Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents (BPAs), according to findings presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.1

“This safety analysis confirms the importance to give a bone-protecting agent when treating patients with CRPC and bone metastases,” Silke Gillessen, MD, Oncology Institute of Southern Switzerland, said during a presentation of the safety analysis.

In the randomized phase 3 EORTC-1333-GUCG/Peace-3 trial (NCT02194842), investigators randomized patients 1:1 to receive either enzalutamide at 160 mg daily plus radium-223 at 55 kBq/kg every 4 weeks for 6 cycles, or enzalutamide alone.

The study population included patients with bone-predominant mCRPC (≥2 bone metastases); asymptomatic or mildly asymptomatic disease; a WHO performance score of 0 or 1; no prior treatment with cyp17 inhibitors, enzalutamide, other radionucleotides, or hemibody radiotherapy; and no known brain or visceral metastases.

Radiographic progression-free survival served as the primary end point.

Following results of fractures occurring in the ERA223 trial (NCT02043678),2 the investigators of the EORTC-1333-GUCG/PEACE-3 trial decided to send out an urgent safety letter. “In this, it was made mandatory to use a bone-protecting agent in all patients for at least 6 weeks before starting radium-223. In April 2018, an IDMC analysis was done, and the recommendation was to continue the trial, but to use a bone-protecting agent in all patients from both arms,” explained Gillessen. “The IDMC is regularly monitoring the trial, and after the review in December last year, recommended to present the updated numbers regarding bone fractures to the scientific community.”

In her presentation at the 2021 ASCO Annual Meeting, Gillessen offered updated results of the safety analysis from the trial, highlighting the impact of BPAs on fracture rates.

As of the April 2021 cut-off, of the 267 patients randomized to both treatment arms, 74 in each were given BPAs.

Before administering the safety letter, 45.2% of patients had not received a BPA, compared with just 3% who had not after the letter was sent out.

The cumulative incidence of fractures at 1 year was 37.1% (95% CI, 21.3%-53.0%) in the combination arm and 15.6% (95% CI, 5.6%-30.3%) in the enzalutamide alone arm. In men who received a BPA, the 1-year incidence of fractures was reduced to 2.7% (95% CI, 0.5%-8.5%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

At 18 months, the cumulative incidence was 45.9% (95% CI, 28.6%-61.6%) in the combination arm and 21.9% (95% CI, 9.5%-37.5%) in the enzalutamide alone arm, without a BPA. With a BPA, the incidence was 4.3% (95% CI, 1.1%-10.9%) and 2.6% (95% CI, 0.5%-8.3%), respectively.

“According to our study, we will continue and want to motivate all investigators to include [bone-protecting agents in the treatment of] patients. And hopefully, we can still report efficacy results as well. Importantly, the IDMC will also continue to closely monitor the study,” Gillessen said.

Radium-223 is an alpha-emitting radiopharmaceutical that has demonstrated an overall survival benefit in men with mCRPC, with the hypothesis that combining it with a novel androgen receptor (AR) pathway inhibitor could improve clinical outcomes.

In the randomized, double-blind, placebo-controlled ERA223 trial, investigators evaluated the use of concurrent treatment with abiraterone acetate (Zytiga; 1000 mg once daily) plus prednisone (5 mg twice daily) or prednisolone (5 mg twice daily) and radium-223 (55 kBq/kg) in 806 patients with mCRPC.2 Symptomatic skeletal event-free survival served as the primary end point.

BPAs were only permitted in the trial if a patient was receiving them at baseline. Initiation of such agents during the study was prohibited to prevent confounding effects. Therefore, only 60% of patients had not received a BPA at study entry.

In a posthoc analysis of the trial, BPAs significantly reduced the rate of fractures in both treatment arms.

“To better understand the nature of these fractures, an independent review of the fracture events was performed. Interestingly, the maturity of fractures in both groups occurred at sites with no detectable metastasis and were considered osteoporotic or traumatic,” Gillessen explained.

“Treatment with [androgen-deprivation therapy (ADT)] can induce bone loss. And we know that bone-protecting agents can be used in this bone loss and also in osteoporotic fractures in men treated with ADT,” Gillessen said. “Bone protecting agents can also delay the time to a first skeletal-related event [SRE] in men with castration-resistant prostate cancer and bone metastasis.”

Skeletal complications may be common in patients with advanced prostate cancer and result in 2 distinct mechanisms, she added: frailty, or osteoporotic fractures are reported in 11% of patients and SREs occur in up to 40% of those treated with ADT and an AR pathway inhibitor.

“To prevent these SREs, many guidelines recommend using bone-protecting agents for patients with castration-resistant prostate cancer and bone metastasis. Combining gamma radiation and hormonal manipulation is a well validated treatment strategy in prostate cancer,” Gillessen said.

1. Gillessen S, Choudhury A, Rodriguez-Vida A, et al. Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis. 

. 2021;39:(suppl 15; abstr 5002). doi: 10.1200/JCO.2021.39.15_suppl.5002.

2. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. 

Articles

Men with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer who are being treated with radium-223 (Xofigo) plus enzalutamide (Xtandi) can reduce their risk of fractures with the use of bone-protecting agents.

Bone-Protecting Agents Reduce Fracture Risk During Prostate Cancer Treatment

Treatment with the second-generation 4-1BB bi-specific chimeric antigen receptor (CAR) T-cell therapy C-CAR039 led to improved response rates – as well as a favorable safety profile – in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (B-NHL), according to phase 1 data presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

“C-CAR039 has demonstrated a favorable safety profile and highly promising efficacy in patients with relapsed/refractory B-NHL,” Aibin Liang, MD, Tongji Hospital of Tongji University, Shanghai, China, said during an oral presentation of the data.

According to the safety data, 100% of patients experienced at least 1 adverse event (AE) of any grade.

In total, 92.9% of patients reported cytokine release syndrome (CRS); however, Liang noted, that most were grade 1 or 2 and all events were reversible. Only 1 patient, who was treated in the 2.5x106 CAR T cells/kg, experienced grade 3 CRS. The most common symptoms were pyrexia (100%) and hypotension (23.1%).

The median time to onset of CRS events was 2.5 days (range, 0-10), with a median time to resolution of 4 days (range, 1-25). CRS cases were treated with tocilizumab (14.3%), corticosteroids (3.6%), or a combination of the 2 (3.6%).

Two cases of neurologic events – both in the 5.0x106 CAR T cells/kg group – occurred at a median time of onset of 16 days (range, 4-28). The median time to resolution was 31.5 days (range, 11-52).

“CRS in higher dose groups showed shorter time to onset and longer resolution time,” Liang said.

Cytopenias were common, “mostly related to Cy/Flu lymphodepletion and are reversible,” he added, noting that infection was also common, occurring in 53.6% of patients, with only 1 grade 3 event.

The most common grade 3 or higher AEs included lymphopenia (96.$%), leukopenia (89.3%), neutropenia (89.3%), anemia (32.1%), and thrombocytopenia (25%).

For efficacy, median follow-up was 7 months (range, 1.9-17.2).

The overall response rate (ORR) was 92.6% for the entire population, including an 85.2% complete response (CR) rate, 7.4% partial response (PR) rate, 3.7% with stable disease (SD), and 3.7% with progressive disease (PD). Broken down by disease subtype, ORR in those with diffuse large B-Cell Lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), follicular lymphoma (FL), and tFL were 91.7% (CR, 83.3%; PR, 8.3%), 100% (CR, 100%), 100% (CR, 100%), and 100% (CR, 100%), respectively. Liang noted that the CR rate was consistent among key subgroups, including dose level, disease type, cell or origin of cancer, age, sex, stage, IPI, double expressors, extranodal disease, prior lines of therapy, previous response status, previous ASCT, and bridging treatment.

The median time to first response was 1 month (range, 0.9-1.6), as was median time to CR (range, 0.9-6.0). Four patients relapsed at 3, 6, 8, and 9 months, respectively, after achieving CR. Median duration of response (DOR) has not been reached. The 6-month progression-free survival (PFS) was 83.2% (95% CI, 69.1-100).

“C-CAR039 proliferation and expansion in the peripheral blood correlated with B cell depletion,” Liang added.

C-CAR039 – a novel second generation 4-1BB bi-specific CAR T-cell therapy that targets both CD19 and cd20 antigens – has demonstrated in vitro anti-tumor activity against both single- and double-positive CD20/CD19-expressing tumors, as well as superior anti-tumor activity in both in vitro and in vivo to the bi-specific CAR T-cell therapy with the tandem linked scFvs of Leu16 and FMC63, Liang explained.

“This data strongly support moving this CAR design to clinic use as the lead asset,” he added.

Manufacturing the CAR T-cell therapy was carried out in a functionally closed, highly automated serum free system within a median of 6 days (range, 5-11). Median vein-to-vein time was 19 days (range, 12-67).

Dose escalation and expansion studies were conducted to evaluate the safety and efficacy of C-CAR039 in r/r B-NHL patients. C-CAR039 was administered as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

The phase 1 study is an open-label, dose escalation and expansion study conducted across 4 sites in China – designed to evaluate the safety and efficacy of this approach in patients with relapsed/refractory B-NHL.

Investigators administered C-CAR039 as a single intravenous dose after a 3-day cyclophosphamide plus fludarabine conditioning regimen.

Eligibility criteria included patients aged 18 to 75 years; relapsed/refractory B-NHL, including DLBCL, FL, and mantle cell lymphoma (MCL); either CD19- or CD20-positive disease; no active central nervous system (CNS) involvement; and have received anti-CD20 monoclonal antibodies.

The safety assessment included the incidence and severity of treatment-emergent adverse events (TRAEs), while the efficacy assessment was comprised of ORR, DOR, PFS, and OS.

In the trial, patients were treated across 3 doses: 1.0x106 CAR T cells/kg (DL1), 2.5x106 CAR T cells/kg (DL2), and 5.0x106 CAR T cells/kg (DL3).

As of April 20, 2021, 34 patients were infused with C-CAR039. In total, 28 were evaluable for safety, including 4 in the DL1 arm, 15 in the DL2 arm, and 9 in the DL3 arm; while 27 were evaluable for efficacy, including 4 in the DL1 arm, 15 in the DL2 arm, and 8 in the DL3 arm.

Median age was 55.5 years (range, 28-71). The majority of patients were male (89.3%), had diffuse large B-cell lymphoma (89.3%), an ECOG performance score of 0 (64.3%), and were Ann Arbor stage III/IV (75%). Moreover, 8 patients (28.6%) had double-expressor lymphoma.

The median number of prior lines of therapy was 3 (range, 1-5), including ASCT (17.9%), a BTK inhibitor (28.6%), and lenalidomide (Revlimid; 32.1%). Eight patients (28.6%) had never experienced a CR to prior therapies and 5 patients (17.9%) received bridging therapy.

“The early clinical efficacy signal is encouraging and compares favorably to anti-CD19 CAR T and peer therapies,” the study authors concluded. “These findings will be evaluated in more patients with longer follow-up to confirm safety, efficacy and duration of response.”

Liang A, Zhou L, Li P, et al. Safety and efficacy of a novel anti-CD20/CD19 bi-specific CAR T-cell therapy (C-CAR039) in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). 

. 2021;39:suppl 15; abstr 2507. doi: 10.1200/JCO.2021.39.15_suppl.2507.

ASCO Annual Meeting

The second-generation 4-1BB bi-specific CAR T-cell therapy was efficacious and safe in treating patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

Second-Generation CAR T-Cell Therapy Is ‘Highly Promising’ in Relapsed/Refractory B-NHL

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

In previously treated patients with chronic lymphocytic leukemia (CLL) that harbors del(17p) or del(11q), acalabrutinib (Calquence) had similar survival rates but fewer adverse events than ibrutinib (Imbruvica), according to findings presented at the 2021 ASCO Annual Meeting.

“Acalabrutinib is a more selective inhibitor of [Bruton tyrosine kinase (BTK)] and has been known to have less adverse events (AEs) when compared across trials. [Until] today, no clinical trial has directly compared ibrutinib to acalabrutinib in previously treated CLL. Our trial presented here does this,” said John C. Byrd, MD, professor of hematology at The Ohio State University.

Byrd presented findings from an open-label, randomized, noninferiority, phase 3 trial that compared acalabrutinib and ibrutinib in 533 patients.

 Patients were randomized to receive the BTK inhibitor acalabrutinib or ibrutinib until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS), and secondary endpoints were (in hierarchical order): all-grade atrial fibrillation, grade 3 or higher infection, Richter transformation, and overall survival (OS).

Overall, 268 patients received acalabrutinib and 265 received ibrutinib. Median age was 66 years and on average patients had 2 prior lines of therapies; 45.2% of patients had del(17p) and 64.2% had del(11q).

At a median follow-up of 40.9 months, acalabrutinib was noninferior to ibrutinib, with a PFS of 38.4 months in both arms (HR 1.00; 95% CI, 0.79-1.27).

Acalabrutinib was superior in all-grade atrial fibrillation incidence compared to ibrutinib (9.4% versus 16.0%, respectively; 

“When considering de-novo atrial fibrillation flutter occurring in patients who had never had this before, the difference between ibrutinib and acalabrutinib was greater,” Byrd explained. “Patients with acalabrutinib had a 6.2% incidence, whereas ibrutinib was 14.9%. Among patients developing atrial fibrillation and flutter, prior history of this and other risk factors were more common in the acalabrutinib arm.”

Other end points were comparable between the 2 treatments: 30.8% of patients on acalabrutinib and 30.0% of patients on ibrutinib experienced grade 3 or higher infection; 3.8% of patients on acalabrutinib versus 4.9% of those on ibrutinib had Richter transformation.

Average OS was not reached in either arm. There were 63 (23.5%) deaths in the acalabrutinib arm and 73 (27.5%) in the ibrutinib arm.

When it came to frequent (≥20%) all-grade AEs, the acalabrutinib arm had a lower instance of hypertension than ibrutinib (9.4% vs 23.2%, respectively), arthralgia (15.8% vs 22.8%), and diarrhea (34.3% vs 46.0%). Acalabrutinib, however, did have a higher incidence of headache (34.6% vs 20.2%, respectively) and cough (28.9% vs 21.3%) than ibrutinib.

“Despite a similar [independent review committee] progression-free survival, survival non-statistically favored acalabrutinib with 10 fewer deaths,” Byrd said. “These results demonstrate that acalabrutinib is better tolerated and safer than ibrutinib [and has] similar efficacy in previously treated patients with CLL.”

Byrd JC, Hillmen P, Ghia P, et. Al. First results of head-to-head trial of acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 7501.

Study of acalabrutinib (ACP-196) versus ibrutinib in previously treated subjects with high risk CLL. ClinicalTrials.gov Updated May 20, 2021. Accessed June 2, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02477696

Survival rates were similar between the 2 drugs, but acalabrutinib had fewer adverse events.

Acalabrutinib: Same Survival Rates, But Better Tolerated Than Ibrutinib in CLL Treatment

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

Retevmo (selpercatinib) demonstrated response improvements in previously treated patients with 

 fusion-positive non-small cell lung cancer (NSCLC), according to findings presented at the virtual 2021 ASCO Annual Meeting.

“However, results should be interpreted with caution, as a limitation of this analysis was that immediate prior response assessment was based on physician-reported best response in patients’ medical history and may not follow RECIST criteria,” the researchers said.

This study consisted of 218 evaluable patients (median age 61 years) who previously received platinum-based chemotherapy. The majority had an ECOG (or the measurement to describe a patient’s level of functioning in terms of ability to care for themselves, daily activity and physical ability; with zero being fully active and four being disabled) of 0/1, with an average of two (range: 1-15) prior systematic therapies, across 89 sites in 16 countries.

The primary endpoint of the study was objective response rate (or the rate of a measurable response to the treatment), with secondary endpoints of progression-free survival (time during and after treatment when the patient lives without disease progression), duration of response (or the length of time that a tumor continues to respond to treatment without the cancer growing or spreading) and safety.

The study compared each patient’s best overall response to their prior therapy to the response elicited from Retevmo.

The objective response rate with Retevmo was 57% which was “markedly higher,” the researchers wrote, than responses for prior treatment at 16%.

A total of 108 patients (50%) did not respond to prior therapy but did respond to Retevmo. There were 16 patients (7%) who responded to both Retevmo and prior therapy, 18 patients (8%) who responded to prior therapy but not Retevmo and 76 patients (35%) who did not respond to either.

Objective response rate was improved regardless of prior therapy, chemotherapy plus immune checkpoint inhibitor (57% versus 14%), single-agent immune checkpoint inhibitor (48% versus 3%) or chemotherapy (58% versus 15%).

Fewer patients had progressive disease with Retevmo best overall response (2%), compared with immediate prior therapy (28%). Median duration of response was also longer compared with prior therapy, with an average of 11.8 months versus 3.4 months.

“A global, randomized, phase 3 trial (LIBRETTO-431; NCT04194944) evaluating (Retevmo) compared with standard frontline therapy (Altima/ carboplatin with or without Keytruda) is ongoing,” the researchers concluded.

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Previously treated patients with non-small cell lung cancer tended to have better responses with Retevmo than they did with prior treatments. 

Retevmo Shows Improvement for Previously Treated Patients With Non-Small Cell Lung Cancer 

Adjuvant carboplatin and paclitaxel after standard cisplatin-based chemoradiation did not demonstrate improved overall survival or progression-free survival in patients with locally advanced cervical cancer, according to findings from the phase 3 OUTBACK trial that were presented at the 2021 ASCO Annual Meeting.

“Adjuvant chemotherapy given after standard platinum-based chemoradiation for women with locally advanced cervical cancer did not improve OS or PFS. So, the standard treatment should continue to be pelvic chemoradiation with concurrent weekly cisplatin,” lead study author Linda R. Mileshkin, MD, medical oncologist, Peter McCallum Cancer Centre, Melbourne, Australia, said during a presscast ahead of the meeting.

“Our findings don't support giving adjuvant chemotherapy with carboplatin and paclitaxel after chemoradiation with weekly cisplatin. Further research should focus on adjuvant therapies that might be more tolerable and effective when given after standard therapy,” she added.

In the international, randomized phase 3 OUTBACK trial (NCT01414608), the investigators aimed to determine the survival effects from administering adjuvant chemotherapy after standard chemoradiation, compared with standard chemoradiation alone, in 919 patients with locally advanced cervical cancer recruited from April 2011 to June 2017

In total, investigators randomized patients 1:1 to receive either standard cisplatin-based chemo-radiation followed by adjuvant chemotherapy (n = 463) with 4 cycles of carboplatin and paclitaxel or standard cisplatin-based chemo-radiation (n = 456). Adjuvant chemotherapy was administered in 361 women (78%).

Trial eligibility consisted of locally advanced cervical cancer (FIGO 2008 stage IB1 & node positive, IB2, II, IIIB, or IVA); an ECOG score of 0 to 2; squamous cell, adenocarcinoma, or adenosquamous cancer; no nodal disease above L3/4; and disease that was suitable for primary treatment with chemo-radiation with curative intent. Women were stratified by nodal status, participating site, FIGO stage, age, and planned extended-field radiotherapy.

OS at 5 years served as the primary end point. Secondary endpoints included PFS, adverse events (AEs), and patterns of disease recurrence.

Median follow-up was 60 months (IQR, 45-65).

The adjuvant chemotherapy arm demonstrated similar OS at 5 years, compared with the control arm (72% vs 71%, respectively; P = .8), for an HR of 0.90, (95% CI, 0.70-1.17), as well as similar PFS at 5 years (63% vs 61%; P = .61), for an HR of 0.87 (95% CI, 0.70-1.08).

In addition, patterns of disease recurrence were similar in the two treatment groups.

“Even when we looked at subsets of women with high-risk disease, such as those with node positive involvement, there was no benefit from the intervention,” Mileshkin added.

Within a year of randomization, grade 3 to 5 AEs typically seen with chemotherapy occurred in significantly more patients in the adjuvant chemotherapy arm, compared with the control arm (81% vs 62%, respectively). Lastly, Mileshkin noted that quality of life was worse during adjuvant chemotherapy and for the following 3 to 6 months, but returned to being similar between the groups from 12 months onwards.

Cervical cancer is a major global health problem, according to Mileshkin, with more than half a million women diagnosed with the disease each year, “and more than 3000 women will die of this cancer each year, making it the fourth leading cause of cancer-related death in women. … But most women die from cervical cancer…because of the development of distant metastatic disease.”

Although prior, smaller studies suggested that giving more chemotherapy after chemoradiation could improve survival. “And these findings changed practice in some centers,” Mileshkin explained. “However, the international community felt that there were some flaws in these trials and that it was important to perform a confirmatory trial.”

ASCO president Lori J. Pierce, MD, FASTRO, FASCO, added to the OUTBACK trial’s significance. “As we heard, physicians are currently using adjuvant chemotherapy based upon preliminary data and promise it could work. We clearly see it does not work and need to discontinue that practice,” she said. “This tells us that, as clinical researchers, we need more trials for patients with locally advanced cervical cancer using a different therapeutic approach. And I think it also clearly shows the importance of the outcomes of clinical trials, even if the results are negative. Both positive trials and negative trials clearly inform practice.”


Mileshkin LR, MooreKN, Barnes E, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase 3 OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). Presented at: American Society of Clinical Oncology Annual Meeting; June 4-8, 2021; Virtual. Abstract LBA3.

This article was originally published on OncLive as, "

Adjuvant Chemotherapy Fails to Improve PFS and OS in Locally Advanced Cervical Cancer.

Adjuvant carboplatin and paclitaxel after standard cisplatin-based chemoradiation did not demonstrate improved overall survival or progression-free survival in patients with locally advanced cervical cancer.

Adjuvant Chemo Does Not Improve Survival in Locally Advanced Cervical Cancer

Pralsetinib (Gavreto) elicited promising responses and tolerability in patients with 

 fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.

“These data are real important because it supports the importance of early biomarker testing for all patients with metastatic NSCLC prior to treatment initiation to inform optimal healthcare decisions,” said Giuseppe Curigliano, MD, PhD, associate professor of medical oncology at the University of Milano in Italy and head of the division of early drug development at the European Institute of Oncology in Italy, at the 2021 virtual ASCO Annual Meeting about updated data from the ARROW trial.

The phase 1/2 study was conducted at 84 sites in 13 countries. In particular, the safety population for this study included 233 patients with 

 fusion-positive NSCLC and 238 patients with other RET-altered solid tumors. In particular, 216 patients (median age, 60 years; 48% men) with 

fusion-positive NSCLC had measurable disease.

Originally patients who were treatment-naïve were not eligible, which was a requirement that was later removed by a protocol amendment. There were 25 patients who were enrolled after this eligibility revision (median age, 54 years; 44% men).

The study had a primary endpoint of objective response rate (ORR). Follow-up was conducted for a median of 17.1 months.

For the 216 patients who received pralsetinib and were 

 fusion-positive, the ORR was 69% (95%, CI, 62-75), DCR was 92% (95%, CI; 87-95), CBR was 77% (95%, CI; 71-82) and median DoR was 22.3 months (95%, CI; 15.1-not reached).

In the post-eligibility population with 25 patients, the ORR was 88% (95% CI, 69-98), CBR was 88% (95% CI, 69-98), DCR was 96% (95% CI, 80-100). In addition, median DoR and median PFS was not reached.

“The most important observation is that in the expansion cohort of real-world and first-line treatment of (non-small cell lung cancer) patients with 

fusion-positive tumor, the overall response rate was 88%, providing support for RET inhibitor as a first-line standard of care because the response rate was better in this population (with) respect to the previous eligibility criteria population,” Curigliano said.

The median duration of response in patients with prior platinum-based chemotherapy was 22.3 months (95% CI, 15.1-not reached). Curigliano added that it was too early to analyze data regarding the duration of response in treatment-naïve patients.

Overall, 26 patients (6%) out of 471 patients in the entire study discontinued treatment due to treatment-related adverse events. In all tumor types, 15% of patients had treatment-related neutropenia leading to treatment interruption whereas 14% had neutropenia from the treatment which resulted in a dose reduction. Less than 1% of patients discontinued treatment from treatment-related neutropenia.

“It means that pralsetinib was very well tolerated,” Curigliano said.

Curigliano, G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: Update from the ARROW trial. Presented at: 2021 ASCO Annual Meeting; June 4-8, 2021; Virtual. Abstract 9089.

Pralsetinib elicited promising responses and tolerability in patients with RET fusion-positive non-small cell lung cancer (NSCLC), including those who were not eligible for platinum-based therapy.  

 Pralsetinib Is Tolerable, Durable in RET Fusion+ NSCLC

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

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.

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