Interim findings from 2 expansion cohorts of the phase 1/2 innovaTV 205 trial (NCT03786081) showed that tisotumab vedotin, in combination with carboplatin as frontline therapy and pembrolizumab (Keytruda) as second- or third-line therapy, induced noteworthy responses in patients with recurrent or metastatic cervical cancer, according to findings presented at the 2021 ESMO Congress.

At a median follow-up of 7.9 months in the tisotumab vedotin/carboplatin cohort (n = 33), the objective response rate (ORR) was 55% (n = 18; 95% CI, 36%-72%), comprising 4 complete responses (12%; CRs) and 14 partial responses (42%; PRs); there were 12 cases of stable disease (36%; SD).

At a median follow-up of 13.0 months in the tisotumab vedotin/pembrolizumab cohort (n = 34), the ORR was 38% (n = 13; 95% CI, 22%-56%), comprising 2 CRs (6%) and 11 PRs (32%); there were 12 cases of SD (35%).

“Acknowledging the limited sample size, both first-line tisotumab vedotin plus carboplatin and second- and third-line tisotumab vedotin plus pembrolizumab showed encouraging and durable antitumor activity in patients with recurrent or metastatic cervical cancer,” said lead study author Ignace B. Vergote, MD, PhD, head of the Department of Obstetrics and Gynecology and Gynecologic Oncology, Catholic University of Leuven, in Belgium, in a virtual presentation of the data.

Frontline platinum and taxane chemotherapy plus bevacizumab (Avastin), if eligible, has improved survival for patients with recurrent or metastatic cervical cancer, but more effective and safer treatments are needed.

Tisotumab vedotin, an antibody-drug conjugate (ADC) that targets tissue factor, is under study for the treatment of several solid tumors, including cervical cancer.

On April 9, 2021, the FDA granted a priority review to the biologics license application (BLA) for tisotumab vedotin as a potential treatment for patients with recurrent or metastatic cervical cancer with progressive disease on, or following, chemotherapy.

The application was based on findings from the phase 2 innovaTV 204 trial (NCT03438396), which showed that 2 mg/kg of intravenous (IV) treatment with the ADC given every 3 weeks led to an ORR of 24% and a median duration of response (DOR) of 8.3 months in previously treated patients with recurrent or metastatic cervical cancer.

 Additionally, the agent had a manageable safety profile.

The recommended phase 2 dose for tisotumab vedotin in combination with pembrolizumab, carboplatin, and bevacizumab in patients with recurrent or metastatic cervical cancer enrolled in innovaTV 205 was recently reported at the 2021 International Gynecologic Cancer Society Annual Global Meeting.

The focus of the present analysis is on the carboplatin and pembrolizumab cohorts. In the carboplatin cohort, patients with no prior systemic therapy for recurrent or metastatic cervical cancer received 2 mg/kg of IV tisotumab vedotin every 3 weeks plus IV carboplatin at an area under the curve of 5 every 3 weeks. In the pembrolizumab cohort, patients with recurrent or metastatic cervical cancer with disease progression on or after 1 or 2 prior systemic treatments received 2 mg/kg of IV tisotumab vedotin every 3 weeks plus 200 mg of IV pembrolizumab every 3 weeks.

ORR per RECIST v1.1 criteria served as the primary end point; secondary end points included adverse effects (AEs) and laboratory parameters, DOR, time to response, progression-free survival (PFS), overall survival (OS), and pharmacokinetic concentrations and anti-drug antibodies associated with tisotumab vedotin.

The baseline demographics and clinical characteristics indicated that in the carboplatin and pembrolizumab cohorts, the median age was 51.0 vs 47.0 years, respectively. The majority of patients in both cohorts had an ECOG performance status of 0, squamous histology, and prior chemoradiation.

In the pembrolizumab cohort, 81.5% of patients (n = 22) were PD-L1 positive, and the majority of patients had received 1 line of prior treatment (n = 26; 74.3%) and prior bevacizumab (n = 18; 51.4%).

Additional results showed in the tisotumab vedotin/carboplatin cohort, the median PFS was 9.5 months (95% CI, 4.0-not reached [NR]), and the median OS was NR (range, 0.8+ to 14.1+). The median DOR was 8.3 months (95% CI, 4.2-NR). The median time to response was 1.4 months (range, 1.1-4.4).

The median duration of exposure was 4.9 months (range, 1-9) with tisotumab vedotin vs 4.1 months (range 1-9) with carboplatin. The median number of cycles initiated was 6.0 (range, 1-12) with tisotumab vedotin and carboplatin.

In the tisotumab vedotin/pembrolizumab cohort, the median PFS was 5.6 months (95% CI, 2.7-13.7), and the median OS was NR (range, 1.3-17.5+). The median DOR was 13.8 months (95% CI, 2.8-NR). The median time to response was 1.4 months (range, 1.3-5.8).

The median duration of exposure was 4.1 months (range, 1-16) with tisotumab vedotin vs 4.3 months (range 1-17) with pembrolizumab. The median number of cycles initiated was 6.0 (range, 1-21) with tisotumab vedotin and 6.0 months (range, 1-25) with pembrolizumab.

In terms of safety, in the tisotumab vedotin/carboplatin cohort, all patients had at least 1 treatment-emergent AE (TEAE); 97% (n = 32) of these events were related to tisotumab vedotin. Grade 3 or greater AEs occurred in 78.8% (n = 26) of patients; 57.6% (n = 19) of these events were related to tisotumab vedotin.

Serious AEs occurred in 42.4% of patients (n = 14); 15.2% (n = 5) of these events were related to tisotumab vedotin. No patients in the cohort had a fatal event.

In the tisotumab vedotin/pembrolizumab cohort, all patients had at least 1 TEAE; 97.1% (n = 34) of these events were related to tisotumab vedotin. Grade 3 or greater AEs occurred in 74.3% (n = 26) of patients; 45.7% (n = 16) of these events were related to tisotumab vedotin.

Serious AEs occurred in 51.4% of patients (n = 18); 14.3% (n = 5) of these events were related to tisotumab vedotin. One fatal event was reported in the cohort but was not determined to be related to tisotumab vedotin.

AEs that occurred in approximately half of patients in both cohorts included ocular events, bleeding events, and peripheral neuropathy.

“These data support further research to evaluate additional tisotumab vedotin combinations as interventions in recurrent or metastatic cervical cancer. The dose expansion cohort of tisotumab vedotin and pembrolizumab in first-line recurrent or metastatic cervical cancer in this study is being evaluated and will be reported at a future medical meeting,” concluded Vergote.

1. Vergote IB, Monk BJ, O’Cearbhaill RE, et al. Tisotumab vedotin (TV) + carboplatin (carbo) in first-line (1L) or + pembrolizumab (pembro) in previously treated (2L/3L) recurrent or metastatic cervical cancer (r/mCC): interim results of ENGOT-Cx8/GOG-3024/innovaTV 205 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 723MO.

2. Seagen and Genmab announce US FDA filing acceptance for priority review of tisotumab vedotin biologics license application for patients with recurrent or metastatic cervical cancer. News release. April 9, 2021. Accessed September 19, 2021. 

3. Coleman RL, Lorusso D, Gennigens C, et al. Tisotumab vedotin in previously treated recurrent or metastatic cervical cancer: results from the phase 2 innovaTV 204/GOG-3023/ENGOT-cx6 study. 

. 2020;31(suppl 4):S1162-S1163. doi:10.1016/j.annonc.2020.08.2262

4. Monk BJ, Van Gorp T, Lorusso D, et al. Tisotumab vedotin + bevacizumab or pembrolizumab or carboplatin in recurrent/metastatic cervical cancer: phase 1b/2 ENGOT-Cx8/GOG-3024/innovaTV 205 study dose-escalation results. Presented at: 2021 IGCS Annual Global Meeting; August 30-September 2, 2021; virtual. Plenary 5.

Articles

Interim findings presented at the 2021 ESMO congress suggest that tisotumab vedotin plus frontline carboplatin and second-/third-Line pembrolizumab may be a suitable treatment option for recurrent/metastatic cervical cancer. 

Tisotumab Vedotin Combinations May Be Associated with Meaningful Responses in Recurrent/Metastatic Cervical Cancer

Twenty percent of the patients with malignant pleural mesothelioma at the Vall d’Hebron University Hospitals became infected with COVID-19 during the first year of the pandemic. This led to both a high hospitalization and mortality rate among this population, showed findings from a descriptive study that was presented during the 2021 World Conference on Lung Cancer.

The results showed that 7 patients (18%) were diagnosed with COVID-19 by a reverse transcription polymerase chain reaction test; the median overall survival (OS) of these patients was 17.8 months from cancer diagnosis.

Five of these patients died; reasons for death included COVID-19 (n = 4) and progressive disease (n = 1). The median OS of these patients was 0.4 months since COVID-19 diagnosis.

Patients with thoracic malignancies may be particularly vulnerable to COVID-19, lead study author Susana Cedres, MD, PhD, a medical oncologist in the Thoracic Tumors Unit at the Vall d’Hebron University Hospital and Institute of Oncology in Barcelona, Spain, said in explaining the basis for the study in a virtual presentation of the data.

Although the effect of SARS-CoV-2 infection has previously been evaluated in 200 patients with thoracic malignancies in the TERAVOLT registry, only 8 patients with malignant pleural mesothelioma were included in the assessment.

In the United States, tuberculosis, drug use disorder, hepatitis, HIV/AIDS, cardiomyopathy, diabetes, and malignant pleural mesothelioma has been associated with worse COVID-19 related mortality outcomes.

Therefore, investigators sought to tease out the effect of COVID-19 infection on patients with malignant pleural mesothelioma at Vall d’Hebron University Hospital.

In the study, investigators compiled the medical records of 38 patients with malignant pleural mesothelioma who had visited Vall d’Hebron University Hospital between March 2020 and March 2021.

The data that was collected included information on demographics, comorbidities, oncological background, and course of COVID-19 illness.

Regarding the patient characteristics of those diagnosed with COVID-19, the median age was 62 years (range, 62-87). The study population comprised 4 men (57%) and 4 women (43%). Four patients were non-smokers (57%), and 3 patients were current or former smokers (43%).

All 7 patients (100%) had epithelioid histology. Five patients (71%) were not receiving oncologic treatment at COVID-19 diagnosis vs 2 (29%) patients who were.

Additionally, investigators stratified patients by 6 characteristics at COVID-19 diagnosis: comorbidity, concomitant treatment, clinical onset, laboratory, hospitalization, and respiratory symptoms.

Regarding comorbidities, 4 patients (57%) had a cardiovascular comorbidity, 1 patient (14%) had a respiratory comorbidity, and 1 patient (14%) had a renal comorbidity.

Regarding concomitant treatments, 4 patients (57%) were receiving antiplatelet or anticoagulant therapy, 2 patients (29%) were receiving antidiabetic therapy, and 1 patient (14%) was receiving corticosteroids.

Regarding clinical onset, 4 patients (57%) had symptomatic onset, and 3 patients (43%) had asymptomatic onset.

Regarding laboratory results, 6 patients (85%) had lymphopenia, 4 patients (57%) had high d-dimer, and 4 patients (57%) had high IL-6.

Regarding hospitalization, 6 patients (85%) were hospitalized, and 1 patient (14%) was not.

Regarding respiratory symptoms, 4 patients (57%) had bilateral pneumonia, and 6 patients (85%) had oxygen support.

Cedres S, Assaf JD, Iranzo P, et al. Clinical characteristics and outcomes in patients with malignant pleural mesothelioma (MPM) with COVID-19 infection. Presented at: 2021 World Conference on Lung Cancer; September 8-14, 20

Patients with both COVID-19 and malignant pleural mesothelioma showed high rates of hospitalization and mortality. 

Study Identifies High Mortality Rates in Patients with COVID-19 and Malignant Pleural Mesothelioma 

Zanubrutinib (Brukinsa) is now FDA approved for the treatment of adults with Waldenström Macroglobulinemia.

“We are delighted by today’s FDA approval for [zanubrutinib] in its second indication, offering a new treatment option with demonstrated efficacy and safety benefits for patients with Waldenström’s macroglobulinemia. As shown in the ASPEN trial [NCT03053440], [zanubrutinib] can improve treatment outcomes for these patients and potentially make a positive impact on their lives,” Jane Huang, MD, chief medical officer of Hematology at BeiGene, said in a press release.

The regulatory decision was primarily based on data from the multicenter, open-label, phase 3 ASPEN trial, which compared zanubrutinib with ibrutinib (Imbruvica) in patients with Waldenström macroglobulinemia.

 presented during the 2020 ASCO Virtual Scientific Program showed that the BTK inhibitor was associated with a higher complete response or very good partial response (CR+VGPR) rate of 28.4% vs 19.2% with ibrutinib (

 = .0921).2 However, this did not meet the primary study hypothesis, which was superiority with CR+VGPR in the zanubrutinib arm per an independent review committee.

Moreover, the best overall response rate per investigator assessment in the zanubrutinib and ibrutinib arms at the time of the August 2019 data cutoff, were 28.4% vs 17.2%, respectively (

 = .0437); at the time of the January 2020 data cutoff, these rates were 30.4% versus 18.2%, respectively (

In the trial, 201 patients with Waldenström macroglobulinemia and a 

 mutation were randomized 1:1 to receive either 160 mg of zanubrutinib twice daily (n = 102) or 420 mg of ibrutinib once daily (n = 99). Patients were stratified based on 

 vs missing) and how many previous therapies were received (0 vs 1 to 3 vs 3 or more). Another cohort of 28 patients who did not harbor 

 mutations were given 160 mg of zanubrutinib daily.

The primary objective of the trial was to compare the efficacy of zanubrutinib with ibrutinib. The primary end point was CR+VGPR rate in patients with activating mutations. Key secondary objectives included further comparing the efficacy, clinical benefit, and anti-lymphoma effects of zanubrutinib vs ibrutinib and to explore the safety and tolerability of the 2 agents. Exploratory objectives comprised characterization of the pharmacokinetics of zanubrutinib in this patient population and to compare quality of life by EORTC QLQ-C30 and EQ-5D.

One-third, or 33.3% of patients who received zanubrutinib were over 75 years compared with 22.2% of those given ibrutinib. Moreover, patients on the zanubrutinib arm had higher rates of anemia than those on the ibrutinib arm, at 65.7% vs 53.5%, respectively. Most patients across the treatment arms received 1 to 3 previous therapies.

Regarding safety, those who had zanubrutinib experienced lower rates of atrial fibrillation compared with ibrutinib (2.0% vs 15.3%, respectively), as well hypertension (10.9% vs 17.3%), major bleeding (5.9% vs 9.2%), grade 3 or higher toxicities (58.4% vs 63.3%), adverse effects resulting in treatment discontinuation (4.0% vs 9.2%), and toxicity-related death (1.0% vs 4.1%).

Although rates of grade 3 or higher infections were comparable between the investigational and control arms, at 17.8% and 19.4%, respectively, zanubrutinib proved to have a higher rate of neutropenia vs ibrutinib, at 29.7% vs 13.3%, respectively.

U.S. FDA Grants BRUKINSA® (zanubrutinib) approval in Waldenström’s Macroglobulinemia. News release. BeiGene. September 1, 2021. Accessed September 1, 2021. 

Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström macroglobulinemia (WM). 

. 2020;38(suppl 15):8007. doi:10.1200/JCO.2020.38.15_suppl.8007

This article was originally published on OncLive as “FDA Approves Zanubrutinib in Waldenström Macroglobulinemia”

FDA Green Lights Zanubrutinib for Adults with Waldenström Macroglobulinemia

KRAS G12C inhibitors have developed greatly over recent years, expanding the number of effective targeted therapies in non-small cell lung cancer (NSCLC). Researchers expect that efforts to assess predictive co-mutations, acquired resistance, and combination strategies will continue to advance the effectiveness of these agents even more, explained Karen L. Reckamp, MD.

“We’re still in the very early stages of understanding KRAS signaling, even though it has been studied for decades. We’re really at the tip of the iceberg in evaluating KRAS in NSCLC. The next steps are going to include defining the subsets that benefit and can be predictive for benefit to specific inhibitors or specific combinations,” said Reckamp, director of the Division of Medical Oncology, the associate director of Clinical Research, and the medical oncology director of the Lung Institute at the Samuel Oschin Cancer Center at Cedars-Sinai Medical Center.

In a presentation during the keynote lecture on KRAS pathway inhibitors in lung cancer at the 

 International Lung Cancer Congress®, a program hosted by the Physicians’ Education Resource®, LLC, Reckamp highlighted the data with adagrasib and sotorasib (Lumakras), 2 highly selective and potent oral small-molecule KRAS G12C inhibitors, and outlined ongoing research targeted toward improving patient selection and efficacy of these agents.

In the registrational phase 1/2 KRYSTAL-1 trial (NCT03785249), adagrasib was evaluated in previously treated patients with 

Among 51 patients evaluable for efficacy, 45% achieved a partial response to adagrasib (n = 23) at a twice-daily dose of 600 mg, with a disease control rate (DCR) of 96% (n = 49).1

“Most patients benefitted from this therapy, and the majority of patients had some tumor shrinkage,” said Reckamp.

“We’ve also seen some data with adagrasib on co-mutations, [suggesting that] KEAP1 mutations seem to be problematic and may be less responsive [to adagrasib] than patients with 

On June 25, 2021, the FDA granted a breakthrough therapy designation to adagrasib for use in patients with KRAS G12C–mutated NSCLC following previous systemic therapy based on findings from KRYSTAL-1.2

In the phase 2 CodeBreaK 100 trial (NCT03600883), sotorasib was evaluated in patients with pretreated 

 G12C–mutated NSCLC. Updated findings from the trial, which were presented during the 

, demonstrated that at a median follow-up of 15.3 months, sotorasib, given at 960 mg once daily, was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]) and a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2).3

The objective response rate (ORR) was 37.1% (95% CI, 28.6%-46.2%), which included 4 complete responses (CRs). The median duration of response (DOR) was 11.1 months (95% CI, 6.9–NE), and the DCR rate was 80.6% (95% CI, 72.6%-87.2%).3

The clinical activity observed with sotorasib was consistent across prespecified subgroups, including age, ECOG performance status, number of prior lines of treatment, and prior PD-1/PD-L1–directed therapy alone or in combination with platinum-based chemotherapy. Notably, for patients who received a prior PD-1/PD-L1 inhibitor but not chemotherapy, the ORR was 69.2% (95% CI, 38.6%-90.9%) and the median OS was 17.7 months (95% CI, 11.7–NE).

“As we get larger trials, we can start to tease out these subgroups a little bit more to see who is actually responding. For patients who had had only prior [treatment with a] PD-1 [inhibitor], we see the highest response rate and the longest OS,” said Reckamp.

Based on earlier findings of CodeBreaK 100, the FDA approved sotorasib in May 2021 as the first targeted treatment for adult patients with NSCLC whose tumors harbor 

 G12C mutations and who have received at least 1 prior systemic therapy.4

Additionally, sotorasib demonstrated activity in molecularly-defined subgroups from exploratory analyses within the study, including in those with 

 wild-type disease (n = 22), the ORR with sotorasib was 50%, the median PFS was 11.0 months, and the median OS was 15.3 months.3 The ORR was 23% in patients with 

-mutant disease (n = 7); and 42% in patients with 

 wild-type disease (n = 62). Also in these subgroups, the median PFS was 2.6 months, 5.5 months, and 6.8 months, respectively; the median OS was 4.8 months, 7.5 months, and not evaluable, respectively.

“The numbers are incredibly small, and I hesitate to make decisions based on these mutations, but we will be looking at these further,” said Reckamp.

To that end, the phase 2 Lung-MAP S1900E study (NCT04625647) is evaluating sotorasib specifically in patients with co-mutations, including 

Another research avenue is exploring the utility of SHP2 inhibitors in overcoming resistance to KRAS G12C inhibitors, said Reckamp. In an ongoing phase 1 trial (NCT03114319), the orally bioavailable, selective, first-in-class allosteric inhibitor of wild-type 

, TNO155, is being studied in patients with advanced solid tumors.

Initial findings from the study, which were presented during the 2021 ASCO Annual Meeting, demonstrated a best response of stable disease, lasting a median duration of 5.6 months (95% CI, 1.6-32.9).5

In another phase 1 trial (NCT03634982), results of which were presented during the 2021 AACR Annual Meeting, demonstrated a DCR of 75% (n = 12 of 16) with the SHP2 inhibitor RMC-4630 in patients with 

However, the modest single-agent activity of these agents and emerging data regarding the complexity of resistance to KRAS G12C inhibitors, including the activation of other RAS isoforms, other 

 activating mutations, the loss of G12C through a mutational switch to a different 

 mutation, and alteration of drug binding through 

 Y96D,7,8 underscore the importance of identifying effective combination strategies, explained Reckamp.

“Now, we’re trying to find the most rationale combinations by looking at MEK inhibitors, CDK4/6 inhibitors, SOS inhibitors, and SHP2 inhibitors, [targets] in adjacent pathways, such as EGF, and immunotherapy,” concluded Reckamp.

Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. 

. 2020;138(suppl 2):S1-S2. doi:10.1016/S0959-8049(20)31076-5

Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from US Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics, Inc. June 24, 2021. Accessed July 31, 2021. https://prn.to/2SXZWqe.

Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. 

. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003

FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed July 31, 2021. https://bit.ly/3c172Ah.

Brana I, Shapiro G, Johnson ML, et al. Initial results from a dose finding study of TNO155, a SHP2 inhibitor, in adults with advanced solid tumors. 

. 2021;39(suppl 15):3005. doi:10.1200/JCO.2021.39.15_suppl.3005

Koczywas M, Haura E, Janne PA, et al. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers. 

. 2021;81(13):LB001. doi:10.1158/1538-7445.AM2021-LB001

Tanaka N, Lin JJ, Li C, et al. Clinical acquired resistance to KRASG12C inhibition through a novel KRAS switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. 

 Published online June 16, 2021. doi:10.1158/2159-8290.CD-21-0365

Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS G12C-targeted therapy. 

. 2021;11(6):1345-1352. doi:10.1158/2159-8290.CD-20-1616

This article was originally published on OncLive as “

KRAS Inhibitors Reach New Milestones in NSCLC”

The continued development of KRAS G12C inhibitors for the treatment of non-small cell lung cancer shows that researchers are making breakthroughs in the treatment landscape. 

KRAS Inhibitors Meet New Turning Point in Non-Small Cell Lung Cancer 

CDK4/6 inhibitors have demonstrated promise in treating patients with estrogen receptor (ER)–positive, HER2-negative breast cancer in both a neoadjuvant and adjuvant setting. However, according to Joyce A. O’Shaughnessy, MD, investigators still need to confirm the durable benefit in the adjuvant setting before they can be incorporated into routine clinical practice. O’Shaughnessy spoke on the topic at the 20th Annual International Congress on the Future of Breast Cancer® West, a virtual program hosted by Physicians’ Education Resource®, LLC.

O’Shaughnessy is the chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center of Texas Oncology, as well as the 2016 Giant of Cancer Care® in Community Outreach.

In the neoadjuvant setting, the phase 2 NeoPalAna trial (NCT01723774) enrolled pre- and postmenopausal patients with stage II and III ER-positive, HER2-negative breast cancer. Patients received 4 weeks of anastrozole followed by 16 weeks of anastrozole plus palbociclib (Ibrance) followed by a 3- to 5-week treatment-free interval before surgery.1

The results showed that the complete cell cycle arrest (CCAC; Ki-67 <2.7%) rate increased from 28% after 4 weeks of anastrozole to 87% after 2 weeks of treatment with the combination. However, Ki-67 rebounded at the time of surgery, except in patients who stayed on palbociclib, suggesting that continuous treatment with palbociclib is necessary to maintain the response.

In the phase 2 FELINE trial (NCT02712723), patients were randomized to placebo plus letrozole, intermittent letrozole plus ribociclib (Kisqali), or continuous letrozole plus ribociclib. There was no difference in the preoperative endocrine prognostic index 0 score. However, the rate of patients with a Ki-67 of 2.7% or less at surgery was 71.4% with the addition of ribociclib vs 63.3% with letrozole alone (

 = .4225). Moreover, the addition of ribociclib led to a higher rate of node negativity vs letrozole alone, at 46.5% vs 35.5%, respectively (

However, as in the NeoPalAna trial, during the period of being off ribociclib prior to surgery, the Ki-67 rebounded in a subset of patients.

“There was a group [whose Ki-67 remained] very suppressed, so it’s just a proportion of the patients that are having a rebound in their Ki-67,” said O’Shaughnessy. “This really raises the question of how long we need to keep the preoperative or adjuvant therapy going in order to continue the [Ki-67] suppression,” said O’Shaughnessy.

The phase 2 NeoMONARCH trial (NCT02441946) enrolled postmenopausal patients with stage I, II, IIIA, or IIIB, hormone receptor (HR)–positive, HER2-negative breast cancer. Patients were randomized to anastrozole, anastrozole plus abemaciclib (Verzenio), or abemaciclib alone.3

The results demonstrated that the percent changes in Ki-67 from baseline to week 2 were 92.86%, 90.52%, and 62.78% in the abemaciclib/anastrozole, abemaciclib alone, and anastrozole alone arms, respectively.

Moreover, the rates of CCCA, which O’Shaughnessy termed a “very good end point,” were 67.8%, 57.7%, and 14.3%, respectively.

“Clearly, we’re getting much greater suppression of proliferation with the preoperative CDK4/6 inhibitors, regardless of which [agent you use],” said O’Shaughnessy.

The final neoadjuvant study O’Shaughnessy highlighted, the phase 2 CORALLEEN trial (NCT03248427), randomized postmenopausal patients with stage I to IIIA, HR-positive, HER2-negative disease with luminal B biology to doxorubicin and cyclophosphamide plus paclitaxel or letrozole plus ribociclib for 6 months.4

The study, which adopted the Prosigna risk of recurrence (ROR) score as the primary end point, showed no absolute difference in the ROR score between arms from baseline to surgery.

“The CDK4/6 inhibitor doesn’t look any worse than chemotherapy, but we can’t really say it’s any better,” said O’Shaughnessy.

“Are we ready to use [these agents] preoperatively? I would say probably not yet because we don’t know the duration the CDK4/6 inhibitor [should be given]. We really need the adjuvant data to know whether we [should] give them preoperatively,” said O’Shaughnessy.

In the adjuvant setting, O’Shaughnessy called attention to 3 trials. The first, the phase 3 PALLAS trial (NCT02513394), randomized patients with stage II to III, HR-positive, HER2-negative breast cancer to 2 years of palbociclib plus endocrine therapy or endocrine therapy alone.5

At a median follow-up of 23.7 months, the 3-year invasive disease-free survival (IDFS) rate was 88.2% with palbociclib/endocrine therapy vs 88.5% with endocrine therapy alone (HR, 0.93; 95% CI, 0.76-1.15; 

 = .51).4 The 3-year distant relapse-free survival (DRFS) rate was 89.3% and 90.7%, respectively (HR, 1.00; 95% CI, 0.79-1.27; 

“There was no benefit from the palbociclib. It’s a bit of a mystery why that is,” said O’Shaughnessy.

In the phase 3 monarchE trial (NCT031559970), patients with node-positive, high-risk, early HR-positive, HER2-negative breast cancer were randomized to 2 years of abemaciclib plus standard endocrine therapy or endocrine therapy alone.

“[monarchE] enrolled the highest-risk patients. The [trial investigators] really selected patients who were going to recur within 2 or 3 years,” said O’Shaughnessy.

The primary results indicated that at a median follow-up of 19.1 months, abemaciclib/endocrine therapy reduced the risk of invasive disease by 25.3% vs endocrine therapy alone (HR, 0.747; 95% CI, 0.598-0.932; 2-sided 

 = .0096). The 2-year IDFS rates were 92.2% in the abemaciclib/endocrine therapy arm vs 88.7% in the endocrine-alone arm.6

Additional results demonstrated that the addition of abemaciclib to endocrine therapy had a significant impact on DRFS across all prespecified subgroups, reducing the risk of distant recurrence by 28.3% (HR, 0.717; 95% CI, 0.559-0.920; 

 = .0085). The 2-year DRFS rates were 93.6% with abemaciclib/endocrine therapy vs 90.3% with endocrine therapy alone.

Updated findings from monarchE demonstrated that the risk of developing an IDFS event was reduced by 28.7% with abemaciclib/endocrine therapy (HR, 0.713; 95% CI, 0.583-0.871; 

 = .0009).7 The 2-year IDFS rates were 92.3% in the abemaciclib/endocrine therapy arm vs 89.3% in the endocrine-alone arm. Moreover, the risk of distant recurrence was reduced by 31.3% with abemaciclib/endocrine therapy (HR, 0.687; 95% CI, 0.551-0.858; 

 = .0009). The 2-year DRFS rates were 93.8% with abemaciclib/endocrine therapy vs 90.8% with endocrine therapy alone.

Moreover, in a prespecified subgroup analysis that was presented at the 2021 ASCO Annual Meeting, patients who had received neoadjuvant chemotherapy experienced an absolute improvement in 2-year IDFS and 2-year DRFS of approximately 6% with abemaciclib.8

“The curves are clearly pulling apart. We hope they’ll continue to pull apart, but it’s too soon to tell,” said O’Shaughnessy.

The final phase 3 trial, PENELOPE-B (NCT01864746), randomized patients with HR-positive, HER2-negative disease who did not achieve a pathologic complete response to neoadjuvant chemotherapy to 1 year of palbociclib or placebo.

Results showed that at a median follow-up of 42.8 months, the number of IDFS events in the palbociclib/endocrine therapy arm was 152 vs 156 in the placebo/endocrine therapy arm (stratified HR, 0.93; 95% CI, 0.74-1.17; 

 = .525).9 At 2 years, the estimated IDFS rates were 88.3% and 84.0%, respectively. Moreover, the estimated 3-year IDFS rates were 81.2% with palbociclib vs 77.7% with placebo, while the 4-year IDFS rates were 73.0% vs 72.4%, respectively.

“We need to see additional data at 3 and 4 years in order to really know whether those curves can continue to pull apart,” said O’Shaughnessy.

Ongoing trials to keep an eye on include the phase 2 CARABELA (NCT04293393) and phase 3 ADAPTlate (NCT04565054), eMonarcHER (NCT04752332), NATALEE (NCT03701334), and POETIC-A (NCT04584853) trials, concluded O’Shaughnessy.

Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 Inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer. 

. 2017;23(15):4055-4065. doi:10.1158/1078-0432.CCR-16-3206

Khan QJ, O’Dea A, Bardia A, et al. Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial). 

. 2020;38(suppl 15):505. doi:10.1200/JCO.2020.38.15_suppl.505

Hurvitz SA, Martin M, Press MF, et al. Potent cell-cycle inhibition and upregulation of immune response with abemaciclib and anastrozole in neoMONARCH, phase II neoadjuvant study in HR +/HER2 - breast cancer. 

. 2020;26(3):566-580. doi:10.1158/1078-0432.CCR-19-1425

Prat A, Saura C, Pascual T, et al. Ribociclib plus letrozole versus chemotherapy for postmenopausal women with hormone receptor-positive, HER2-negative, luminal B breast cancer (CORALLEEN): an open-label, multicentre, randomised, phase 2 trial. 

. 2020;21(1):33-43. doi:10.1016/S1470-2045(19)30786-7

Mayer EL, Dueck AC, Martin M, et al. Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study. 

. 2021;22(2):212-222. doi:10.1016/S1470-2045(20)30642-2

Johnston SRD, Harbeck N, Hegg R, et al. Abemaciclib combined with endocrine therapy for the adjuvant treatment of HR+, HER2−, node-positive, high-risk, early breast cancer (monarchE). 

. 2020;38(34):3987-3998. doi:10.1200/JCO.20.02514

O’Shaughnessy JA, Johnston S, Harbeck N, et al. Primary outcome analysis of invasive disease-free survival for monarchE: abemaciclib combined with adjuvant endocrine therapy for high risk early breast cancer. 

. 2021;81(4). doi:10.1158/1538-7445.SABCS20-GS1-01

Martin M, Hegg R, Kim SB, et al. Abemaciclib combined with adjuvant endocrine therapy in patients with high risk early breast cancer who received neoadjuvant chemotherapy (NAC). 

. 2021;39(suppl 15):517. doi:10.1200/JCO.2021.39.15_suppl.517

Loibl S, Marme F, Martin M, et al. Palbociclib for residual high-risk invasive HR-positive and HER2-negative early breast cancer-the Penelope-B trial. 

 2021;39(14):1518-1530. doi:10.1200/JCO.20.03639

This article was originally published on OncLive as 

“CDK4/6 Inhibitors Continue to Build Traction in Early-Stage ER+/HER2- Breast Cancer”

CDK4/6 inhibitors have demonstrated promise in treating patients with estrogen receptor (ER)–positive, HER2-negative breast cancer in both a neoadjuvant and adjuvant setting.



CDK4/6 Inhibitors Gain Momentum in Early-Stage Breast Cancer, But More Research is Still Needed

Recent data indicated that nearly a fifth of patients with multiple myeloma who received 2 doses of the SARS-CoV-2 vaccinations did not develop SARS-Cov-2 spike-binding IgG antibodies. Researchers worry that this population is potentially at a greater risk for developing severe COVID-19, according to study published in 

Lead study author Oliver Van Oekelen, MD, and colleagues evaluated SARS-CoV-2 spike-binding immunoglobulin G (IgG) antibody levels in 320 patients with multiple myeloma who received COVID-19 vaccinations in early 2021. Most patients (69.1%) received the BNT162b2 vaccine by Pfizer, 27.2% received Moderna’s mRNA-1273 vaccine, and 3.8% received an unknown mRNA vaccine.

Of these patients, 260 (81.3%) had SARS-CoV-2 spike-binding IgG antibody levels measured at least 10 days after receiving the second vaccine dose (range, 11-118). Of the fully vaccinated patients, 84.2% (219/260) developed measurable SARS-CoV-2 spike-binding IgG antibody levels.

“What was more important, and in a way, a little bit more worrying to us, was that more than 15% of the patients had no detectable IgG after receiving 2 [doses of the] vaccine at least 10 days prior,” Van Oekelen said. Forty-one (15.8%) patients did not develop any SARS-CoV-2 spike-binding IgG antibodies.

“That was somewhat surprising, although it has been confirmed in other cancer types, especially in different blood cancer types, by other groups.”

Additionally, 24 (58.5%) of the nonresponders were receiving CD38-directed therapy at the time of vaccination, 13 (31.7%) were receiving BCMA-directed bispecific antibody therapy, and 4 (9.8%) had received BCMA-directed CAR-T therapy more than 3 months prior.

“We also saw, at least at [the time of the analysis], that at least 10 patients after partial [n = 7] or complete vaccination [n = 3], developed COVID-19, and a handful of these patients were hospitalized. Some of these patients went to the intensive care unit, suggesting that patients that don’t have any IgG antibodies might be at risk for contracting the virus.”

®, Van Oekelen, a PhD candidate and graduate assistant in the Graduate School of Biomedical Sciences at Mount Sinai, discussed the results and implications of the study, as well as plans for further research.

®: Why was it important to study SARS-CoV-2 spike antibody responses to the COVID-19 vaccine in patients with multiple myeloma?

: Patients with multiple myeloma are immunocompromised, either because of the disease itself, whichcauses a dysfunction of the immune system, or the treatments that they’re receiving. Very often patients are getting multiple lines of chemotherapy or immunotherapy, and we know that these drugs have an effect on the immune system. At the same time, we have studies now showing excellent efficacy for all the vaccines that are available in the United States. We wanted to see whether that efficacy translated to our patients as well, because we were worried that perhaps they might not have as good of an immune response to the vaccine.

What methods were used to evaluate patients’ immune responses to the vaccine?

We collected blood and saliva in several patients with myeloma who enrolled on our trial at multiple time points. We collected [the specimens] before vaccination, and then at some prespecified time points after, and it’s still going on as we’re trying to measure the longitudinal response as well. We combined that data with retrospective analysis from patients who were seen in our clinic at Mount Sinai, and those time points were not prespecified, but just measurements that were taken by clinicians at their discretion. That allowed us to get a comprehensive picture in about 300 patients to see whether they mount antibodies to the mRNA vaccines.

What did the findings show? Did anything come as a surprise to you?

Patients with myeloma had significantly lower levels of IgG to the SARS-CoV-2 protein after vaccination [compared with healthy individuals], which was not that surprising. In general, for other diseases, or for other vaccinations, we don’t tend to measure these IgG levels. We do it now because [COVID-19 is] a new disease, and we want to understand it better. But as I said earlier, [low levels of IgG] can be because of the immunosuppressive effect of drugs or the disease itself.

We also had patients who had COVID-19. One question we had when we saw that 15% of the patients mounted no antibodies or no IgG at all was: Who are those patients? What is their profile? When we looked at which patients were unable to develop antibodies, we saw it was mostly patients that were on a CD38-directed monoclonal antibody and patients that were receiving BCMA-directed treatments. Both drugs are known to affect B cells, so that was not that unexpected, but it’s [an] important [finding], especially as CD38-directed treatment is being used extensively in myeloma at this point and the BCMA-directed treatments are growing rapidly. We’re [now] trying to figure out exactly how to explain the fact that these drugs were most associated with not developing antibodies.

The second question was: Does it matter? Does it matter that patients have no antibodies? [We learned that] that clearly matters.

Could the lack of antibodies indicate a delayed response to the vaccine that may become more apparent with a booster shot?

We have data now that, in some patients, extends up to 100 days after vaccination. Just by waiting, there is very little chance that patients who do not have detectable antibodies will get them over time. The important question is: What should we do about it? How should we approach these patients? There have been some data in transplant patients who are also immunosuppressed because of the drugs they receive against rejection, that giving a third shot at 3 or 6 months, or perhaps giving a different vaccine after getting 2 shots, helps some patients to achieve serial positivity or develop antibodies. It’s really a question of whether this could be translated to patients with cancer. We are looking into options to study this. Some of the companies are exploring booster shots as well. It will be important, especially in high-risk patients such as patients with cancer to see whether that can help some patients mount antibodies and be protected.

Even though the study was done in patients with multiple myeloma, could the findings be extrapolated to patients with solid tumors and other immunocompromised individuals?

Multiple myeloma is a disease of the plasma cells, which are the cells that are producing antibodies in normal circumstances, and so, in a way, it is not surprising to see that they have trouble making antibodies because they receive treatments that suppress [malignant] plasma cells and healthy plasma cells to some extent. We have seen similar results come out, sometimes in smaller cohorts or in more heterogeneous cohorts, where a significant proportion of patients failed to develop antibodies. It’s not always 15%; in some diseases, it’s probably a little bit more, and in others, it might be a little bit less. It’s important to identify these people to give them the proper counseling. That’s the most important approach that we take at Mount Sinai. We try to measure these antibodies at least once in patients after vaccination so that we can give them appropriate counsel. We owe it to our patients. Many of those patients have been taking a lot of precautionary measures, more so than many healthy people. We owe it to them to give them good counsel and good advice and tell them whether they should be careful going forward as the country is opening.


Patients with multiple myeloma are potentially at greater risk of developing severe COVID-19 after the SARS-COv-2 vaccination induced suboptimal antibody response. 


Caroline Seymour

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