therapy, they must be ≥pT2 or ≥pN1, whereas those who had received neoadjuvant chemotherapy could not have achieved pCR. The second subgroup comprised 325 patients with hormone receptor–positive, HER2-negative breast cancer, who had ≥4 positive nodes if they had received adjuvant chemotherapy or, if they had received neoadjuvant chemotherapy, no pCR with a clinical and pathologic stage score ≥3. The patients were stratified by hormone receptor status, previous neoadjuvant vs adjuvant chemotherapy, and previous platinum-based chemotherapy, and they were randomized 1:1 to receive olaparib 300 mg (n = 921) or placebo (n = 915) twice daily for 1 year.

The primary endpoint was invasive DFS, and secondary endpoints were distant DFS, OS, and safety. This prespecified interim analysis of the intention-to-treat (ITT) population was triggered when the trial accrued 165 invasive disease or death events in the first 900 patients enrolled.

OlympiA: Baseline Characteristics

Joyce A. O’Shaughnessy, MD:
This was an extremely high‑risk population.13 In the olaparib arm, 71.3% of patients had germline BRCA1 mutation, 28.3% had BRCA2 mutation, and 0.2% had both. In the placebo arm, 73.2% of patients had BRCA1 mutation, 26.1% had BRCA2, and 0.5% had both. Approximately 82% of patients in each arm had TNBC and 17% to 18% had hormone receptor–positive disease.

The patients were almost evenly split between previous neoadjuvant and adjuvant chemotherapy. Most patients had received an anthracycline and taxane, and 26% of patients in each arm had received platinum-based chemotherapy.

OlympiA: iDFS (Primary Endpoint)

Joyce A. O’Shaughnessy, MD:
In this interim analysis, adjuvant olaparib significantly prolonged invasive DFS vs placebo.13 The 3-year rate of invasive DFS was 85.9% vs 77.1%, respectively, translating to an 8.8% difference (stratified HR: 0.58; 99.5% CI: 0.41-0.82; P <.001). The invasive DFS benefit with olaparib was consistent across many patient subgroups, including those defined by previous neoadjuvant vs adjuvant treatment, previous platinum, hormone receptor status, and BRCA mutation status.

OlympiA: Distant DFS

Joyce A. O’Shaughnessy, MD:
Similarly, olaparib significantly improved distant DFS, with a 3-year distant DFS rate of 87.5% vs 80.4% with placebo (stratified HR: 0.57; 99.5% CI: 0.39-0.83; P <.001).13

OlympiA: Overall Survival

Joyce A. O’Shaughnessy, MD:
The improvement in 3-year OS with olaparib was 92.0% vs 88.3% with placebo (stratified HR: 0.68; 99% CI: 0.44-1.05; P = .02).13 This was not statistically significant because it did not cross the early-reporting efficacy boundary of P = .01. The main cause of death in both arms was breast cancer. It will be interesting to see the follow-up with more mature data.

OlympiA: Adverse Events, Treatment Exposure, and Quality of Life

Joyce A. O’Shaughnessy, MD:
The safety profile of olaparib in this analysis was consistent with what we expect to see with this agent.13,14 There was a higher rate of AEs with olaparib vs placebo, but most events were low grade. Anemia was the most frequent grade ≥3 AE and occurred in 8.7% of patients in the olaparib arm vs 0.3% of patients in the placebo arm; 5.8% of patients receiving olaparib needed transfusions vs 0.9% of patients receiving placebo. Dose reductions were also much more common among patients receiving olaparib, with 25% requiring dose reductions vs 5.2% with placebo.

OlympiA: Safety

Joyce A. O’Shaughnessy, MD:
Of importance, there was no increase in the rate of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients receiving olaparib vs placebo.13 There were 2 cases (0.2%) of MDS/AML in the olaparib arm vs 3 cases (0.3%) in the placebo arm. These low numbers will hopefully hold up with more mature data.

Overall, there were 3 AEs that led to deaths: 1 cardiac arrest in a patient receiving olaparib and, in the placebo arm, 1 case each of AML and ovarian cancer.

OlympiA: Clinical Implications

Joyce A. O’Shaughnessy, MD:
These are very positive results from the OlympiA trial and are a prime example of how good patient selection can contribute to excellent efficacy outcomes. In my many years of experience, every failed trial I have been involved with has suffered from lack of knowledge about which patients to enroll in the study. The OlympiA trial, much like the monarchE trial we will discuss shortly, enrolled patients with aggressive disease, those at highest risk for early recurrence. The improvements in invasive and distant DFS—and in OS, although that did not quite reach statistical significance—were very impressive.

I was also happy to see that olaparib worked equally well in patients with BRCA1 and BRCA2 mutations. This is critical: We need to start testing for germline BRCA1/2 status in every patient with HER2-negative disease. This marks a change in diagnostic strategy. For a patient who is going to receive chemotherapy, germline testing does not need to be done immediately. But for patients who are not going to receive chemotherapy, germline testing results are key for determining if olaparib is a good option.

We can also think about other criteria for selecting patients who will benefit from olaparib. The OlympiA trial required hormone receptor–positive patients with previous adjuvant therapy to have ≥4 positive lymph nodes. But hormone receptor–positive patients with 1‑3 positive nodes are also at high risk, and I think it makes sense to give olaparib to these people as well. There is not a large difference between disease involving 4 vs 3 nodes, and I do not think we need to be so restrictive.

Finally, the safety data with olaparib were reassuring. I was glad to see a trend toward fewer central nervous system occurrences and such a small number of new primary malignancies, along with no difference in the rate of MDS/AML between those treated with olaparib vs placebo. These are exciting, transformative data for clinical practice.

monarchE: Subgroup Analysis of Abemaciclib + Adjuvant Endocrine Therapy vs Endocrine Therapy Alone in Patients With High-Risk, Hormone Receptor–Positive, HER2-Negative Early-Stage Breast Cancer Who Received Previous Neoadjuvant Chemotherapy

Joyce A. O’Shaughnessy, MD:
With larger and more highly proliferative cancers, clinical practice is moving toward greater use of preoperative chemotherapy. For example, the phase III KEYNOTE‑756 trial is assessing neoadjuvant and adjuvant pembrolizumab in patients with grade 3, ER‑positive disease.15 But with so many patients exhibiting residual disease after neoadjuvant therapy, there is a pressing need for a study focused on that high‑risk population in the adjuvant setting.

The phase III monarchE trial is another example of a study enriching for patients at high risk of very early recurrence.16,17 monarchE enrolled a patient population that is highly unlikely to benefit from endocrine therapy alone. This trial enrolled a total of 5637 patients with high-risk, node-positive, hormone receptor–positive, HER2-negative early-stage breast cancer who fell into 1 of 2 cohorts. Cohort 1 comprised individuals with ³4 positive lymph nodes or 1-3 positive lymph nodes plus histologic grade 3 disease and/or a tumor size ³5 cm. Cohort 2 comprised those with 1-3 positive lymph nodes, Ki67 ³20%, non–grade 3 disease, and a tumor size <5 cm. Patients were stratified by previous chemotherapy (neoadjuvant vs adjuvant vs none), menopausal status, and region, and they were randomized to receive 5-10 years of physician’s choice of endocrine therapy with or without abemaciclib 150 mg twice daily for up to 2 years.

In the primary outcome analysis, abemaciclib plus endocrine therapy demonstrated superior invasive DFS vs endocrine therapy alone (HR: 0.75; 95% CI: 0.60-0.93; P = .01), with a 2-year invasive DFS rate of 92.2% vs 88.7%, respectively.16 Similarly, the 2-year distant DFS rate was 93.6% vs 90.3% (HR: 0.72; 95% CI: 0.56-0.92; P = .010).18 That is an impressive benefit.

At ASCO 2021, Martin and colleagues17 presented results from the prespecified subgroup of patients who had received neoadjuvant chemotherapy, which comprised 36% of the ITT population (n = 2056). Most of this subgroup had received standard neoadjuvant therapy with an anthracycline plus taxane. I think it is very helpful that the monarchE study is targeting this very high-risk patient group.

monarchE NAC Subgroup Analysis: Patient Characteristics

Joyce A. O’Shaughnessy, MD:
In this subgroup, approximately one half of the patients in each arm were premenopausal, which was a greater proportion than in the ITT population.17 More than one half had ≥4 positive lymph nodes even after neoadjuvant therapy; I want to emphasize that not only did these patients have residual disease, but they had residual nodal disease. A small number of patients—3 in the abemaciclib arm and 6 in the endocrine therapy–only arm—had no positive lymph nodes in their breast, although they must have been node positive.

At diagnosis, the patients in this subgroup had a larger radiologic tumor size compared with the ITT population, with 28% to 30% having tumors ≥5 cm vs 17% to 18% in the ITT population. At surgery, 61% to 62% of patients in this subgroup had stage T2 or T3 disease.

monarchE NAC Subgroup Analysis: Invasive DFS (Primary Endpoint)

Joyce A. O’Shaughnessy, MD:

Turning now to the primary endpoint of invasive DFS in this subgroup, we see that adding abemaciclib to adjuvant endocrine therapy significantly reduced the risk of an invasive DFS event.17 The 2-year invasive DFS rate was 87.2% in the abemaciclib arm vs 80.6% with endocrine therapy alone (HR: 0.614; 95% CI: 0.473-0.797; nominal P = .0002). That means nearly 20% of patients who received endocrine therapy alone recurred within 2 years, which is a notable proportion of patients—particularly given that these patients all received optimal chemotherapy.

monarchE NAC Subgroup Analysis: Distant RFS

Joyce A. O’Shaughnessy, MD:

Similarly, adding abemaciclib to adjuvant endocrine therapy demonstrated a clinically meaningful reduction in the risk of a distant recurrence‑free survival (RFS) event vs endocrine therapy alone in this subgroup.17 The 2-year distant RFS rate was 89.5% in the abemaciclib arm vs 82.8% with endocrine therapy alone (HR: 0.609; 95% CI: 0.459-0.809; nominal P = .0006).

monarchE NAC Subgroup Analysis: Invasive DFS and Distant RFS by Tumor Size at Diagnosis and Surgery

Joyce A. O’Shaughnessy, MD:
Martin and colleagues17 conducted exploratory analyses of survival outcomes stratified by tumor size both at diagnosis and at surgery in this subgroup. Adding abemaciclib to adjuvant endocrine therapy reduced the risk of invasive DFS and distant RFS events regardless of the tumor size. Among patients in this subgroup who received abemaciclib, the 2-year invasive DFS and distant RFS rates were higher in patients with smaller tumors. Of interest, that was not always true among patients who received endocrine therapy alone.

monarchE NAC Subgroup Analysis: Treatment-Emergent AEs

Joyce A. O’Shaughnessy, MD:
Overall, the safety profile of abemaciclib added to adjuvant endocrine therapy was manageable.17 The main treatment-emergent AE with abemaciclib is diarrhea, which occurred at any grade in 82.5% of patients in this subgroup who received abemaciclib vs 8.1% of patients who received endocrine therapy alone. The rates of grade 3 diarrhea were 8.2% vs 0.2%, respectively.

monarchE NAC Subgroup Analysis: Clinical Implications

Joyce A. O’Shaughnessy, MD:
These data show that the addition of abemaciclib to adjuvant endocrine therapy improves outcomes in patients with high-risk early-stage breast cancer after neoadjuvant therapy.17 A 6.6% improvement in the 2-year invasive DFS rate in the highest‑risk patients is very impressive.

Regarding the diarrhea associated with abemaciclib, physicians have gained experience managing this AE using abemaciclib in the metastatic setting. We have learned to advise patients to use loperamide as needed and modify their diet toward bland, smaller meals. With these approaches, diarrhea tends to improve dramatically after approximately 4-6 weeks, so I think taking abemaciclib for up to 2 years is feasible in the setting of early-stage breast cancer. The positive efficacy data in this setting may also increase motivation to stay on the drug or dose reduce rather than discontinuing treatment for diarrhea.

For patients with preexisting gastrointestinal conditions, such as irritable bowel syndrome (IBD) or Crohn disease, abemaciclib might require some adjustments to minimize their risk of diarrhea. I would not hesitate to use abemaciclib in a patient with IBD, but I would talk with the patient about strategies for minimizing IBD symptoms when starting abemaciclib. With Crohn disease, ulcerative colitis, and other chronic diarrhea comorbidities, I would collaborate with the patient’s gastrointestinal specialist to optimize their therapy for the bowel disease and would also consider starting the patient with a lower dose of abemaciclib (eg, 100 mg twice daily). If their bowel disease is under control and they are not having diarrhea, I would be fine treating them with abemaciclib.

The MONARCH 2 and MONARCH 3 trials evaluating abemaciclib-based therapy in advanced disease reported an increased risk of a venous thromboembolism with abemaciclib (5% vs <1% with an aromatase inhibitor plus placebo or fulvestrant plus placebo).19 In this advanced setting, the rates of interstitial lung disease (ILD) are also low and very manageable. It is certainly important to be aware of ILD, but I do not consider it a major concern here.

Overall, I consider the tolerability and safety of abemaciclib plus endocrine therapy to be very good. The benefits of the regimen far outweigh the risks in these very high-risk patients. To me, the only remaining issue is whether patients should stay on abemaciclib longer, perhaps up to 5 years. Do you want to take a high-risk patient off a drug that is benefiting them? To answer this, we will have to wait and see how the long-term data hold up when we reach a median follow-up of 5 years.

With abemaciclib, we finally have a tool that is non–cross‑resistant between chemotherapy and endocrine therapy options. However, it has not yet received regulatory approval in this early disease setting. For our patients who are at the highest risk and resistant to endocrine therapy, this poses a dilemma. We have patients who, even after neoadjuvant therapy and surgery, have 10 positive nodes. We know these patients have metastatic disease; we are simply waiting for it to become detectable. Should we start abemaciclib now in those patients? Based on these monarchE data, that use seems justified. The results from the neoadjuvant subgroup suggest that the higher risk the patient, the more they may benefit from abemaciclib.

In my practice, I am only using abemaciclib in very high-risk patients who likely already have micrometastatic disease—patients who would have metastases revealed by a PET scan and MRI of the spine, even though their metastatic disease has not quite yet clinically manifested. I am otherwise being quite cautious in using abemaciclib. Fortunately, I have not had difficulty receiving insurance approval when I have described the patient population in my notes, probably because I use abemaciclib with an aromatase inhibitor—making this approach close enough to the package insert.

MONALEESA-3: Updated OS Analysis of Ribociclib Plus Fulvestrant vs Placebo Plus Fulvestrant in Postmenopausal Patients With Hormone Receptor–Positive, HER2-Negative Advanced Breast Cancer

Joyce A. O’Shaughnessy, MD:
Moving on to the advanced setting, we will first discuss the updated survival results from MONALEESA-3. In 2018, positive results from this trial led the FDA to expand the indications for ribociclib to include treatment in combination with fulvestrant of postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer as initial endocrine therapy or following progressive disease on endocrine therapy.20

MONALEESA-3 was a randomized, double-blind phase III trial that compared ribociclib vs placebo in combination with fulvestrant in men and postmenopausal women with hormone receptor–positive, HER2-negative advanced breast cancer.21 These patients had no previous chemotherapy and ≤1 line of previous endocrine therapy for advanced disease. The trial enrolled 726 patients, who were stratified by the presence of liver/lung metastases and whether they had previous endocrine therapy, then randomized 2:1 to oral ribociclib 600 mg vs placebo daily for 3 weeks on/1 week off, along with fulvestrant 500 mg injected on the first day of each cycle and an extra dose on Day 15 of the first cycle.

I believe there are several reasons the investigators chose to partner ribociclib with fulvestrant. First, fulvestrant is the standard drug used after progression on a first-line aromatase inhibitor. Second, although other trials such as MONARCH 2 and PALOMA‑3 have reported data on a CDK4/6 inhibitor plus fulvestrant in the second-line setting, we are lacking data on first-line use of fulvestrant.22-25 And third, this trial would provide useful treatment information when faced with a patient who could not tolerate aromatase inhibitors in the adjuvant setting.

The primary endpoint was investigator-assessed PFS. In the primary trial analysis, the addition of ribociclib to fulvestrant significantly improved PFS to a median of 20.5 vs 12.8 months with placebo plus fulvestrant (HR: 0.593; 95% CI: 0.480-0.732; P <.0010).21 This PFS benefit was maintained in a second interim analysis, which also demonstrated significantly prolonged median OS with ribociclib plus fulvestrant vs placebo plus fulvestrant in the overall population (not reached vs 40.0 months; HR: 0.72; 95% CI: 0.57-0.92; P = .00455).26

At ASCO 2021, Slamon and colleagues27,28 presented an exploratory analysis of additional endpoints, including updated OS, time to first chemotherapy, chemotherapy-free survival, PFS2, subsequent antineoplastic therapy, and safety, after a median follow-up of 56.3 months.

MONALEESA-3 Update: OS in Overall Population

Joyce A. O’Shaughnessy, MD:
The updated OS results maintained the survival advantages previously reported with ribociclib plus fulvestrant.26,28 The 5-year OS rate was 46% in patients who received ribociclib plus fulvestrant vs 31.1% with placebo plus fulvestrant. There was a greater than 1 year improvement in median OS with ribociclib; median OS was 53.7 months in the ribociclib arm vs 41.5 months in the placebo arm (HR: 0.726; 95% CI: 0.588-0.897).

MONALEESA-3 Update: OS Subgroup Analyses

Joyce A. O’Shaughnessy, MD:
In the subgroup analyses, the OS data for the first-line population are very encouraging.28 The median OS was not reached for patients receiving first-line ribociclib plus fulvestrant vs 51.8 months with placebo plus fulvestrant (HR: 0.640; 95% CI: 0.464-0.883). The second-line data are also good, with a median OS of 39.7 vs 33.7 months, respectively (HR: 0.780; 95% CI: 0.587-1.037). This is the first survival data we have in the first‑line setting in a postmenopausal population. Even though the first‑line population was not that large in this study, these results show that ribociclib plus fulvestrant is a very powerful combination for these patients.

Of importance, we also saw a benefit with ribociclib in patients who have primary endocrine therapy–resistant disease, although we should note that this was a small population of only 78 patients. This contrasts with the final survival analysis of the PALOMA-3 trial presented at ASCO 2021, where the benefit from palbociclib was only observed in the endocrine therapy–sensitive population and not the endocrine therapy–resistant population.29 However, the MONARCH2 trial also showed an OS benefit with abemaciclib plus fulvestrant in patients with primary endocrine therapy–resistant disease.23

In a 2020 pooled analysis of MONALEESA‑3 and MONALEESA‑7, ribociclib plus fulvestrant also showed a substantial survival benefit in patients with liver metastases.30

Overall, these results highlight how ribociclib plus fulvestrant is a useful combination for the patients with the worst prognosis.

MONALEESA-3 Update: Time to First Chemotherapy, Chemotherapy-Free Survival, PFS2

Joyce A. O’Shaughnessy, MD:
We can also see a clear benefit with ribociclib plus fulvestrant in time to first chemotherapy, chemotherapy-free survival, and PFS2.28 Compared with placebo plus fulvestrant, ribociclib plus fulvestrant delayed first chemotherapy by nearly 20 months and extended chemotherapy-free survival by more than 10 months. The PFS2 benefit was especially pronounced in the first-line setting (HR: 0.63; 95% CI: 0.47-0.84).

MONALEESA-3 Update: Subsequent Antineoplastic Treatment

Joyce A. O’Shaughnessy, MD:
Most patients discontinued the study regimen in both arms, with 81.9% of those who received ribociclib and 86.4% of those who received placebo receiving subsequent therapy.28 The most common subsequent treatments were chemotherapy alone or hormone therapy alone or in combination with another treatment. In the ribociclib arm, 14% of patients and 30% of those who received placebo went on to receive a subsequent CDK4/6 inhibitor, most commonly palbociclib.

MONALEESA-3 Update: AEs of Special Interest

Joyce A. O’Shaughnessy, MD:
As we would expect, the addition of ribociclib to fulvestrant was associated with higher rates of hematologic toxicities vs the addition of placebo.28 Nearly 60% of patients in the ribociclib arm experienced grade ≥3 neutropenia and 17% experienced grade ≥3 leukopenia vs 0.8% and 0% in the placebo arm, respectively.

On the other hand, the rate of pulmonary embolism in the ribociclib arm was low at 0.4%. Hepatobiliary toxicity with ribociclib was slightly elevated, with 10.6% experiencing grade 3 events and 3.3% experiencing grade 4 events. In the ribociclib arm, 10 patients (2.1%) experienced any-grade ILD/pneumonitis, but only 2 (0.4%) were grade 3; in the placebo arm, the overall rate was 0.8% with no high-grade events. Pulmonary toxicity looks high at 38.1% in the ribociclib arm, but it was observed in 32.0% of patients in the placebo arm as well. Overall, these numbers are reassuring.

Ribociclib was also associated with QT interval prolongation in 8.5% of patients; these were mostly low-grade events, but 3.1% did experience grade ≥3.

These results tell us that it is important to perform EKGs and monitor liver function tests in patients taking this agent. That being said, these events are related to peak plasma effects and can typically be managed with dose reductions.20 Like most agents, once we know what to monitor for, the toxicities associated with ribociclib are generally manageable.

MONALEESA-3 Update: Clinical Implications

Joyce A. O’Shaughnessy, MD:
The key takeaway from this MONALEESA-3 update is that ribociclib plus fulvestrant is a very good first‑line combination in hormone receptor–positive, HER2-negative advanced breast cancer.

Doctors and patients now have treatment choices in this setting. We have 3 CDK4/6 inhibitors FDA approved for breast cancer—abemaciclib,19 palbociclib,31 and ribociclib20—and I think there are important differences among them.

For patients with less aggressive disease that is endocrine therapy sensitive and who may have had a long disease‑free interval, perhaps with bone‑only disease, these patients do very well with palbociclib plus letrozole. We know from the PARSIFAL study that there is no difference in benefit when pairing palbociclib with fulvestrant vs letrozole; furthermore, patients on palbociclib plus letrozole do not have to come in for injections.32 Compared with the other CDK4/6 inhibitors, palbociclib has less liver toxicity and does not require EKG monitoring.33

Abemaciclib or ribociclib are good options for patients with more aggressive disease or endocrine therapy resistance. The PALLAS and PENELOPE‑B trials suggest that palbociclib is not the optimal drug for patients with more aggressive disease at risk for early recurrence.34,35 I feel that the abemaciclib data from MONARCH-2 and MONARCH-3 show the strongest benefit with this agent for patients with liver metastases, high‑grade disease, short disease‑free interval, and primary endocrine therapy resistance.23,36,37 The monarchE study is now showing that abemaciclib benefits patients experiencing disease recurrence within 2 years. For these patients, I would lean toward using abemaciclib, but I think that ribociclib is still an excellent choice in the first‑line setting.

Ribociclib straddles both worlds, with encouraging data in both endocrine therapy–sensitive and endocrine therapy–resistant disease, and presents a very good option for patients.

ASCENT: Patient Subgroup Analyses of Sacituzumab Govitecan vs Chemotherapy in Metastatic TNBC

Joyce A. O’Shaughnessy, MD:
ASCENT was a phase III trial comparing the TROP-2–directed antibody–drug conjugate sacituzumab govitecan vs single-agent chemotherapy in patients with unresectable locally advanced or metastatic TNBC previously treated with ≥2 systemic therapies.38  This trial enrolled 529 patients who were stratified by geography, number of previous lines of chemotherapy, and presence of brain metastases, then randomized 1:1 to receive sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of each 21-day cycle vs physician’s choice of single-agent chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary endpoint was PFS by independent review in patients without brain metastases. Secondary endpoints included investigator-assessed PFS, OS, overall response rate (ORR), duration of response (DoR), time to response, and safety.

The results of the primary analysis were very exciting. Sacituzumab govitecan significantly improved both median PFS (5.6 vs 1.7 months with chemotherapy; HR: 0.41; 95% CI: 0.32-0.52; P <.001) and OS (12.1 vs 6.7 months, respectively; HR: 0.48; 95% CI: 0.38-0.59; P <.001). Sacituzumab govitecan also exhibited an improved ORR of 35% vs 5% with chemotherapy. ASCENT was halted early based on efficacy by unanimous recommendation of the data and safety monitoring committee. Based on these positive results, in April 2021 the FDA expanded the indications for sacituzumab govitecan to include treatment of adults with unresectable locally advanced or metastatic TNBC previously treated with ≥2 previous systemic therapies, of which ≥1 therapy must have been for metastatic disease.39,40

At ASCO 2021, my colleagues and I presented several subgroup analyses of the ASCENT trial in patients aged younger than 65 years vs 65 years or older41; by individual chemotherapy agent42; and in patients in the second-line setting who had disease recurrence within 12 months of neoadjuvant or adjuvant therapy.43

ASCENT Subgroup Analyses: Baseline Characteristics of Patients Without Brain Mets Aged 65 Years or Older

Joyce A. O’Shaughnessy, MD:
The first subgroup analysis that we will discuss was presented by Kalinsky and colleagues41 on the efficacy and safety of the study treatments in patients without brain metastases who were aged 65 years or older. The baseline characteristics of this subgroup were comparable to the overall trial population. Sacituzumab govitecan was received by 44 patients in this subgroup. Of the 46 patients who received chemotherapy as study treatment, 46% received eribulin, 22% each received vinorelbine and gemcitabine, and 11% received capecitabine.

ASCENT Subgroup Analyses: PFS in Older vs Younger Subgroups

Joyce A. O’Shaughnessy, MD:
Looking at PFS in this subgroup, we can see that the older women had a greater benefit with sacituzumab govitecan than the younger subgroup.41 The median PFS with sacituzumab govitecan was 7.1 vs 2.4 months with chemotherapy in patients aged 65 years or older and 4.6 vs 1.7 months, respectively, in patients aged younger than 65 years. This corresponded to statistically significant reductions in risk of 78% for the older subgroup (P <.0001) and 54% in the younger subgroup (P <.0001).

ASCENT Subgroup Analyses: OS in Older vs Younger Subgroups

Joyce A. O’Shaughnessy, MD:
Similarly, OS outcomes with sacituzumab govitecan were better in the older patient group.41 The median OS with sacituzumab govitecan was 15.3 vs 8.2 months with chemotherapy in patients aged 65 years or older and 11.2 vs 6.6 months, respectively, in patients aged younger than 65 years. Again, sacituzumab govitecan was associated with a significantly greater reduction in risk of death in the older subgroup (risk reduction: 63%; P = .0003) compared with the younger subgroup (risk reduction: 50%; P <.0001). In general, the PFS and OS benefits with sacituzumab govitecan vs chemotherapy were similar between the older subgroup and the overall population.

ASCENT Subgroup Analyses: Responses in Older vs Younger Subgroups

Joyce A. O’Shaughnessy, MD:
In both age subgroups, sacituzumab govitecan improved response rates compared with chemotherapy.41 In the older subgroup, the ORR with sacituzumab govitecan was 50%, including complete response (CR) in 7%. None of the older patients receiving chemotherapy achieved a response. In the younger subgroup, the ORR with sacituzumab govitecan was 31%, with CR in 4%; in this subgroup, 6% of patients receiving chemotherapy experienced a response, including CR in 1%. Among patients receiving sacituzumab govitecan, the median DoR was 7.1 months in the older subgroup vs 5.8 months in the younger subgroup.

In the very small subset of patients aged 75 years or older, 2 out of 7 who received sacituzumab govitecan experienced a best response of partial response (PR) vs none of the 11 patients who received chemotherapy.

ASCENT Subgroup Analyses: Safety by Age Group

Joyce A. O’Shaughnessy, MD:
The older subgroup had higher rates of toxicity in both treatment arms.41 Older patients who received sacituzumab govitecan did not have notably more toxicity than those who received chemotherapy, although grade ≥3 treatment-related adverse events (TRAEs) occurred in 63% with sacituzumab govitecan vs 54% with chemotherapy. There was 1 death attributed to a TRAE of neutropenic sepsis deemed related to eribulin. Of note, even the oldest patients were able to tolerate this treatment; the frequency of AEs in patients aged 75 years or older was similar to the frequency in patients aged 65 years or older.

However, older patients did require more dose reductions due to AEs than younger patients. Among those receiving sacituzumab govitecan, 35% of older patients needed dose reductions vs 19% of younger patients. Older patients in the chemotherapy arm also required more dose reductions, although the numerical difference between the age groups was smaller (33% vs 24%, respectively). In the older subgroup, key TRAEs that led to dose reduction with sacituzumab govitecan included neutropenia, fatigue/asthenia, diarrhea, febrile neutropenia, and nausea.

Of importance, very few patients in any of the subgroups stopped treatment due to toxicity. Overall, sacituzumab govitecan treatment was very tolerable and feasible, even in the oldest patients.

ASCENT Subgroup Analyses: Efficacy of Sacituzumab Govitecan vs Individual Chemotherapy Agent in Patients Without Brain Mets

Joyce A. O’Shaughnessy, MD:
My colleagues and I presented the next subgroup analysis, which focused on the efficacy and safety of individual chemotherapy agents in patients without brain metastases.42 Recall that the chemotherapy arm of the ASCENT trial allowed physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine. Baseline characteristics were balanced between the sacituzumab govitecan arm and the individual chemotherapy regimens.

Overall, the results of this subgroup analysis showed that regardless of your preferred chemotherapy in the physician’s choice arm, sacituzumab govitecan demonstrated better outcomes vs each of the individual agents. The median PFS was 5.6 months with sacituzumab govitecan vs 1.6-2.7 months with individual chemotherapy agents (HR: 0.41; 95% CI: 0.32-0.52; P <.001). The median OS was 12.1 vs 5.2-8.4 months, respectively (HR: 0.48; 95% CI: 0.38-0.59; P <.001). The ORR was 35% with sacituzumab govitecan vs only 3% to 6% with each of the agents.

ASCENT Subgroup Analyses: Safety of Sacituzumab Govitecan vs Individual Chemotherapy Agent

Joyce A. O’Shaughnessy, MD:
The safety profiles of the individual agents were consistent with those seen in the overall pooled chemotherapy arm.42 Sacituzumab govitecan was associated with higher rates of grade ≥3 hematologic toxicities, including neutropenia, leukopenia, and febrile neutropenia; more patients used granulocyte colony-stimulating factor for neutropenia with sacituzumab govitecan than with chemotherapy. However, the toxicities were manageable, although as I noted previously, there was 1 treatment-related death due to neutropenic sepsis attributed to eribulin.

ASCENT Subgroup Analyses: Sacituzumab Govitecan vs Chemotherapy in Patients With Recurrent TNBC After Recent (Neo)adjuvant Therapy

Joyce A. O’Shaughnessy, MD:
Turning now to the final subgroup analysis by Carey and colleagues,43 this subanalysis involved a relatively small number of patients—33 in the sacituzumab govitecan arm and 32 in the chemotherapy arm—who experienced recurrence within 12 months of adjuvant or neoadjuvant chemotherapy. This is a very challenging group of patients to treat.

The baseline characteristics of this subgroup were comparable to those of the overall population. Much like the overall population, outcomes in this subgroup strongly favored sacituzumab govitecan. The median PFS was 5.7 months with sacituzumab govitecan vs just 1.5 months with chemotherapy (HR: 0.41; 95% CI: 0.22-0.76). The median OS was 10.9 vs 4.9 months, respectively (HR: 0.51; 95% CI: 0.28-0.91). The ORR was 30% with sacituzumab govitecan vs 3% with chemotherapy.

ASCENT Subgroup Analyses: Safety in Patients With Recurrent TNBC After Recent (Neo)adjuvant Therapy

Joyce A. O’Shaughnessy, MD:
No unexpected safety signals were observed in this subgroup.43 The safety profile with sacituzumab govitecan was consistent with that in the overall population.

ASCENT Subgroup Analyses: Clinical Implications

Joyce A. O’Shaughnessy, MD:
Sacituzumab govitecan is clearly an improvement over standard chemotherapy options for this patient population, offering a pronounced survival benefit even in those with poor prognosis and who are likely to experience rapid disease recurrence. I think this agent bodes well for the curative setting for patients who have residual disease after preoperative therapy.

These results show us that sacituzumab govitecan is highly non–cross‑resistant even in the most difficult-to-treat patient population, which is very encouraging. When patients with TNBC come back with recurrence within a year, I would like to give those patients first‑line sacituzumab govitecan. The current indication requires ≥2 previous lines of therapy, of which ≥1 must have been for metastatic disease. But these ASCENT subgroup analyses clearly demonstrate how poor the outcomes are with chemotherapy for high-risk patients. Sacituzumab govitecan could fill the need for a more effective first-line therapy for this high-risk population.

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