on the phase 2 CodeBreaK100 trial (NCT03600883) reported continued durable clinical benefit with Sotorasib (Lumakras) in the treatment of KRAS p.G12C-mutated non-small cell lung cancer (NSCLC).

At a median follow-up of 15.3 months, sotorasib was associated with a median overall survival (OS) of 12.5 months (95% CI, 10.0–not evaluable [NE]), a median progression-free survival (PFS) of 6.8 months (95% CI, 5.1-8.2), and an objective response rate (ORR) of 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).

“This makes sotorasib the first KRAS G12C inhibitor to demonstrate an OS benefit in a registrational phase 2 clinical trial,” Ferdinandos Skoulidis, MD, PhD, lead study author and assistant professor in the Department of Thoracic and Head and Neck Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a presentation during the meeting. “The efficacy of sotorasib was observed across various patient subgroups prespecified by baseline patient characteristics.”

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

-mutant tumors remain poor, and novel therapies are needed for those who progress on frontline therapy with checkpoint inhibition alone or with platinum-doublet chemotherapy, Skoulidis said.

Sotorasib is a first-in-class, irreversible, and selective KRAS G12C inhibitor that has demonstrated durable clinical benefit in previously treated patients with 

 p.G12C-mutant NSCLC. Based on earlier findings of CodeBreaK, the FDA approved sotorasib in May 2021 as the first treatment for adult patients with non–small cell lung cancer whose tumors harbor 

 G12C mutations and who have received at least 1 prior systemic therapy.3

With the longer follow-up of the phase 2 CodeBreaK100 trial, investigators presented updated efficacy and safety data, including mature OS, with a data cutoff date of March 15, 2021. The findings also incorporated data from biomarker subgroups and baseline characteristics.

In the phase 2 CodeBreaK100 trial, investigators enrolled 126 patients with locally advanced or metastatic NSCLC with a 

 p.G12C mutation as assessed by central testing of tumor biopsies to receive sotorasib orally at 960 mg once daily until disease progression. Patients with stable brain metastases were permitted.

Patients underwent radiographic scans every 6 weeks up to week 48 and once every 12 weeks thereafter. The primary end point of the trial was ORR via RECIST v1.1 criteria by independent central review; key secondary end points include DOR, disease control rate (DCR), time to response, PFS, OS, and safety.

The median age was 63.5 years (range, 37-80), and 30.2% of patients had an ECOG performance status of 0. Most patients (92.9%) were current or former smokers, and patients either had 1 (42.9%), 2 (34.9%), or 3 (22.2%) prior lines of systemic therapy. The types of prior treatment were platinum-based chemotherapy (89.7%), PD-1/PD-L1 inhibition (91.3%), or platinum-based chemotherapy plus PD-1/PD-L1 inhibition (81.0%).

The 37.1% ORR was comprised of a 3.2% (n = 4) CR rate and a 33.9% (n = 42) partial response rate; the stable disease rate was 43.5% (n = 54), and 16.1% (n = 20) of patients had progressive disease. Four patients could not be evaluated or were missing scans. The DCR was 80.6% (95% CI, 72.6%-87.2%), and the median time to response was 1.35 months.

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).

Efficacy was also evaluated in exploratory analyses of molecularly defined subgroups. Skoulidis noted that the likelihood of response to sotorasib was independent of whether patients had a 

 p.G12C mutant allele frequency. Tumor mutational burden (TMB) was also not a predictive factor of response; the ORR was 40% in those with TMB-high disease (≥10 mutations/megabase [mb]) and 42% in patients with TMB-low disease (<10 mutations/mb). Moreover, responses occurred in patients with co-occurring mutations in 

“This is important because inactivating somatic mutations in 

 have been previously associated with worse clinical outcomes with standard-of-care systemic therapies, including chemoimmunotherapy, platinum-doublet chemotherapy, checkpoint inhibitor monotherapy, as well as chemotherapy with docetaxel,” Skoulidis said.

Additionally, investigators noted that in patients 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. The ORR was 23% in patients with 

-mutant disease; and 42% in patients with 

 wild-type disease. 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.

“Although, it should be noted that objective responses to sotorasib were observed in 20% of 

Regarding safety, mostly grade 1/2 treatment-related adverse events (TRAEs) were observed. All-grade TRAEs occurred in 69.8% of patients and grade 3 events in 19.8% of patients. The most common grade 3 TRAEs included diarrhea (4.0%), increased alanine aminotransferase (ALT; 6.3%), increased aspartate aminotransferase (AST; 5.6%), increased blood alkaline phosphatase (0.8%).

TRAEs that led to dose modifications occurred in 22.2% (n = 28) of patients, and treatment discontinuations due to TRAEs occurred in 7.1% (n = 9) of patients. The latter included drug-induced liver injury (n = 3), liver function test increase (n = 1), increased ALT (n = 2), increased AST (n = 2), increased alkaline phosphatase (n = 1), increased transaminases (n = 1), pneumonitis (n = 2), and dyspnea (n = 1).

The confirmatory phase 3 CodeBreak200 trial (NCT04303780), which is evaluating sotorasib vs docetaxel in patients with pretreated 

 p.G12C-mutated NSCLC, is currently ongoing.

1. 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 

p.G12C mutated non-small cell lung cancer. 

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

2. Skoulidis F, Li BT, Dy GK, et al. Sotorasib for lung cancers with 

. Published online June 4, 2021. doi:10.1056/NEJMoa2103695

3. FDA approves first targeted therapy for lung cancer mutation previously considered resistant to drug therapy. News release. FDA. May 28, 2021. Accessed June 4, 2021. 

This article was originally published on Cancer Network as 

“Sotorasib to Treat KRAS p.G12C+ NSCLC Produced Durable Clinical Benefit”

Articles

Sotorasib produced continued durable clinical benefit in patients with pretreated KRAS p.G12C+ NSCLC.  

Sotorasib Produces Durable Clinical Benefit in Treatment of KRAS p.G12C + NSCLC 

Durable improvements were seen with nivolumab (Opdivo) alone or in combination with ipilimumab (Yervoy) compared to treatment with single-agent ipilimumab in patients with previously untreated advanced melanoma, according to a 6.5-year follow-up of the CheckMate-067 trial presented at the 2021 ASCO Annual Meeting.

The long-term data showed that the median OS with the combination was 72.1 months (95% CI, 38.2–not reached) and 36.9 months with nivolumab alone (95% CI, 28.2-58.7), compared with 19.9 months with ipilimumab alone (95% CI, 16.8-24.6). This is reportedly the longest median OS in a phase 3 clinical trial of advanced melanoma.

Additionally, the 6.5-year progression-free survival (PFS) rate was 34% with nivolumab and ipilimumab and the median PFS was 11.5 months. The rates were 29% and 7% with nivolumab and ipilimumab as single agents, respectively; the median PFS was 6.9 months and 2.9 months, respectively.

“The sustained OS and PFS benefit shown with nivolumab-based treatment, particularly the nivolumab plus ipilimumab combination, has changed the way we look at long-term efficacy outcomes for patients with advanced melanoma,” Jedd D. Wolchok, MD, PhD, FASCO, lead author and chief of the Immuno-Oncology Service, Human Oncology and Pathogenesis Program, at Memorial Sloan Kettering Cancer Center, stated in a press release.2 “These new results from the CheckMate-067 trial, with nearly half of patients treated with the nivolumab and ipilimumab combination surviving to 6.5 years, confirm the durable, sustained benefit of the combination in patients with advanced melanoma.”

In 2015, the FDA approved the combination of nivolumab and ipilimumab for the treatment of patients with metastatic melanoma, based on earlier findings from CheckMate-067. Nivolumab is also approved for use as a single agent in this patient population.

In the double-blind, phase 3 CheckMate-067 study, investigators randomized patients with previously untreated unresectable advanced (stage III or IV) melanoma 1:1:1 to receive the combination of nivolumab at 1 mg/kg and ipilimumab at 3 mg/kg for 4 doses, followed by nivolumab at 3 mg/kg every 2 weeks (n = 314), nivolumab alone at 3 mg/kg every 2 weeks plus placebo (n = 316), or ipilimumab alone at 3 mg/kg every 3 weeks for 4 doses plus placebo (n = 315). Treatment was administered until disease progression or unacceptable toxicity.

Patients were stratified by PD-L1 status, 

 mutational status, and metastasis stage.

The co-primary end points of the trial were PFS and OS; secondary end points included objective response rate, descriptive efficacy assessments, and safety.

At the 6.5-year analysis, 49% of patients were alive and in follow-up. Of this percentage, 77% of patients who were treated with nivolumab plus ipilimumab were reported to be off of therapy and did not receive subsequent systemic treatment. Sixty-nine percent of those on nivolumab alone, and 43% of those on single-agent ipilimumab also have been off of treatment and did not require subsequent systemic therapy.

The clinical benefit was sustained and observed with both nivolumab/ipilimumab and nivolumab alone across relevant key subgroups, which included those with 

 wild-type tumors, and patients with baseline liver metastases.

 wild-type melanoma, the OS rate was 46% in those who received the combination, 42% for nivolumab alone, and 22% for ipilimumab alone. In those with liver metastases, the OS rates were 38%, 31%, and 22% for the combination, nivolumab monotherapy, and ipilimumab monotherapy, respectively.

In the combination arm, as well as in the single-agent nivolumab arm, the median duration of response (DOR) has still not yet been reached; the median DOR was 19.2 months for those on the ipilimumab arm.

Regarding safety, the profile of nivolumab and ipilimumab combined was found to be consistent with prior data of the regimen and no new safety signals were observed. No additional treatment-related deaths had occurred since the 5-year analysis of CheckMate-067.

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 59% of patients on the nivolumab/ipilimumab arm, in 24% on the nivolumab-alone arm, and in 28% of patients on the ipilimumab arm.

“These results build upon our decade-long legacy in treating melanoma, which began when the average life expectancy following a diagnosis of metastatic melanoma was roughly six months and less than 10% of patients survived beyond five years,” stated Gina Fusaro, development lead, melanoma, Bristol Myers Squibb.

 “With some of the longest follow-up with immunotherapies to date, Opdivo and Yervoy have consistently demonstrated durable, long-term survival benefits for patients diagnosed with advanced melanoma.”

Previously, 5-year follow-up findings from CheckMate-067, which were published in the 

, showed that the median OS with nivolumab/ipilimumab was not reached and was 36.9 months with nivolumab alone, compared with 19.9 months with ipilimumab alone (HR, 0.52 for nivolumab/ipilimumab vs ipilimumab; HR, 0.63 for nivolumab vs ipilimumab). The median follow-up was 60 months.

At 5 years, the OS rate was 52% with nivolumab plus ipilimumab, 44% with nivolumab alone, and 26% with ipilimumab alone.

Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. J Clin Oncol. 2021;39(suppl 15):9506. doi:10.1200/JCO.2021.39.15_suppl.9506

Six-and-a-half-year outcomes for Opdivo (nivolumab) in combination with Yervoy (ipilimumab) continue to demonstrate durable long-term survival benefits in patients with advanced melanoma. News release. Bristol Myers Squibb. May 19, 2021. Accessed June 6, 2021. https://bit.ly/3pnRufC

Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. 

. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836

Nivolumab with or without ipilimumab improved survival over ipilimumab alone in patients with previously untreated advanced melanoma. 

Melanoma Outcomes Are Improved With Nivolumab Alone or With Ipilimumab

The FDA has granted an accelerated approval to loncastuximab tesirine (Zynlonta) for the treatment of adult patients with relapsed/refractory large B-cell lymphoma following 2 or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma.

The approval for loncastuximab tesirine is based on findings from the pivotal phase 2 LOTIS 2 study, in which the CD19-directed antibody and alkylating agent conjugate elicted a 48.3% objective response rate (ORR), which included a 24.1% complete response (CR) rate in patients with relapsed/refractory disease who had received 2 or more previous lines of systemic treatment.2

In the multicenter, open-label, single arm phase 2 LOTIS 2 study, investigators evaluated the safety and efficacy of 

 in patients with relapsed/refractory DLBCL who had received 2 or more previous lines of systemic treatment; all patients received a median of 3 lines of prior therapy.

Loncastuximab tesirine was administered as a 30-minute infusion at a 150-μg/kg dose once every 3 weeks for the first 2 cycles. In subsequent cycles, the drug was administered at a dose of 75 μg/kg. Treatment was given for 1 year, or until disease progression, unacceptable toxicity, or when other discontinuation criteria were met.

At the April 6, 2020 data cutoff, 145 participants were enrolled to the trial; these patients had received a mean of 4.3 cycles of the ADC (range, 1-15). Additional data revealed during the 

2020 European Hematology Association (EHA) Congress

 showed that loncastuximab tesirine induced an ORR of 37.9% in patients who were refractory to their frontline treatment; this rate was 36.9% in patients who were refractory to their last-line previous treatment. The median duration response achieved with the ADC was 10.25 months.

Regarding safety, loncastuximab tesirine was found to be tolerable and no new safety signals had been observed. The most common grade 3 or higher treatment-emergent adverse effects reported with the ADC in 10% or more patients comprised neutropenia (25.5%) with low incidence of febrile neutropenia (3.4%), thrombocytopenia (17.9%), increased gamma-glutamyl transferase (16.6%), and anemia (10.3%).

Loncastuximab tesirine is also under examination in combination with ibrutinib

 (Imbruvica) in patients with relapsed/refractory DLBCL or mantle cell lymphoma (MCL). In the phase 1/2 trial, the ADC was administered in 30-minute IV infusions as part of a standard 3+3 dose-escalation trial design. Patients received doses of 60 μg/kg or 90 μg/kg. Loncastuximab tesirine was given every 3 weeks for the first 2 doses, with concurrent fixed-dose oral ibrutinib given at 560 mg/day for up to 1 year.

At the April 6, 2020 data cutoff of, a total of 25 participants had been enrolled to the trial; 23 of these patients had DLBCL, while 2 patients had MCL. Eighteen patients were evaluable for antitumor activity. Interim data from the phase 1 portion of the research, which were also presented during the 2020 EHA Congress, demonstrated that the combination elicited an ORR of 66.7% with a CR rate of 50.0% across the dose levels. Moreover, at the recommended phase 2 dose of 60 μg/kg, the combination induced an ORR of 75.0% with a 58.3% CR rate.

The phase 3 confirmatory LOTIS 5 trial (NCT04384484) is assessing the combination of loncastuximab tesirine and rituximab (Rituxan) vs chemoimmunotherapy in patients with relapsed/refractory DLBCL.3

ADC Therapeutics announces maturing data from pivotal phase 2 clinical trial and phase 1/2 combination clinical trial of loncastuximab tesirine (Lonca) in patients with relapsed or refractory diffuse large B-cell lymphoma. News release. ADC Therapeutics SA. June 12, 2020. Accessed November 20, 2020. 

Study to evaluate loncastuximab tesirine with rituximab versus immunochemotherapy in participants with relapsed or refractory diffuse large B-cell lymphoma. Clinicaltrials.gov. Updated September 17, 2020. Accessed November 20, 2020. 

https://clinicaltrials.gov/ct2/show/NCT04384484

This article was originally published on OncLive as, "

FDA Approves Loncastuximab Tesirine for Relapsed/Refractory Large B-Cell Lymphoma.

FDA Approves Loncastuximab Tesirine for Relapsed/Refractory DLBCL

The FDA has approved idecabtagene vicleucel (ide-cel; Abecma) as the first BCMA-directed chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

The approval is based on findings from the pivotal, phase 2 KarMMA trial, in which ide-cel elicited an overall response rate (ORR) of 72% (95% CI, 62%-81%) and a stringent complete response (sCR) rate of 28% (95% CI, 19%-38%) in an efficacy evaluable population (n = 100) of patients with relapsed/refractory myeloma who had received at least 4 prior treatments.

Ide-cel is approved as a one-time infusion with a recommended dose range of 300 to 460 x 106 CAR-positive T cells.

“In the KarMMa study, ide-cel elicited rapid responses in the majority of patients, and these deep and durable responses were observed in patients with triple-class exposed and refractory multiple myeloma,” said Nikhil C. Munshi, MD, associate director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “As a treating physician, I often work with patients with relapsed or refractory multiple myeloma who are in critical need of new therapies. Now, with the approval of ide-cel as the first anti-BCMA CAR T cell therapy, we are excited to finally be able to offer patients a new, effective personalized treatment option that is delivered through a single infusion.”

KarMMA included a total of 128 patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies, including an IMiD, a PI, and an anti-CD39 antibody. The median age of the participants was 61 years, and 35% of patients had high-risk cytogenetics. About half of patients, or 51%, had high tumor burden, while 39% had extramedullary disease and 85% had 50% or higher tumor BCMA expression. Forty-five percent of participants had an ECOG performance status of 0, 53% had a status of 1, and 2% had a status of 2. R-ISS stage disease was I in 11% of patients, II in 70% of patients, and III in 16%. Overall, participants had received a median of 6 previous treatments (range, 3-16).

The majority of patients, or 94%, had undergone 1 previous autologous stem cell transplant; 34% had undergone more than 1 of these procedures. Moreover, 88% of participants had been given bridging therapies during CAR T-cell manufacturing, but only 4% responded to that treatment. Ninety-four percent of patients proved to be refractory to anti-CD38 antibodies, and the majority, or 84%, were determined to be triple refractory.

In the trial, participants were given at the following CAR T cell doses: 150 x 106 (n = 4), 200 x 106 (n = 70), or 450 x 106 (n = 54). The median follow-up was 18 months for the first dosing cohort, 15.8 months in the second, and 12.4 months in the third. Across the entire study population, the median follow-up was 13.3 months. The primary end point of the trial was ORR, and key secondary end points were comprised of CR, DOR, PFS, overall survival (OS), and quality of life.

Additional findings showed that responses with ide-cel were rapid and durable; the median time to response was 30 days (range, 15-88) and the median duration of response was 11 months (95% CI, 10.3-11.4) for all responders and 19 months (95% CI: 11.4–not estimable [NE]) for those who achieved a sCR. Of the 28 patients who achieved a sCR, approximately 65% (95% CI, 42%-81%) had remissions that lasted at least 1 year.

Ide-cel does come with a Boxed Warning for cytokine release syndrome (CRS), neurologic toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged cytopenia.

Regarding safety in the KarMMa trial, ide-cel was associated with mostly low-grade occurrence of cytokine release syndrome (CRS) and neurotoxicity (NT). Any-grade CRS occurred in 85% of patients via the Lee grading system; grade 3 or higher CRS occurred in 9% of patients. One patient died from CRS. The median time to onset of CRS was 1 day (range, 1-23) and the median duration of CRS was 7 days (range, 1-63).

Any-grade and grade 3 or higher NT occurred in 28% and 4% of patients, respectively. One patient had ongoing grade 2 NT at the time of death, and the median time to onset of NT was 2 days (range, 1-42). NT did resolve in 92% of patients and median time to resolution was 5 days (range, 1-61).

Furthermore, hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) occurred in 4% of patients, including 1 patient who developed fatal multi-organ HLH/MAS with CRS and 1 patient with fatal bronchopulmonary aspergillosis; HLH/MAS contributed to the fatal outcome. Three cases of grade 2 HLH/MAS resolved.

Forty-one percent and 49% of patients experienced prolonged grade 3/4 neutropenia and thrombocytopenia, respectively. Three patients underwent stem cell transplant for hematopoietic reconstitution because of prolonged cytopenia, 2 of whom died from complications of prolonged cytopenia that occurred in the setting of ongoing or prior severe CRS or HLH/MAS.

The most common (≥20%) types of nonlaboratory adverse events (AEs) included CRS, infections, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.

Serious AEs occurred in 67% of patients; the most common (≥5%) were CRS (18%), general physical health deterioration (10%), pneumonia (12%), infections (19%), viral infections (9%), sepsis (7%), and febrile neutropenia (6%). The most common grade 3/4 nonlaboratory adverse reactions were febrile neutropenia (16%) and infections (14%). Fatal AEs were reported in 6% of patients.

“Our journey to today’s approval of Abecma started nearly a decade ago with pioneering research at bluebird bio and has been driven ever since by our mission to provide patients with multiple myeloma a new approach to fight this relentless disease. This achievement would not have been possible without all of the patients, caregivers, investigators and healthcare staff who participated in our clinical studies, as well as the tremendous collaboration with the FDA,” said Nick Leschly, chief bluebird, of bluebird bio, which jointly develops ide-cel with Bristol Myers Squibb. “Today’s announcement represents an important milestone for bluebird bio, marking both our first approved treatment in oncology and our first approved treatment in the United States.”

U.S. Food and Drug Administration approves Bristol Myers Squibb’s and bluebird bio’s Abecma (idecabtagene vicleucel), the first anti-BCMA CAR T cell therapy for relapsed or refractory multiple myeloma. News release. Bristol Myers Squibb and bluebird bio. March 26, 2021. Accessed March 26, 2021. https://bwnews.pr/39jWjjd

The FDA has approved idecabtagene vicleucel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

FDA Approves Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer (TNBC) as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm, explained William J. Gradishar, MD, in a presentation during the NCCN 2021 Virtual Annual Conference.

“In early-stage disease, anthracycline/taxane therapy—the sequence not so critical—remains foundational,” Gradishar said. “The addition of […] checkpoint inhibitors can increase the [pathologic complete response] rate, but the data in the adjuvant setting are still awaited. We need event-free survival to determine the overall impact.”

Moreover, for patients with residual disease following neoadjuvant therapy, capecitabine is an appropriate treatment, said Gradishar, professor of medicine of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

However, in the metastatic setting, immunotherapy has improved progression-free and overall survival (OS) in a subset of patients with TNBC, and the antibody-drug conjugates (ADCs) have provided another option for those who have progressed on prior treatment.

All these advances with evidence-backed data led to updates in the latest version of the National Comprehensive Cancer Network® Guidelines Version 2.2021 in Invasive Breast Cancer.

The updated guidelines list the following as preferred preoperative/adjuvant therapy regimens—as category 2A recommendations —in HER2-negative breast cancer:

Dose-dense doxorubicin/cyclophosphamide followed by paclitaxel every 2 weeks

Dose-dense doxorubicin/cyclophosphamide followed by weekly paclitaxel

Capecitabine for patients with TNBC and residual disease after preoperative treatment with taxane-, alkylator-, and anthracycline-based chemotherapy

In the metastatic setting, the following regimens are noted as category 1 recommendations in HER2-negative metastatic breast cancer:

Atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) as a preferred frontline therapy for patients with PD-L1 expression with 1% or greater tumor-infiltration immune cells (ICs)

Pembrolizumab (Keytruda) plus chemotherapy (either nab-paclitaxel, paclitaxel, or gemcitabine and carboplatin) as a preferred frontline therapy for PD-L1–positive patients with a combined positive score (CPS) of 10 or higher

Carboplatin and cisplatin for TNBC and germline 

Sacituzumab govitecan (Trodelvy) is also considered a recommended regimen in recurrent or stage IV HER2-negative breast cancer. A number of chemotherapy regimens also remain as preferred options in the NCCN guidelines for use in the metastatic setting.

In his presentation on the evidence behind the guideline updates, Gradishar touched upon selecting optimal localized therapy for patients with locally advanced TNBC, recognizing key patient factors to influence systemic treatment selection for metastatic disease, and optimally managing common adverse effects (AEs) linked with new agents used to manage this malignancy.

Gradishar homed in on the summary of neoadjuvant platinum-based therapy in TNBC, adding that carboplatin augments pathologic complete response (pCR) in TNBC. For example, when carboplatin was added to chemotherapy regimens for patients with TNBC in the GeparSixto, CALGB 40603, and BrighTNess studies, the pCR rates increased to 53.2%, 54%, 58% and 53% (both BrighTNess), respectively.

However, there has been controversy with using platinum agents concomitantly with chemotherapy, which was seen in GeparSixto. Also, in CALGB 40603, the addition of carboplatin resulted in markedly higher toxicity, which led to significantly fewer patients (less than 65%) receiving 11 to 12 doses of paclitaxel vs the control group (more than 85%).

A meta-analysis of 9 randomized trials evaluated the role of platinum-based therapy as neoadjuvant therapy for TNBC (n = 2109). Data showed that platinum therapy significantly improved pCR from 37.0% to 52.1% (odds ratio [OR], 1.96; 95% CI, 1.46-2.62; 

 <.001), even when restricting the analysis to 3 studies with standard chemotherapy regimens (n = 611; OR, 2.53; 95% CI, 1.37-4.66; 

However, no improvement was observed in a subset of patients with germline 

 mutations (OR, 1.17; 95% CI, 0.51-2.67; 

 = .711). There was also a significantly higher risk of grade 3/4 hematologic adverse events (AEs).

The guidelines state that, “Several studies have shown improved pCR rates with the incorporation of platinum. However, long-term outcomes remain unknown. The routine use of platinum agents as part of neoadjuvant therapy for TNBC is not recommended for most patients (including 

 mutation carriers), but it may be considered in select patients, such as those for whom achieving better local control is necessary.”

Citing the updated guidelines, Gradishar noted that the inclusion of platinum agents in the neoadjuvant setting remains controversial.

“For most patients, this would not be viewed as standard, but it could be used in individual patients,” he added.

Capecitabine has also been noted in the guidelines as an option for patients with residual disease following neoadjuvant therapy. In the CREATE-X trial, which had 887 evaluable patients with stage I to IIIB, HER2-negative breast cancer, who did not have a pCR and/or were node positive after surgery and neoadjuvant chemotherapy, patients received capecitabine at 2500 mg/m2 daily on days 1 to 14, repeated every 3 weeks for 8 cycles, plus standard therapy or standard therapy alone.

Thirty-two percent of patients had TNBC, 95% were treated with anthracyclines and taxanes, and 41% were node positive.6 Results showed that the real impact of capecitabine was seen in the TNBC subset, in regard to disease-free survival (DFS; HR, 0.58; 95% CI, 0.39-0.87) and overall survival (OS; HR, 0.52; 95% CI, 0.30-0.90).

“The use of capecitabine can be justified in such patients with residual triple-negative disease following preoperative therapy,” said Gradishar, citing the ongoing ECOG-ACRIN EA1131 (NCT02445391) and SWOG 1418 (NCT02954874) trials as efforts to evaluate adjuvant capecitabine in basal-like residual TNBC and adjuvant pembrolizumab (Keytruda) in TNBC, respectively.

Immunotherapy for PD-L1–Positive Disease

Checkpoint blockade has been evaluated in both the neoadjuvant and metastatic settings. In his presentation, Gradishar focused on the IMpassion031 trial of neoadjuvant atezolizumab with nab-paclitaxel, which showed a pCR rate of 58% compared with 41% with chemotherapy alone (

KEYNOTE-522, a phase 3 trial of pembrolizumab and carboplatin/paclitaxel vs carboplatin/paclitaxel and placebo in previously untreated patients with stage II or III TNBC, garnered attention in 2020 and 2021 this year. At an interim analysis with a median follow-up of 15.5 months, data showed that pembrolizumab improved event-free survival (EFS) over chemotherapy alone (HR, 0.63; 95% CI, 0.43-0.93).

“pCR rates that go up are great, but does it translate into an improvement in EFS, and hopefully, downstream even further [with] overall survival?” asked Gradishar. “If you ask the question: Who are the patients who are gaining the greatest benefit? For the most part, [it is] in the patients with PD-L1–positive disease.”

Data from KEYNOTE-522 were further extrapolated at an FDA Oncology Drugs Advisory Board Meeting (ODAC) on February 8, 2021. Although the pembrolizumab arm did have an improved pCR rate versus placebo with neoadjuvant chemotherapy, the ODAC committee voted 10 to 0 against an approval of pembrolizumab in this setting, adding that a regulatory decision should be deferred until further data from KEYNOTE-522 become available.

“The biggest reason is not because the pCR rate was questioned, but rather, the pCR rate over time, was actually starting to decrease,” Gradishar shared. “Most importantly, there were insufficient data at that point to say [whether this] affected EFS. This does not stick a dagger in the idea of checkpoint inhibitors preoperatively, but rather, it requires further follow-up to see whether the impact is going to have an outcome measure on the overall outcome of patients.”

The current role for immunotherapy in the metastatic setting of TNBC is based upon the IMpassion130, IMpassion131, and KEYNOTE-355 studies, Gradishar emphasized.

In the phase 3 IMpassion130 trial, atezolizumab plus nab-paclitaxel compared with nab-paclitaxel and placebo was evaluated in the first-line treatment of patients with metastatic or unresectable locally advanced TNBC (n = 902). Patients had to be treatment naïve in the metastatic setting and have an ECOG performance status of 0 or 1. The co-primary end points were progression-free survival (PFS) and OS in both the intent-to-treat (ITT) and PD-L1–positive population.

PD-L1 IC status was assessed via the SP142 assay. In the PD-L1–positive population, the median PFS was 7.5 months compared with 5.3 months for the atezolizumab and placebo arms, respectively (HR, 0.63; 95% CI, 0.50-0.80; 

 <.0001).10 A similar trend was seen in this subset for OS at 25.0 and 18.0 months, respectively (HR, 0.71; 95% CI, 0.54-0.93). No benefit was observed with atezolizumab in the PD-L1–negative groups for PFS (HR, 0.93) nor OS (HR, 0.97).

Most recently, at the ESMO 2020 Virtual Congress, findings of the final OS analysis showed that the median OS with atezolizumab was 25.4 months vs 17.9 months for placebo/nab-paclitaxel (HR, 0.67; 95% CI, 0.53-0.86) in the PD-L1–positive population.11 The 3-year OS rates were 36% and 22% in this subgroup, respectively.

Similarly, in the phase 3 KEYNOTE-355 study, patients with previously untreated locally recurrent inoperable or metastatic TNBC, with no active central nervous system metastases or active autoimmune disease, were randomized 2:1 to receive pembrolizumab/chemotherapy or placebo/chemotherapy until disease progression or cessation of study treatment. Chemotherapy regimens consisted of nab-paclitaxel, paclitaxel, and gemcitabine and carboplatin.

Data showed that, in the ITT population, PFS was favored in the pembrolizumab/chemotherapy arm vs placebo/chemotherapy at 7.5 months and 5.6 months, respectively (HR, 0.82; 95% CI, 0.69-0.97), but was higher in those with PD-L1 combined positive score (CPS) of 1 or greater (HR, 0.74; 

 value boundary of .00111 was not met.12 This benefit was even higher in patients with a PD-L1 CPS of 10 or greater (HR, 0.65; 

 = .0012). In the ITT population, statistical significance was not tested due to the prespecified hierarchical testing strategy.

“In this dataset, we don’t yet have a survival advantage that has been demonstrated or reported,” explained Gradishar. “We simply don’t have enough events yet to report OS.”

However, it was the double-blind, placebo-controlled, randomized, phase 3 IMpassion131 study that Gradishar coined as a “fly in the ointment.”

Here, atezolizumab was combined with paclitaxel compared with paclitaxel/placebo in a similar patient population. At a primary analysis of the PD-L1–positive population, the median PFS was 6.0 months with the atezolizumab arm and 5.7 months with placebo/paclitaxel, demonstrating a stratified HR of 0.82 (95% CI, 0.60-1.12; log-rank 

 = .20).13 Updated OS findings, at a data cutoff date of August 19, 2020, showed that the median OS was 22.1 months and 28.3 months with atezolizumab/paclitaxel and paclitaxel/placebo (HR, 1.12; 95% CI, 0.76-1.65). The benefit was similar in the ITT population (HR, 1.11; 95% CI, 0.87-1.42).

Some key reasons for the discordant results between this trial and IMpassion130, Gradishar noted, could be that IMpassion131 utilized corticosteroids, and also utilized paclitaxel vs nab-paclitaxel in IMpassion130.

Safety has also been an area of investigation with checkpoint blockade in metastatic TNBC, specially with organ-specific immune-related AEs, such as pneumonitis, pruritis, rash, anemia, and colitis, among others.

“If you look at severe or high-grade AEs, they are relatively uncommon and can be managed for most patients, but certainly as these agents go into the earlier-stage settings, these become more of an issue,” Gradishar noted.

The ADC sacituzumab govitecan was granted an accelerated approval in April 2020 for the treatment of adult patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease, based on phase 1/2 findings.14

Moreover, the confirmatory phase 3 ASCENT study showed further benefit with the agent in this setting. The median PFS by blinded independent central review was 5.6 months (95% CI, 4.3-6.3) in the sacituzumab govitecan arm compared with 1.7 months (95% CI, 1.5-2.6) with physician’s choice of single-agent chemotherapy in patients with previously treated metastatic TNBC (HR, 0.41; 95% CI, 0.32-0.52; 

Additional data presented at the 2020 San Antonio Breast Cancer Symposium showed that the benefit with sacituzumab govitecan is seen independent of the level of Trop-2 expression or 

“Sacituzumab govitecan is the newest kid on the block, and this is a drug that has utility in patients with triple-negative disease who have progressed through other therapies,” said Gradishar.

Two phase 3 trials in advanced breast cancer highlight the significance of PARP inhibition and therefore have had an impact on the latest guidelines: OympiAD and EMBRACA.

-mutated, HER2-negative metastatic breast cancer, who had received at least 2 prior lines of chemotherapy, were randomized 2:1 to receive olaparib or physician’s choice of treatment. Olaparib was linked with a significant reduction in the risk of death in patients who received it as a frontline treatment versus chemotherapy (HR, 0.51; 95% CI, 0.29-0.90; 

 = .02), but not in those who had received prior chemotherapy (HR, 1.13; 95% CI, 0.79-1.64; 

The EMBRACA trial enrolled patients with germline 

-mutated, HER2-negative locally advanced or advanced breast cancer who had received at least 3 prior lines of chemotherapy. Here, the median PFS was 8.6 months (95% CI, 7.2-9.3) with talazoparib and 5

6 months (95% CI, 4.2-6.7) with chemotherapy (HR, 0.54; 95% CI, 0.41-0.71; 

One-year PFS rates were 37% and 20%, respectively.

Gradishar noted that talazoparib and olaparib both improve PFS in patients with germline 

-mutated metastatic breast cancer compared with chemotherapy, and that talazoparib is also promising as a single-agent neoadjuvant therapy in germline 

 mutation and have high PD-L1 expression, Gradishar suggested using a checkpoint inhibitor with chemotherapy first before going onto a PARP inhibitor.

NCCN Guidelines update: triple-negative breast cancer. Presented at: NCCN 2021 Virtual Annual Conference; March 18-20; 2021; Virtual.

von Minckwitz G, Schneeweiss A, Loibl S, et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. 

. 2014;15(7):747-756. doi:10.1016/S1470-2045(14)70160-3

Sikov WM, Berry DA, Perou CM, et al. Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). 

. 2015;33(1):13-21. doi:10.1200/JCO.2014.57.0572

Loibl S, O’Shaughnessy J, Untch M, et al. Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. 

. 2018;19(4):497-509. doi: 10.1016/S1470-2045(18)30111-6

Poggio F, Bruzzone M, Ceppi M, et al. Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis. 

. 2018;29(7):1497-1508. doi: 10.1093/annonc/mdy127

Masuda N, Lee S-J, Ohtani S, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. 

. 2017;376(22):2147-2159. doi:10.1056/NEJMoa1612645

Mittendorf EA, Zhang H, Barrios CH, et al. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. 

. 2020;396(10257):1090-1100. doi:10.1016/S0140-6736(20)31953-X

Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer

. 2020;382(9):810-821.doi:10.1056/NEJMoa1910549

Merck announces outcome of Oncologic Drugs Advisory Committee (ODAC) for Keytruda (pembrolizumab) for treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC). Merck. News release. Published February 9, 2021. Accessed March 19, 2021. 

Schmid P, Rugo HS, Adams S, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2020;21(1):44-59. doi:10.1016/S1470-2045(19)30689-8.

Emens LA, Adams S, Barrios CH, et al. IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-negative breast cancer. 

. 2020;31(suppl_4):S1142-S1215. doi:10.1016/annonc/annonc325

Cortes Jm Cescon DW, Rugo HS, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. 

. 2020;396(10265):1817-1828. doi:10.1016/S0140-6736(20)32531-9

Miles DW, Gligorov J, André F, et al. Primary results from IMpassion131, a double-blind placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/metastatic triple-negative breast cancer (mTNBC). 

Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. 

. 2019;380(8):741-751. doi:10.1056/NEJMoa1814213

Bardia A, Tolaney SM, Loirat D, et al. ASCENT: A randomized phase 3 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with previously treated metastatic triple-negative breast cancer (mTNBC). 

. 2020;31(suppl_4):S1149-S1150. doi:10.1016/j.annonc.2020.08.2245

Hurvitz SA, Tolaney SM, Punie K, et al. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual.

Robson M, Im S-A, Senkus E, et al. OlympiAD final overall survival: Olaparib versus chemotherapy treatment of physician's choice (TPC) in patients with HER2-negative metastatic breast cancer (mBC) and a germline 

m). 2018 AACR Annual Meeting; April 14-18, 2020; Chicago, IL. Abstract CT038.

Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline 

. 2018;379:753-763. doi:10.1056/NEJMoa1802905

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm.

Gina Mauro

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