The FDA approved pembrolizumab (Keytruda) for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, to be continued as an adjuvant monotherapy after surgery.

The approval was based off findings from the randomized, multicenter, double-blind, placebo-controlled KEYNOTE-522 trial (NCT03036488). Data from this study indicated that the use of pembrolizumab as a neoadjuvant therapy with chemotherapy significantly increased the pathologic clinical response. The findings showed a 37% reduction in the risk of disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR, 0.63; 95% CI, 0.48-0.82; 

In addition, adjuvant pembrolizumab following surgery displayed a favorable trend in event-free survival (EFS): 16% vs 24%, respectively (HR, 0.63; 95% CI, 0.48-0.82).

The study reported that adverse events (AEs) were consistent with the preexisting safety profiles of each agent. The median duration of exposure to pembrolizumab was 13.3 months. Fatal reactions from pembrolizumab treatment occurred in 0.9 % of patients. Serious AEs occurred in a little less than half (44%) of patients and included febrile neutropenia, pyrexia, anemia, and neutropenia. The most common AEs resulting in the permanent discontinuation of pembrolizumab were increased alanine aminotransferase, increased aspartate aminotransferase, and rash.

“Even when TNBC is diagnosed early, 30% to 40% of patients will suffer cancer recurrence after standard neoadjuvant chemotherapy and surgery,” said Joyce O’Shaughnessy, MD, chair of Breast Cancer Research, Baylor University Medical Center, Texas Oncology, U.S. Oncology, Dallas, Texas, in a press release. “Therefore, there is a high unmet need for new treatment options. Today’s approval is very welcome news and has the potential to change the treatment paradigm by now including an immunotherapy as part of the regimen for patients with high-risk early-stage TNBC.”

The study evaluated patients who were previously untreated, non-metastatic, and had been diagnosed with centrally confirmed TNBC. Participants were randomized 2:1 to receive either 200 mg of pembrolizumab or preoperative placebo paired with 4 cycles of carboplatin and paclitaxel, continued with 4 cycles of doxorubicin or epirubicin and cyclophosphamide. Following surgery, the 2 groups were then treated with either pembrolizumab or placebo as a monotherapy for either 9 cycles or until unacceptable toxicity was reached. Patients were separated by nodal status, tumor size, and carboplatin schedule.

End points included pathologic complete response and EFS. pCR was defined as an absence of invasive cancer in the breast and lymphs (ypT0/Tis or ypNO) while EFS was measured from the time of randomization to the first occurrence of disease progression. Secondary end points included partial complete response where pCR was defined as ypT0 ypN0 and ypT0/Tis, overall survival and efficacy in the pD-L1 L1þ population.

The age of participants ranged from 22 to 80 years and the mean age was 49. Ninety-nine percent of the participants were female, and 64% were white.

“Triple-negative is a difficult-to-treat type of breast cancer that unfortunately is more common in the U.S. in younger women and in Black women,” expressed Vicki Goodman, MD, vice president, clinical research, Merck Research Laboratories, in a press release. “We are proud to offer a new treatment option for patients faced with this challenging cancer. This neoadjuvant and adjuvant combination with KEYTRUDA is the first immunotherapy regimen to be approved in high-risk early-stage TNBC, marking a meaningful milestone for the breast cancer community.”

This KEYTRUDA combination is the first immunotherapy regimen approved for high-risk early-stage triple-negative breast cancer (TNBC). News release. MERCK. July 27, 2021. Accessed July 27, 2021. https://www.merck.com/news/fda-approves-keytruda-pembrolizumab-for-treatment-of-patients-with-high-risk-early-stage-triple-negative-breast-cancer-in-combination-with-chemotherapy-as-neoadjuvant-treatment-then-continued/

Articles


The FDA has approved the first immunotherapy, pembrolizumab (Keytruda), to treat patients with high-risk early-stage triple-negative breast cancer.


FDA Approves Pembrolizumab for High-Risk Early-Stage TNBC

Plinabulin, an investigational, first-in-class, selective immunomodulating microtube binding agent (SIMBA), has demonstrated a potential capability to prevent chemotherapy-induced neutropenia (CIN) as well as serve as an anticancer agent in treating non-small cell lung cancer (NSCLC). 

 The drug’s status as a potential preventative and active drug is based on its highly differentiated mechanism of action.

Plinabulin binds to the vicinity of the colchicine binding domain of the ß-tubulin in αβ-tubulin heterodimers. The binding occurs at a site and with kinetics that is unique from other tubulin targeting agents.

Moreover, by binding to tubulin, GEF-H1, an immune defense protein, is released by plinabulin. This activates a signaling transduction pathway that leads to dendritic cell (DC) maturation. In turn, DC maturation elicits innate and adaptive immune activity. DC maturation also results in increased antigen presentation and T-cell activation, which appears to contribute to plinabulin’s anticancer activity.

On June 1, 2021, the FDA granted a priority review designation to a new drug application for plinabulin plus granulocyte colony-stimulating factor (G-CSF) for the prevention of CIN.2 The regulatory designation is based on findings from the phase 3 PROTECTIVE-2 trial (Study 106; NCT03294577), as well as 5 supportive trials that enrolled over 1200 patients.

In PROTECTIVE-2, the combination of plinabulin and pegfilgrastim (Neulasta) was 53% more effective in reducing the incidence of CIN vs pegfilgrastim alone in patients with early-stage or stage III breast cancer receiving high–febrile neutropenia risk chemotherapy (n = 221).

The final results of the study, which were presented during the 2021 ASCO Annual Meeting, confirmed that the combination elicited superior CIN protection compared with pegfilgrastim alone.5 The addition of plinabulin also reduced adverse clinical sequalae, did not add toxicity, reduced the severity of grade 4 treatment-emergent adverse effects (AEs), and significantly reduced bone pain (

“We think that the combination protects [patients] throughout the chemotherapy cycle. We know from a long experience that there is a vulnerability or lack of protection within the first week after chemotherapy with pegfilgrastim. Adding plinabulin to pegfilgrastim seems to mitigate that vulnerability or increase the protection in the first week after chemotherapy,” said lead study author of the PROTECTIVE-2 study Douglas W. Blayney, MD, a medical oncologist at Stanford Health Care and a professor of medicine at Stanford Medicine, in an interview during an episode of 

“This will help oncologists and their patients receive more chemotherapy during both weeks of the chemotherapy cycle before the bone marrow recovers normally,” Blayney added.

Plinabulin’s activity has also been evaluated in lung cancer. The agent is currently being evaluated in combination with docetaxel for patients with advanced NSCLC who have measurable lung lesions in the phase 3 DUBLIN-3 trial (Study 103; NCT02504489).

The anticancer results for overall survival are expected in the final quarter of 2021, according to Blayney.

Plinabulin is also being evaluated in combination with the PD-1 inhibitor nivolumab (Opdivo) with the rationale that adding the agent will elicit synergistic immune-enhancing effects.1 Historically, cumulative toxicity has been a concern with nivolumab in combination with other checkpoint inhibitors; however, it is thought that plinabulin/nivolumab may demonstrate improved antitumor activity vs nivolumab alone without significantly increased toxicity. An ongoing phase 1/2 study (NCT02812667) is evaluating the combination in patients with metastatic NSCLC.

Triplet combinations are also under study with plinabulin.

 The combination of plinabulin, nivolumab, and ipilimumab (Yervoy) is being evaluated in a phase 1/2 study (NCT03575793) in patients with recurrent small cell lung cancer to determine whether plinabulin will be synergistic with nivolumab and ipilimumab while limiting immune-related AEs associated with the agents.

Finally, research is ongoing to test the potential benefits of adding plinabulin to PD-1 inhibitors and radiation therapy.

“Given the high incidence of progression with PD-1/PD-L1 antibody therapies in the majority of cancers, we believe this novel triplet approach will restore or enable the immune targeting of cancer in patients that have progressed on checkpoint [inhibitor] therapy,” according to BeyondSpring Pharmaceuticals.

Plinabulin. BeyondSpring Pharmaceuticals. 2021. Accessed July 14, 2021. https://bit.ly/3rjFXPu.

BeyondSpring announces US FDA acceptance and priority review of new drug application for plinabulin and G-CSF combination for the prevention of chemotherapy-induced neutropenia (CIN). News release. BeyondSpring. June 1, 2021. Accessed July 14, 2021. https://bit.ly/2SQVl8U.

Blayney DW, Huang L, Mohanlal R. Superior and clinically meaningful protection against profound neutropenia with the plinabulin/pegfilgrastim (Plin/Peg) combination versus peg in breast cancer patients receiving TAC chemotherapy: phase 3 results from Protective-2 (BPI-2358-106). Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PS13-53-01.

BeyondSpring announces new positive PROTECTIVE-2 phase 3 registrational trial results at the 2020 San Antonio Breast Cancer Symposium. News release. BeyondSpring. December 10, 2020. Accessed July 14, 2021. 

Blayney DW, Shi Y, Adamchuk H, et al. Clinical trial testing superiority of combination plinabulin (Plin) and pegfilgrastim (Peg) versus peg alone in breast cancer treated with high-risk febrile neutropenia risk chemotherapy (chemo): Final results of the phase 3 protective-2 in chemo-induced neutropenia (CIN) prevention. 

. 2021;39(suppl 15):533. doi:10.1200/JCO.2021.39.15_suppl.533

Docetaxel + plinabulin compared to docetaxel + placebo in patients with advanced NSCLC. ClinicalTrials.gov. Updated May 21, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02504489

Nivolumab in combination with plinabulin in patients with metastatic non-small cell lung cancer (NSCLC). ClinicalTrials.gov. Updated February 23, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02812667

A phase I/II study of nivolumab, ipilimumab and plinabulin in patients with recurrent small cell lung cancer. ClinicalTrials.gov. Updated May 28, 2021. Accessed July 14, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03575793

This article was originally published on OncLive as “

Unique Mechanism of Action Positions Plinabulin as a Preventive and Active Therapy in Breast Cancer, NSCLC”


Study results have posited plinabulin as a potentially effective preventative and active therapy due to its unique mechanism of action.


Distinct Mechanism of Action Makes Plinabulin a Potentially Powerful Therapy in Treating Breast Cancer

The phase 3 MINDACT trial (NCT00433589) demonstrated that patients with early-stage breast cancer who have ultralow risk disease indicated by a 70-gene signature show superior survival outcomes.

At a median follow-up of 8.7 years, the 8-year distant metastasis-free interval (DMFI) rate in patients with ultralow-risk disease was 97.0% (95% CI, 95.8%-98.1%) vs 94.5% (95% CI, 93.6%-95.3%) in low-risk patients and 89.2% (95% CI, 87.9%-90.5%) in high-risk patients. The risk of distant metastases or death was significantly lower in ultralow-risk patients vs low-risk patients (Hazard ratio [HR], 0.65; 95% C, 0.45-0.94). Similarly, the risk was lower for low-risk patients, compared with high-risk patients (HR, 2.17; 95% CI, 1.68-2.80). Moreover, the 8-year breast cancer–specific survival (BCSS) rate was 99.6% (95% CI, 99.1%-100%) in patients with ultralow-risk disease, 98.2% (95% CI, 97.7%-98.7%) in those with low-risk disease, and 93.7% (95% CI, 92.6%-94.7%) in those with high-risk disease.

“Our results confirm previously published results of excellent survival in ultralow-risk patients in the largest cohort to date,” presenting author Josephine Lopes Cardozo, MD, a PhD candidate at the Netherlands Cancer Institute and medical fellow at the European Organization for Research and Treatment of Cancer, said during an oral presentation of the data. “As we know, especially in low-risk breast cancers, recurrences occur very late. Longer follow-up will reveal whether the excellent prognosis of ultralow-risk patients continues, as seen in other studies on ultralow-risk [disease].”

Since the 1990s, there has been an increase in the incidence of breast cancer, with a large increase in the incidence of small tumors, and almost no decrease in the incidence of large tumors, according to Lopes Cardozo. However, there has also been an increase in 10-year survival for patients with all stages of breast cancer, with the exception of stage IV disease. This increase in survival rates can be attributed to developments in adjuvant systemic treatment, mammographic screening, and improvements in local and regional treatments.

The 70-gene signature has demonstrated level 1 clinical utility in identifying patients with a preserved outcome when treated with adjuvant endocrine therapy and no chemotherapy, Lopes Cardozo said. Moreover, the 70-gene signature is able to identify patients who are at a low- or high-risk of distant recurrence within 5 years of breast cancer diagnosis. In 2017, a threshold for ultralow-risk disease was defined as a 100% BCSS rate at 15 years in independent validation cohorts of the 70-gene signature, she explained.

Two studies have demonstrated that tumors with a low- and ultralow-risk biology, according to the 70-gene signature, are overrepresented in cancers detected through screening. In one study, a cohort of patients were examined prior to the introduction of widespread screening (1984 to 1992) and compared with another cohort of patients who were examined after widespread screening was adopted (2004-2006). Results indicated that there was a significantly higher proportions of patients with low- and ultralow-risk tumors in the screened cohort vs the prior to the widespread introduction of screening cohort.

Similarly, in Dutch patients who were assessed on the MINDACT trial, a significantly higher rate of low- and ultralow-risk tumors were observed in patients with cancers detected through screening (69%; n = 754) compared with patients whose tumors were found in the intervals between 2 screening rounds (52%; n = 348).

Historically, patients with ultralow-risk tumors, as assessed by the 70-gene signature, have had excellent survival outcomes. In validation cohorts that were used to set the threshold for ultralow-risk tumors, 98% of patients received no adjuvant systemic treatment. Moreover, the 15-year BCSS was 100% for patients with ultralow-risk disease.

Additionally, another prior study analyzed a cohort from the historic STO-3 trial, which examined patients with lymph node–negative breast cancer smaller than 3 cm. Patients were randomized to receive either tamoxifen or no adjuvant systemic treatment. Among patients for whom a 70-gene signature could be performed, 339 received tamoxifen, while 313 received no adjuvant systemic treatment. Results indicated that patients in the cohort with ultralow risk tumors had excellent 20-year BCSS outcomes, with rates of 97% in those who received tamoxifen and 94% in those who received no adjuvant systemic treatment. However, the number of patients with ultralow-risk disease examined on both studies was notably small.

As such, investigators sought to assess survival outcomes in patients with an ultralow-risk tumor biology who were included in the MINDACT trial, as well as examine if the identification of an ultralow-risk patient subgroup by 70-gene signature could help to avoid overtreatment in early-stage breast cancer.

The MINDACT trial enrolled women aged 18 to 70 years old with operable invasive breast cancer and whose tumor size was a maximum of 5 cm. Additionally, patients enrolled on the study could have 0 to 3 positive lymph nodes. Patients with distant metastases were excluded from the trial.

Patients were stratified based on clinical risk by clinical-pathological characteristics and genomic risk based on the 70-gene signature.9 On the study, patients with concordant low-risk stratification received no adjuvant chemotherapy, while those with concordant high-risk stratification did receive chemotherapy. Additionally, the 2 study groups with discordant risk stratification were randomized to follow either the clinical or genomic risk stratification to receive chemotherapy or not, Lopes Cardozo added.

In total, 6693 patients were enrolled on the MINDACT trial. Of those patients, profiling revealed ultralow risk by 70-gene signature in 15% (n = 1000) of patients and 49% (n = 3295) of patients were clinically low risk. Among these patients, approximately 95% presented with hormone receptor (HR)–positive, HER2-negative disease vs 57% of high-risk patients (36%; n = 2398). Additionally, 76% to 85% of patients with low- or ultralow-risk disease received endocrine therapy only or no adjuvant systemic treatment, while 83% of high-risk patients received chemotherapy.

Among the subgroup of patients with ultralow-risk disease, the majority were older than 50 years of age (67%), lymph node-negative (80%), had tumors sized 2 cm or smaller (81%), had grade 1 or 2 disease (96%), and had HR-positive/HER2-negative subtyping (97%). Additionally, 16% of ultralow-risk patients received no adjuvant systemic treatment, 69% received endocrine therapy, and 14% received chemotherapy. Moreover, in terms of clinical risk, 741 of the ultralow risk patients had clinically low-risk tumors, while 259 had clinically high-risk tumors, defined as being larger in size, having a higher grade, and being lymph node positive.

In an assessment of DMFI in genomic ultralow-risk patients by clinical risk, those with clinically low-risk tumors had a slightly higher 8-year DMFI rate of 97.6% (95% CI, 96.4%-98.8%), vs 95.0% (95% CI, 92.3%-97.8%) in those with clinically high-risk tumors.

No statistically significant difference in 8-year BCSS rate was noted among genomic ultralow-risk patients, with the clinically low-risk group achieving a rate of 99.7% (95% CI, 99.3%-100%) and 99.2% (95% CI, 98.0%-100%) in the clinically high-risk group.

Additionally, in patients with ultralow-risk disease who received no adjuvant systemic treatment (n = 157), the 8-year DMFI rate was 97.8% (95% CI, 95.3%-100%), while it was 97.4% (95% CI, 96.1%-98.7%) in those who received endocrine therapy only (n = 685). Lastly, a rate of 94.9% (95% CI, 94.4%-98.7%) was reported in those who received chemotherapy with or without endocrine therapy (n = 144). Notably, 92% of patients who received chemotherapy had clinically high-risk disease.

“The clinical implications of this research are that we can confirm that the 70 gene signature can identify patients with an ultralow risk of recurrence, and that these patients could be candidates for further de-escalation of treatment, thus further reducing overtreatment, and the risk of [adverse] effects,” Lopes Cardozo concluded.

Cardozo J, Drukker C, Schmidt M, et al. Outcome of patients with an ultralow risk 70-gene signature in the MINDACT trial. 

. 2021;39(15):500-500. doi:10.1200/JCO.2021.39.15_suppl.500

Autier P, Boniol M, Koechlin A, et al. Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. 

Piccart M, Veer L, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. 

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Veer L, Dai H, Vijver M, et al. Gene expression profiling predicts clinical outcome of breast cancer. 

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Delahaye L, Drukker C, Dreezen C, et al. A breast cancer gene signature for indolent disease. Breast Cancer Res Treat. 2017;164(2):461–466. doi:10.1007/s10549-017-4262-0

Esserman L, Shieh Y, Rutgers E, et al. Impact of mammographic screening on the detection of good and poor prognosis breast cancers. 

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Drukker C, Tinteren H, Schmidt M, et al. Long-term impact of the 70-gene signature on breast cancer outcome. 

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Esserman L, Yau C, Thompson C, et al. Use of molecular tools to identify patients with indolent breast cancers with ultralow risk over 2 decades. 

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Cardoso F, Veer L, Bogaerts J, et al. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. 

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This article was originally published on OncLive as 

“Ultralow Risk 70 gene Signature is Indicative of Excellent Survival Outcomes in Early Stage Breast Cancer.”


Regardless of clinical risk, the survival prognosis of patients with early-stage breast cancer is high amongst those who have ultralow risk disease indicated by a 70-gene signature. 



Ultralow Risk 70-Gene Promises Superior Survival Outcomes in Patients with Early-Stage Breast Cancer

Sacituzumab govitecan, an antibody drug conjugate, maintained progression-free survival (PFS), overall survival (OS), and response benefits over chemotherapy regimens, regardless of the agents used, according to data from a subanalysis of the phase 3 ASCENT trial (NCT02574455), presented during the 2021 ASCO Annual Meeting.

Sacituzumab govitecan resulted in a longer median PFS compared with any of the physician’s choice chemotherapy options, which included eribulin, vinorelbine, capecitabine, or gemcitabine (HR, 0.41; 95% CI, 0.32-0.52; 

 <.001). The median PFS, by blinded independent central review, was 5.6 months (95% CI, 4.3-6.3) with the ADC, 2.1 months (95% CI, 1.5-2.8) with eribulin, 1.6 months (95% CI, 1.4-2.7) with vinorelbine, 1.6 months (95% CI, 1.4-2.4) with capecitabine, and 2.7 months (95% CI, 1.6-4.8) with gemcitabine.

The ADC also prolonged the median OS over eribulin, vinorelbine, capecitabine, or gemcitabine, at 12.1 months (95% CI, 10.7-14.0) vs 6.9 months (95% CI, 5.8-7.8), 5.9 months (95% CI, 4.5-6.7), 5.2 months (95% CI, 3.5-8.6), and 8.4 months (95% CI, 5.0-9.6), respectively (HR, 0.48; 95% CI, 0.38-0.59; 

 <.001). Sacituzumab govitecan elicited an ORR of 35% vs 5%, 4%, 6%, and 3% with eribulin, vinorelbine, capecitabine, or gemcitabine, respectively.

“The efficacy benefit for median PFS, median OS, and ORR with sacituzumab govitecan vs single-agent chemotherapy in the second-line or greater metastatic TNBC setting in ASCENT was retained when evaluating each chemotherapy agent individually,” Joyce A. O’Shaughnessy, MD, lead study author, cochair of Breast Cancer Research and chair of breast cancer prevention research at Baylor-Sammons Cancer Center of Texas Oncology, said in a poster presentation on the data. “These results confirm that sacituzumab govitecan should be considered as a new standard of care in this patient population.”

For patients with previously treated TNBC, standard treatment has comprised single-agent chemotherapy; however, this approach has been linked with responses rates of under 20% and a short PFS ranging from just 2 to 3 months. Eribulin is a frequently used agent in this population, but median PFS continues to be poor, at less than 3 months.

Sacituzumab govitecan is comprised of a Trop-2 antibody that is paired with SN-38 through a proprietary hydrolysable linker. The agent is unique from other available ADCs in that the antibody is highly specific for Trop-2 and it has a high drug-to-antibody ratio of 7:6:1. Moreover, internalization and enzymatic cleavage by tumor cell is not needed to free SN-38 from the antibody. Notably, the ADC also has a bystander effect because hydrolysis of the linker releases SN-38 extracellularly in the tumor microenvironment.

In April 2021, the FDA granted a full approval to sacituzumab govitecan for the treatment of patients with unresectable locally advanced or metastatic TNBC who have received 2 or more prior systemic therapies, at least 1 of them for metastatic disease. The regulatory decision was based on earlier data from ASCENT, which showed that the agent significantly improved survival over physician’s choice of single-agent chemotherapy in patients with metastatic TNBC who were receiving treatment in the second- or later-line setting.

Earlier data from the trial showed that the median PFS with the ADC was 5.6 months (95% CI, 4.3-6.3) vs 1.7 months (95% CI, 1.5-2.6) with chemotherapy (HR, 0.41; 95% CI, 0.32-0.52; 

 <.001). Moreover, the median OS in the investigative and control arms was 12.1 months (95% CI, 10.7-14.0) and 6.7 months (95% CI, 5.8-7.7), respectively (HR, 0.48; 95% CI, 0.38-0.59; 

In the subanalysis presented during the meeting, investigators evaluated the safety and efficacy of sacituzumab govitecan vs each chemotherapy agent to determine how each drug performed individually.

Of the 529 patients enrolled to the phase 3 study, 235 patients in the ADC arm were negative from brain metastases, as were 233 patients in the chemotherapy arm. In the control arm, eribulin was noted to be the most frequently selected agent (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29).

At the time of data cutoff, 6% (n = 15) of those on the sacituzumab govitecan arm remained on treatment vs 0% of those on the chemotherapy arm. The most frequently reported reasons for study discontinuation included disease progression and withdrawn consent.

Across the arms, the majority of patients were female, and the median age ranged from 50 years to 56 years. The majority of patients were White, had an ECOG performance status of 1, and received more than 3 prior lines of chemotherapy. The median number of prior anticancer regimens received ranged from 3 to 5 lines.

Additional data showed that of those who responded to treatment with sacituzumab govitecan, the complete response (CR) rate was 4% and the partial response (PR) rate was 31%. The clinical benefit rate achieved with the ADC was 45% vs 8% with eribulin, 6% with vinorelbine, 10% with capecitabine, and 14% with gemcitabine. The median duration of response across these subsets was 6.3 months (95% CI, 5.5-9.0), 3.6 months (95% CI, 2.9-4.2), 2.8 months (not evaluable [NE]), NE, and 2.9 months (NE), respectively.

Regarding safety, key treatment-related adverse effects (TRAEs) that were grade 3 or higher in severity experienced with the ADC vs eribulin comprised neutropenia (51% vs 31%), leukopenia (10% vs 5%), diarrhea (10% vs 0%), anemia (8% vs 2%), febrile neutropenia (6% vs 2%), fatigue (3% vs 5%), and peripheral neuropathy (0% vs 2%).

Important grade 3 or higher TRAEs reported with sacituzumab govitecan vs vinorelbine, capecitabine, and gemcitabine combined included neutropenia (51% vs 36%), leukopenia (10% vs 6%), diarrhea (10% vs 1%), anemia (8% vs 8%), febrile neutropenia (6% vs 2%), and fatigue (3% vs 6%).

Additionally, treatment-emergent AEs resulted in discontinuation in 5% of those who received sacituzumab govitecan, 2% of those given eribulin, 10% of those who received vinorelbine, 7% of those given capecitabine, and 9% of those who were administered gemcitabine. Only 1 treatment-related death was reported in the chemotherapy arm; this patient received eribulin and had died from neutropenia sepsis. Notably, no treatment-related deaths occurred with the ADC.

“The safety profile of sacituzumab govitecan vs single-agent chemotherapy in the second-line or greater metastatic TNBC setting in ASCENT was comparable,” O’Shaughnessy concluded.

O’Shaughnessy J, Punie K, Oliveira M, et al. Assessment of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) cohort by agent in the phase 3 ASCENT study of patients (pts) with metastatic triple-negative breast cancer (mTNBC). 

. 2021;39(suppl 15):1077. doi:10.1200/JCO.2021.39.15_suppl.1077

Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. 

. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

Sacituzumab govitecan, an antibody drug conjugate, maintained survival and response benefits over chemotherapy regimens.

Sacituzumab Govitecan Beats All Chemo Regimens in TNBC Treatment

Patients with BRCA1/2-mutant, early HER2-negative breast cancer at a high risk of recurrence saw a clinically meaningful benefit 1 year after standard of care when treated with olaparib (Lynparza), according to data from the phase 3 OlympiA trial (NCT02032823).

Results from the multicenter, randomized, placebo-controlled trial, which were presented during a virtual press briefing ahead of the 

 indicated that after a median follow-up of 2.5 years, patients who received olaparib experienced a 42% reduction in invasive disease-free survival (iDFS), including local and metastatic recurrence of breast cancer, other new cancers, and death due to any cause, (Hazard ratio [HR], 0.58; 99.5% CI, 0.41-0.82; 

 <.0001). Additionally, investigators noted a difference in 3-year iDFS rate between olaparib and placebo of 8.8% (95% CI, 4.5%-13.0%; stratified HR, 0.58; 99.5% CI, 0.41-0.82; 

“The OlympiA study is the first to report the benefits of [an adjuvant] PARP inhibitor for early forms of germline 

–mutation associated cancer,” presenting study author Andrew Tutt, MB, ChB, PhD, FMedSci, head of the Division of Breast Cancer Research, director of the Breast Cancer Now Toby Robins Research Centre, a clinician scientist with the Laboratory and Clinical Trials programme, and consultant clinical oncologist at the Institute of Cancer Research, said. “Patients who received olaparib after surgery and chemotherapy were more likely to be alive without cancer, [as well as] avoid metastasis than the patients who received placebo.”

Patients with HER2-negative early breast cancer who harbor a 

 mutation, which are present in approximately 5% of all breast cancers, are at a high risk of disease recurrence. Although outcomes have been positive for patients with these mutations who have received standard treatments such as surgery, radiotherapy, and chemotherapy, the risk of recurrence remains high for some patients. As such, additional novel targeted therapies are needed in order to reduce the risk of recurrence in this patient population.

Olaparib is a PARP inhibitor that targets DNA repair defects in certain germline-mutant cancers and was previously approved by the FDA in January 2018 for the treatment of patients with germline BRCA-positive, HER2-negative metastatic breast cancer. As such, investigators sought to examine the agent in patients with germline 

–mutated, HER2-negative early breast cancer.

The trial enrolled 1836 patients with HER2-negative breast cancer harboring a germline 

 mutation who were randomized 1:1 to receive either 300 mg of oral olaparib (n = 921) twice daily for 1 year or placebo (n = 915). Additionally, patients needed to have been treated for early stage (stage II-III) breast cancer and have completed surgery and chemotherapy, with or without radiotherapy. Inclusion criteria also required that patients have a high risk of disease recurrence. Those who had received prior treatment with a PARP inhibitor were not eligible to enroll.

The primary end point for the study was iDFS, while secondary end points included distant disease-free survival (DDFS), overall survival (OS), health-related quality of life, and safety.

“Stringent criteria were applied for a planned interim analysis,” Tutt said. “At this analysis, OlympiA’s Independent Data Monitoring Committee found [that] these stringent criteria were met for early reporting.”

Additional findings indicated that after a median follow-up of 2.5 years, patients who were treated with olaparib experienced a 43% reduction in DDFS, including metastatic disease, new cancer, and death due to any cause (HR, 0.57; 99.5% CI, 0.39-0.83; 

 <.0001). The difference in 3-year DDFS rate between olaparib and placebo was 7.1% (95% CI, 3.0%-11.1%; stratified HR, 0.57; 99.5%, 0.39-0.83; 

At the time of the early primary end point report, OS data were considered immature. However, while fewer deaths were reported in patients receiving olaparib vs placebo, OS was not significantly different between the 2 study cohorts at a median follow up of 2.5 years(HR, 0.68; 99% CI, 0.44-1.05; 

 = .024). Moreover, the difference in 3-year OS rate between the 2 arms was 3.7% (95% CI, 0.3%-7.1%).

In terms of the safety profile, the adverse effects (AEs) reported in the olaparib group were consistent with what has been previously reported with the agent. Additionally, Olaparib did not increase serious AEs, including hospital admissions or occurrences of other cancers such as leukemia. However, grade 3 or higher AEs were reported more often in patients receiving treatment with olaparib, and included anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (2%).

The most common AEs of any grade reported in patients who received olaparib included nausea (57%), fatigue (40%), anemia (23%), vomiting (23%), and headache (20%). Moreover, the most common any grade AEs in the placebo arm were fatigue (27%), nausea (23%), headache (17%), diarrhea (14%), and arthralgia (12%).

1. Tutt A, Garber J, Kaufman B, et al. OlympiA: a phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline BRCA1/2 mutations and high-risk HER2-negative early breast cancer. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract LBA1

2. Olaparib as adjuvant treatment in patients with germline BRCA mutated high risk HER2 negative primary breast cancer (OlympiA). ClinicalTrials.gov. Updated March 9, 2021. Accessed June 2, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02032823

Patients with BRCA1/2-mutant, early HER2-negative breast cancer at a high risk of recurrence saw a clinically meaningful benefit 1 year after standard of care when treated with olaparib.

Olaparib Is Beneficial 1 Year After Standard of Care Therapies in BRCA, High-Risk, Early HER2- Breast Cancer

Screenings for breast cancer, colorectal cancer (CRC), and prostate cancer declined sharply from March to May 2020 vs the same time span in 2019, suggesting that public health efforts, such as increased use of screening modalities that do not require a procedure, are needed to address the deficit caused by the COVID-19 pandemic, according to findings from a study that were published in 

Within the 3-month period in 2020, the sharpest decline in screening for breast cancer, CRC, and prostate cancer was observed in April 2020 compared with the same month in 2019; screenings declined by 90.8%, 79.3%, and 63.4% in breast cancer, CRC, and prostate cancer, respectively.

Compared with April 2019, the incidence of breast cancer screenings in April 2020 declined from 4287 per 100,000 individuals (95% CI, 4258-4316) to 394 per 100,000 individuals (95% CI, 385-403). The incidence of CRC screenings declined from 2073 per 100,000 individuals (95% CI, 2058-2087) to 430 per 100,000 individuals (95% CI, 423-436). The incidence of prostate cancer screenings declined from 4025 per 100,000 individuals (95% CI, 3993-4057) to 1474 per 100,000 individuals (95% CI, 1454-1493).

Notably, near complete recovery in monthly screening rates were observed by July 2020 for patients with breast cancer and prostate cancer.

"Unfortunately, by causing cancellations of appointments and cancer screenings, COVID will indirectly cause an increase in cancer deaths—another negative consequence of COVID that has not yet received much public attention," said lead study author Ronald C. Chen, MD, MPH, the Joe and Jean Brandmeyer Endowed Chair in the Department of Radiation Oncology at the University of Kansas Medical Center.

The COVID-19 pandemic significantly affected all elements of health care, including cancer treatment and screening, across the United States in 2020, Chen and co-authors wrote.1 Stay-at-home orders and safety guidelines issued by the CDC to minimize COVID-19 transmission resulted in a significant decline in non-emergency clinical visits, particularly among older, high-risk patients, explained Chen and co-authors.

The study evaluated 3 distinct cohorts of patients from the HealthCore Integrated Research Database, which comprises single-payer administrative claims data and enrollment information from about 60 million patients in Medicare Advantage and commercial insurance plans across the United States. The cohorts included women with breast cancer, men and women with CRC, and men with prostate cancer.

Cancer screenings were evaluated from 2018 to 2020. Evaluable individuals for breast cancer screening or CRC screening were aged 50 to 79 years, and evaluable individuals for prostate cancer screening were aged 50 to 69 years. Individuals had to have at least 2 years of continuous enrollment before the first day of the index month. Restrictions based on medical claims and personal history codes for cancers of interest further refined the evaluable population.

“Excluding individuals with a history of the cancer of interest allowed us to more accurately assess cancer screening,” wrote Chen and co-authors.

Additional results from the study revealed that despite the rebound in monthly cancer screening rates, a deficit in total cancer screenings from January to July 2020 remained compared with January to July 2019. This translated to a United States–population deficit in breast cancer, CRC, and prostate cancer screenings of approximately 3.9 million women, 3.8 million men and women, and 1.6 million men, respectively. Moreover, the total deficit in cancer screenings was estimated at 9.4 million individuals in 2020 compared with 2019.

By geographic region, the Northeastern United States reported the sharpest decline in cancer screenings in March, April, and May for all 3 cancer types. The Western region had a slower recovery in screening during June and July compared with the Midwest and South regions.

Regarding socioeconomic status, prior to the pandemic, screening rates were higher for all 3 cancer types in the highest 2 socioeconomic index quartiles compared with the lower 2 socioeconomic index quartiles. However, the highest socioeconomic index quartile reported the largest decline in screening for all 3 cancer types from January to July 2020 compared with the same period in 2019. Moreover, the decline narrowed the gap in screening rates across the quartiles in 2020 vs 2019.

Other key findings from the study showed that increasing age was associated with less screening in all 3 cancer types. Individuals in the higher quartiles were screened less for breast cancer and CRC in April 2020 compared with individuals in the lower quartiles.

Notably, individuals who utilized telemedicine services had higher rates of cancer screening across the 3 cancer types evaluated.

“Telehealth has a measurable positive effect on whether patients get their cancer screenings,” Chen said.2 “This study also justifies a continued use of telehealth even after the pandemic.”

Chen and co-authors reported that analyzing only insured individuals, the lack of racial/ethnic diversity in the study population, the use of nonspecific codes for screening, and the inclusion of individuals without a history of cancer were limitations of the study.

“As a physician, I wasn’t surprised to see that screenings had declined, but this study measures by how much. There needs to be a concerted public health educational campaign across the country to reinforce the importance of cancer screening. Hospitals across the country also need to devote effort to contact patients to reschedule canceled screening tests, in order to minimize the delay in screening and cancer diagnoses from the missed tests,” concluded Chen.2

Chen RC, Haynes K, Du S, et al. Association of cancer screening deficit in the United States with the COVID-19 pandemic. 

. Published online April 29, 2021. Accessed May 13, 2021. doi:10.1001/jamaoncol.2021.0884

Massive negative impact of COVID-19 on cancer screenings quantified in KU Medical Center faculty study published in JAMA Oncology. News release. April 29, 2021. Accessed May 13, 2021. https://bit.ly/3ojB2fJ.

This article was originally published on OncLive as, "

Routine Screening Rates for Breast, Colorectal, and Prostate Cancers Decline During COVID-19 Pandemic

Public health efforts must address new methods of cancer screening, an expert says.

Routine Cancer Screening Declined During the COVID-19 Pandemic

Updated survival data from the phase 3 Short-HER trial (NCT00629278) presented during the ESMO Breast Cancer Virtual Congress 2021 confirm the promising long-term results obtained with 9 weeks of adjuvant trastuzumab (Herceptin) in patients with HER2-positive early breast cancer who have low and intermediate risk factors, a population that is representative of most patients seen in clinical practice.

After a median follow-up of 8.7 years, patients who received 1 year of trastuzumab had a 5-year disease-free survival (DFS) rate of 87.9% vs 85.8% those who received it for 9 weeks (hazard ratio [HR], 1.09; 90% CI, 0.88-1.35). Moreover, patients had a 5-year overall survival (OS) rate of 95.1% in both arms, respectively (HR, 1.18; 90% CI, 0.86-1.62).

“Patients classified as low/intermediate risk on the basis of [tumor] size and nodal status represent 84.6% of the Short-HER study population. In this patient population, long-term DFS and OS are superimposable between the 2 treatment arms,” Pier Franco Conte, MD, a full professor of oncology at the University of Padova, Italy; director of the Division of Medical Oncology at the Istituto Oncologico Veneto in Padova; and chairman of Rete Oncologica Veneta, said in a presentation on the findings. “Although 1 year of trastuzumab remains a standard, de-escalation of treatment is a reasonable option for a large proportion of a real-world population of [patients with] HER2-positive early breast cancer.”

The superiority of combining 1 year of trastuzumab with adjuvant chemotherapy over chemotherapy alone in patients with HER2-positive early breast cancer was demonstrated in the phase 3 HERA (NCT00045032), Joint Analysis B31-N9831, and N9831 trials.

 In November 2006, trastuzumab was approved by the FDA as an adjuvant therapy for patients with HER2-positive, node-positive breast cancer as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel.

“It was very clear at the time that the choice of a 1-year duration of trastuzumab administration was based empirically and that a similar degree of benefit had already been reported with the small FinHER study with 9 weeks of trastuzumab,” Conte noted.

The Short-HER trial, which was an investigator-driven, noninferiority study, started off with an initial sample size of 2500 patients; however, as of February 2011, this was amended to 1250 patients. The study was conducted across 82 investigational sites in Italy and had a recruitment period that ran from December 2007 to October 2013. The primary analysis was completed after 189 DFS events at 5.2 years median follow-up.

The trial enrolled patients with HER2-positive, node positive, or high-risk node-negative disease. “Patients were then randomized to receive either 1 year of trastuzumab plus chemotherapy, which included 4 courses of doxorubicin and cyclophosphamide, followed by 4 courses of a taxane, vs 3 courses of docetaxel combined with 9 weeks of weekly trastuzumab followed by 3 courses of fluorouracil, epirubicin hydrochloride, and cyclophosphamide,” Conte said. Stratification factors included hormone receptor status and nodal status. Patients who were aged 65 years or older received docetaxel at 80 mg/sqm dose of docetaxel. Eleven percent of patients who received the longer duration of trastuzumab were given paclitaxel at 175 mg/sqm.

The overall patient population had a median age of 55 years (range, 25-78), and 64.0% were postmenopausal. Moreover, 40.6% of patients had stage I disease, 43.8% had stage II disease, and 15.2% had stage III disease. Most patients were node negative (53.5%), although 30.7% of patients had 1 to 3 positive nodes and 15.8% had at least 4 positive nodes. Additionally, 68.2% of patients had hormone receptor–positive status.

The DFS reported in the primary analysis of the trial showcased a HR of 1.13 (90%, CI, 0.89-1.42). Investigators reported that the probability that the shorter duration of treatment would be noninferior to that of the longer duration was 78% .

 Moreover, the primary analysis identified an association between a longer duration of treatment and a longer and higher incidence of cardiac events. The incidence of grade 2 or higher cardiac events was 13.1% in the long-duration treatment arm vs 4.3% in the short-duration treatment arm.

The updated results of the study had a median follow-up of 8.7 years with 237 DFS events and 109 deaths.

Investigators also examined DFS and OS outcomes with respect to risk category. “The high-risk group clearly has worse outcomes in terms of both DFS and OS, while both low- and intermediate-risk groups had very good DFS and OS estimates,” Conte said.

Patients in the low-risk group experienced a 5-year DFS of 91% in both treatment arms (HR, 0.91). In the intermediate-risk group, those who were treated with the longer duration of treatment had a 5-year DFS rate of 88% vs 89% with the shorter duration (HR, 0.88); the 5-year DFS rates in the high-risk group for the longer and shorter treatment durations were 82% and 64%, respectively (HR, 2.06).

Additionally, the 5-year OS rate for patients in the low-risk group who received the longer duration of treatment was 97% vs 99% with the shorter duration (HR, 0.57). In the intermediate-risk group, these rates were 96% and 95%, respectively (HR, 1.14), while they were 95% ad 91%, respectively, in the high-risk group (HR, 1.09).

Conte P, Frassoldati A, Bisagni G, et al. Nine weeks vs 1 year adjuvant trastuzumab: long term outcomes of the Short-HER randomized trial. Presented at: ESMO Breast Cancer Virtual Congress 2021. May 5-8, 2021; Virtual. Abstract 401.

Herceptin (Trastuzumab) in treating women with human epidermal growth factor receptor (HER) 2-positive primary breast cancer (HERA). ClinicalTrials.org. Updated April 27, 2017. Accessed May 7, 2021. https://clinicaltrials.gov/ct2/show/NCT00045032

Doxorubicin and cyclophosphamide plus paclitaxel with or without trastuzumab in treating women with node-positive breast cancer that overexpresses HER2. ClinicalTrials.gov. Updated April 29, 2021. Accessed May 7, 2021. 

https://clinicaltrials.gov/ct2/show/NCT00004067

Doxorubicin hydrochloride, cyclophosphamide, and paclitaxel with or without trastuzumab in treating women with HER2-positive node-positive or high-risk node-negative breast cancer. ClinicalTrials.gov. Updated August 2020. Accessed May 7, 2021. 

https://clinicaltrials.gov/ct2/show/NCT00005970

FDA approves Herceptin for the adjuvant treatment of HER2-positive node-positive breast cancer. News release. FDA. November 16, 2006. Accessed May 7, 2021. 

Conte P, Bisagni G, Frassoldati A, et al. Final analysis of the phase III multicentric Italian study Short-HER: 9 weeks vs 1 year adjuvant trastuzumab for HER21 early breast cancer. 

. 2017;28(suppl 6):vi1-vi2. doi:10.1093/annonc/mdx421

Shorter Duration of Adjuvant Trastuzumab Shows Long-Term Survival Benefit in Select HER2+ Early Breast Cancer.

A 9-week trastuzumab regimen may be favorable for patients with HER2-positive early breast cancer who have low and intermediate risk factors. 

Shorter Adjuvant Trastuzumab Has Long-Term Benefits for HER2+ Breast Cancer

Post-treatment care for breast cancer survivors must be personalized to address each survivor’s unique experiences, according to a study presented at the ESMO Breast Cancer Virtual Congress 2021. Women in the low- and intermediate-burden subgroups had symptom scores better or equal to the average Dutch woman but many in the high-burden subgroup were significantly worse than average for all 11 symptoms evaluated.

The low subgroup reported a lower symptom burden compared to the general population. The intermediate subgroup experienced burden similar to the general population, although scores for fatigue, insomnia, and cognitive symptoms were slightly worse.

Symptom burden in the high subgroup was significantly than the general population. Compared with the intermediate subgroup, patients in the high burden group were more likely to have at least 1 comorbidity (relative risk ratio (RRR), 2.75; 95% CI, 1.22-6.19; 

 = .015) and more likely to have multiple comorbidities (RRR, 9.19; 95% CI; 3.70-22.8; 

“I was pleasantly surprised to find that so many survivors were doing as well or even better than the average Dutch woman,” lead author Kelly de Ligt, PhD, from the Netherlands Cancer Institute in Amsterdam, said in a news release.

de Ligt added that the findings in the high-burden subgroup were alarming. “This was the smallest group, only 15% of our population, but nonetheless, 1 in 6 women in our study had worse scores than the general population for all symptoms. The differences, ranging between 15 and 20 percentage points, were large enough to be considered not just statistically significant, but clinically relevant as well.”

More and more women are living longer following a diagnosis of breast cancer. The 10-year survival rate is greater than 70% in Europe and 84% for non-metastatic invasive disease in the United States.

 Quality of life is extremely important for these patients and de Ligt said these findings confirm the necessity for personalized approaches to the follow-up of cancer patients, some of whom still require special attention as long as 5 years after diagnosis.

de Ligt and her colleagues surveyed 404 women who received surgery with or without adjuvant treatment for stage I to III breast cancer selected from the Netherlands Cancer Registry. Participants were 1 to 5 years postdiagnosis and compared with a representative sample of 1300 women from the general population.

Investigators assessed participants for fatigue, nausea, pain, dyspnea, insomnia, appetite, constipation, diarrhea, financial burden, and emotional and cognitive symptoms on a scale 0-100 through the EORTC-QLQ-C30. Participants were then segregated into low- (28.7%), intermediate- (55.4%), and high-burden groups (14.6%) based on their responses.

de Ligt and her team also determined that patients with comorbidities such as heart disease and diabetes were more likely to experience a high symptom burden. de Ligt said the association was so strong that investigators could not connect the level of symptom burden with the type of therapy received.

“Future research should attempt to measure patients’ health-related quality of life through Patient Reported Outcome Measures (PROMs) before the start of treatment for breast cancer and afterwards to allow us to measure the effect of the therapy,” she said.

de Light KM, de Rooij BH, Walraven I, et al. Towards tailored follow-up care for breast cancer survivors: cluster analyses based on symptom burden. Presented at: ESMO Breast Cancer Virtual Congress 2021. Abst # 134P_PR. 

Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow up. 

Breast cancer: statistics. Cancer.net. January 2021. Accessed May 4, 2021. https://www.cancer.net/cancer-types/breast-cancer/statistics

Breast Cancer Survivors Need More Tailored Follow-Up Care

Each patient with breast cancer has a unique experience. Their survivorship care should reflect that.

Breast Cancer