The phase 3 KEYNOTE-826 trial (NCT036355667) indicated improved survival and repose rates when patients with cervical cancer receiving treatment in the first-line setting were given pembrolizumab (Keytruda) plus chemotherapy with or without bevacizumab (Avastin), according to a presentation from the 

2021 European Society of Medical Oncology Congress

In the subset of patients with a PD-L1 combined positive score (CPS) of 1 or higher, the median progression-free survival (PFS) in the investigative and control arms was 10.4 months (95% CI, 9.7-12.3) vs 8.2 months (95% CI, 6.3-8.5), respectively (HR, 0.62; 95% CI, 0.50-0.77; P < .001). In this group, the median overall survival (OS) was not reached (NR) at the time of the data cutoff in the investigative arm (95% CI, 19.8–NR) vs 16.3 months (95% CI, 14.5-19.4) in the control arm (HR, 0.64; 95% CI, 0.50-0.81; P < .001).

In the all-comer population, the median PFS was 10.4 months (95% CI, 9.1-12.1) in the investigative arm vs 8.2 months (95% CI, 6.4-8.4) in the control arm (HR, 0.65; 95% CI, 0.53-0.79; P < .001). The median OS in this population was 24.4 months (19.2–NR) with pembrolizumab vs 16.5 months (95% CI, 14.5-19.4) with placebo (HR, 0.67; 95% CI, 0.54-0.84; P < .001).

In the group of patients who had a PD-L1 CPS of 10 or higher, the median PFS with pembrolizumab plus chemotherapy with or without bevacizumab was 10.4 months (95% CI, 8.9-15.1) vs 8.1 months (95% CI, 6.2-8.8) with chemotherapy with or without bevacizumab (HR, 0.58; 95% CI, 0.44-0.77; P < .001). The median OS was also NR (95% CI, 19.1-NR) in the investigative arm vs 16.4 months (95% CI, 14.0-25.0) in the control arm (HR, 0.61; 95% CI, 0.44-0.84; P = .001).

“Adding pembrolizumab to chemotherapy with or without bevacizumab provides statistically significant, clinically meaningful improvements in PFS and OS in patients with persistent, recurrent, or metastatic cervical cancer. The significant benefit was observed in all primary analysis populations and was generally consistent across protocol-specified subgroups,” lead study author Nicoletta Colombo, MD, PhD, director of the Gynecologic Oncology Division at the European Institute of Oncology and associate professor of Obstetrics and Gynecology at the University of Milan-Bicocca in Milan, Italy, said in a presentation of the findings. “Overall, data from KEYNOTE-826 suggest that pembrolizumab plus platinum-based chemotherapy with or without bevacizumab may be a new first-line standard of care for the treatment [of these patients].”

Platinum-based chemotherapy has served as standard treatment for patients with persistent, recurrent, or metastatic cervical cancer, with the preferred regimen being platinum, paclitaxel, and bevacizumab. Although PD-1 inhibitors, such as pembrolizumab and cemiplimab (Libtayo),

have previously demonstrated efficacy in patients with previously treated cervical cancer, no data are available to indicate whether the addition of a PD-L1 inhibitor to chemotherapy with or without bevacizumab would improve outcomes.

To this end, investigators launched the double-blind KEYNOTE-826 trial, which enrolled patients with persistent, recurrent, or metastatic cervical cancer that was not amenable to curative treatment.

Eligible patients needed to have an ECOG performance status of 0 or 1 and could not have previously received systemic chemotherapy. However, prior radiotherapy and chemoradiotherapy was allowed.

A total of 617 participants were randomized 1:1 to receive intravenous (IV) pembrolizumab at 200 mg every 3 weeks for up to 35 cycles plus paclitaxel and cisplatin or carboplatin every 3 weeks for up to 6 cycles with or without IV bevacizumab at 15 mg/kg every 3 weeks (n = 308) or placebo plus chemotherapy with or without bevacizumab at the same dose and schedule (n = 309).

Stratification factors included metastatic disease at diagnosis (yes vs no), PD-L1 CPS (<1 vs 1 to <10 vs ≥10), and planned bevacizumab use (yes vs no).

The dual primary end points of the study were investigator-assessed OS and PFS per RECIST v1.1 criteria; key secondary end points comprised overall response rate (ORR), duration of response (DOR), 12-month PFS, and safety. Patient-reported outcomes (PROs) were evaluated using the EuroQoL EQ-5D-5L Visual Analog Scale (VAS) score and served as an exploratory end point.

The PFS and OS benefit of adding pembrolizumab were evaluated sequentially in 3 patient populations: those with PD-L1 CPS of 1 or higher, all comers, and those with a PD-L1 CPS of 10 or higher. The overall alpha was controlled at one-sided 2.5% across the 6 primary hypotheses and all planned analysis. The statistical analysis plan permits 2 interim analyses prior to a final analysis.

The first interim analysis was planned to occur when approximately 370 events of disease progression or death were reported in the population of patients with a PD-L1 CPS of 1 or higher. At that time, all primary hypotheses were to be tested, noted Colombo.

As of a data cutoff of May 3, 2021, 307 patients on the investigative arm and 309 patients on the control arm received treatment.

“The median follow-up duration was almost 3 years, and approximately twice as many patients in the pembrolizumab arm remain on, or have completed, study treatment,” Colombo said.

Baseline characteristics in the all-comer and PD-L1 CPS subsets were well balanced between the 2 treatment arms, Colombo added.

Among the all-comer population, the median age between the arms was 50.5 years (range, 22-82). Moreover, 43.3% of patients had an ECOG performance status of 1, 72.3% had squamous cell disease, and 48.3% had previously received chemoradiation or radiation.

At initial diagnosis, 30.8% of patients had stage IVB disease, and 19.8% had metastatic disease at the time of study entry. Regarding PD-L1 status, 51.4% of patients had a CPS of 10 or higher, 37.4% had a CPS between 1 and 10, and 11.2% had a CPS of less than 1. Bevacizumab was used in 63.1% of patients during the study.

Additional data reported during the meeting showed that the 12-month PFS rates in the investigative and control arms within the subset of patients with a PD-L1 CPS of 1 or higher were 45.5% (95% CI, 39.2%-51.5%) and 34.1% (95% CI, 28.3%-40.0%), respectively. In the all-comer population, these rates were 44.7% (95% CI, 38.8%-50.4%) and 33.5% (95% CI, 28.0%-39.1%), respectively. Lastly, in the subset of patients with a PD-L1 CPS of 10 or higher, these rates were 44.6% (95% CI, 36.3%-52.5%) and 33.5% (95% CI, 25.9%-41.2%), respectively.

“The benefit of adding pembrolizumab was generally consistent across the protocol-specified subgroups, with all HRs favoring the pembrolizumab arm and all 95% CIs overlapping,” Colombo said.

The OS benefit of adding pembrolizumab was generally consistent across all protocol-specified subgroups. Notably, the HR favored the addition of pembrolizumab in both bevacizumab subgroups, suggesting that the addition of the immunotherapy to chemotherapy provides benefit irrespective of whether patients can receive bevacizumab, Colombo said.

“The relative OS benefit observed in the pembrolizumab arm appeared to increase with increasing PD-L1 expression and the HR for the PD-L1–negative population was 1.00,” Colombo added. “But, given the relatively small sample size of this subgroup and the overall study design, robust conclusions regarding the efficacy of pembrolizumab plus chemotherapy with or without bevacizumab in patients with PD-L1–negative tumors cannot be drawn.”

The addition of pembrolizumab to chemotherapy with or without bevacizumab also improved ORRs vs placebo plus chemotherapy with or without bevacizumab across the 3 primary analysis populations.

In the subset of patients with a PD-L1 CPS of 1 or higher, the ORR in the investigative arm was 68.1% (95% CI, 62.2%-73.6%) vs 50.2% (95% CI, 44.1%-56.2%) in the control arm, with a median duration of response (DOR) of 18.0 months (range, 1.3+ to 24.2+) vs 10.4 months (range, 1.5+ to 22.0+), respectively.

In the all-comer population, the ORRs were 65.9% (95% CI, 60.3%-71.2%) vs 50.8% (95% CI, 45.1%-56.5%), respectively, with the same median DORs as were reported in the PD-L1 CPS of 1 or higher subset. Lastly, in the group of patients with a PD-L1 CPS of 10 or higher, the ORRs were 69.6% (95% CI, 61.8%-76.7%) vs 49.1% (95% CI, 41.1%-57.1%), respectively, with median DORs of 21.1 months (range, 1.3+ to 24.2+) vs 9.4 months (range, 2.1+ to 21.5+), respectively.

Investigators collected information on PROs throughout treatment on the trial. Time to deterioration in the EQ-5D-5L VAS score was improved on the pembrolizumab arm, with a HR of 0.75 (95% CI, 0.58-0.97). According to Colombo, the median time to deterioration was not reached in the investigative arm vs 7.7 months in the control arm.

The safety profile of the pembrolizumab regimen was manageable. The incidence of all-cause and treatment-related grade 3 or higher or serious adverse effects (AEs) were all numerically greater in the immunotherapy-containing arm, but patients receiving pembrolizumab were generally on treatment longer vs those receiving placebo, according to Colombo.

“Approximately one-third of patients on the pembrolizumab arm discontinued any treatment component due to an AE,” Colombo said. “The incidence of AEs leading to death were similar in the treatment arms. As expected, the incidence of immune-related AEs was higher in the pembrolizumab arm.”

The most frequent all-cause AEs reported on the investigative and control arms included anemia (61.2% vs 53.4%, respectively), alopecia (56.4% vs 57.9%), nausea (39.7% vs 43.7%), diarrhea (35.5% vs 29.8%) and fatigue (28.7% vs 27.2%), among others. The most common immune-mediated AEs were hypothyroidism (18.2% vs 9.1%) and hyperthyroidism (7.5% vs 2.9%).

Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer: randomized, double-blind, phase 3 KEYNOTE-826 study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA2_PR.

Articles

Patients with cervical cancer receiving pembrolizumab plus chemotherapy with or without bevacizumab in the frontline setting had improvement in overall survival, potentially representing a new standard of care regimen. 

Potential New Standard of Care in First-Line Cervical Cancer May Include Pembrolizumab Plus Chemotherapy Combo

Patients with resected high-risk stage II melanoma who were treated with adjuvant pembrolizumab (Keytruda) saw a minimized risk of death or disease recurrence compared with the placebo group, according to results from the phase 3 KEYNOTE-716 trial (NCT03553836) that were presented during the 

The median recurrence-free survival (RFS) was not reached (NR) with pembrolizumab (95% CI, 22.6–NR) or placebo (95% CI, NR–NR; HR, 0.65; 95% CI, 0.46-0.92; 

 = .00658). The 12-month RFS rates were 90.5% vs 83.1%, respectively.

Findings from an RFS sensitivity analysis that included new primary melanomas demonstrated similar findings (HR, 0.64; 95% CI, 0.46-0.88).

Notably, pembrolizumab improved RFS across most key subgroups analyzed.

“KEYNOTE-617 met its primary end point of RFS at the first protocol-specified analysis,” lead study author Jason J. Luke, MD, FACP, an associate professor of medicine in the Division of Hematology/Oncology and director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, said during a virtual presentation of the data. “Despite this trial hitting its primary end point very early, there are a number of patients who are censored later in the curves. We will continue to see these data mature, and in fact, it is our full expectation that these curves will continue to separate over time.”

The risk of disease recurrence remains high for patients with stage IIB and IIC melanoma.

“High-risk features of primary melanoma include the depth of invasion, T-category, as well as ulceration, such that at 5 and 10 years the melanoma-specific survival observed is similar between stage IIB and IIC compared with IIIA and IIB melanoma,” Luke said.

Pembrolizumab was approved by the FDA in February 2019 for use as adjuvant treatment in patients with melanoma with lymph node involvement following complete resection.

 The regulatory decision was based on findings from the phase 3 KEYNOTE-054 trial (NCT02362594), in which adjuvant pembrolizumab led to a statistically significant improvement in RFS vs placebo in patients with resected stage III melanoma (HR, 0.57; 98.4% CI, 0.43-0.74; 

 < .0001). At 3.5 years of follow-up, the distant metastasis-free survival (DMFS) rates were 65.3% and 49.4%, respectively (HR, 0.60; 95% CI, 049-0.73; 

To be eligible for enrollment on the KEYNOTE-716 trial, patients needed to be aged 12 years or older with newly diagnosed, resected, high-risk, stage II melanoma and have an ECOG performance status of 0 or 1.

Participants were randomized 1:1 to receive 200 mg of adjuvant intravenous pembrolizumab every 3 weeks or the pediatric dose of 2 mg/kg vs placebo for 17 cycles.

“Patients were required to submit baseline diagnostic melanoma tissue at the time of accrual if available,” Luke said. “[Because of] inconsistent and small amounts of tissue, there is no prespecified analysis for PD-L1 status or 

Patients were stratified by T-category (3b vs 4a vs 4b) and pediatric status. The primary end point of the study was RFS per investigator assessment, with DMFS, overall survival, and safety serving as key secondary end points. Health-related quality of life (QOL) served as an exploratory end point of the study.

Overall, 976 patients were randomized. Of the 483 patients treated with pembrolizumab, 133 had treatment ongoing at 14.4 months of follow-up (range, 1.5-26.4) and 206 had completed treatment. Additionally, 144 patients discontinued pembrolizumab because of adverse effects (AEs; m = 75), patient withdrawal (n = 38; n = 3 were COVID-19 related), relapsed/recurrent disease (n = 21), physician decision (n = 6), and protocol violation or other reasons (n = 4).

Of the 486 patients treated with placebo, 152 had treatment ongoing at 14.3 months of follow-up (range, 1-26) and 229 had completed treatment. Additionally, 105 patients discontinued placebo because of AEs (n = 20), patient withdrawal (n = 25; n = 5 were COVID-19 related), relapsed/recurrent disease (n = 54), physician decision (n = 4; n = 3 were COVID-19 related), or protocol violation or other reasons (n = 2).

Baseline characteristics were balanced between arms. In the pembrolizumab arm, patients were a median age of 60 years (range, 16-84); 0.2% of patients (n = 1) was aged between 12 and 17 years, and 37.8% of patients (n = 184) were aged 65 years or older. In the placebo arm, patients were a median age of 61 years (range, 17-87); 0.2% of patients (n = 1) were between 12 and 17 years old, and 39.7% of patients (n = 194) were aged 65 years or older.

Across both arms, the majority of patients were male, had T3b disease, and stage IIB disease.

Additional findings regarding patterns of recurrence in the pembrolizumab arm demonstrated that 88.9% (n = 433) did not have a recurrence event; of the 11.1% (n = 54) who had a recurrence event, 6.4% (n = 31) were regional recurrences in the skin or lymph node

and 4.7% (n = 23) were distant recurrences. In the placebo arm, 83.2% (n = 407) of patients did not have a recurrence event; of the 16.8% of patients who had a recurrence event, 8.4% (n = 41) were regional recurrences in the skin or lymph node and 7.8% (n = 38) were distant recurrences.

“Patterns of recurrence are of particular interest in KEYNOTE-716 given the lack of historical robust data describing this stage II population,” Luke said.

Regarding safety, any-grade AEs were observed in 93.0% of patients treated with pembrolizumab and 89.1% of patients treated with placebo. Any-grade treatment-related AEs (TRAEs) were reported in 79.9% vs 60.9% of patients, respectively. Of these, 16.1% vs 4.3% were grade 3/4 events. Additionally, 15.3% vs 2.5% of TRAEs led to treatment discontinuation, respectively. No deaths from TRAEs were reported in either arm.

Common TRAEs in both arms included hypothyroidism, hyperthyroidism, diarrhea, nausea, fatigue, asthenia, arthralgia, myalgia, decreased alanine aminotransferase, decreased aspartate aminotransferase, pruritus, rash, and maculopapular rash. AEs of interest included hypothyroidism, hyperthyroidism, colitis, adrenal insufficiency, hepatitis, hypophysitis, infusion reactions, myasthenic syndrome, myositis, nephritis, pancreatitis, pneumonitis, sarcoidosis, severe skin reactions, thyroiditis, and type 1 diabetes mellitus (T1DM).

AEs of interest that required management with hormonal therapy were reported in 18.6% (n = 90) of patients treated with pembrolizumab. The AEs requiring treatment included hypothyroidism (13.9%; n = 67), thyroiditis (1.2%; n = 6), hypophysitis (2.1%; n = 10), adrenal insufficiency (2.1%; n = 10), and T1DM (0.4%; n = 2).

“Within in the thyroid events, we see this group of patients who had thyroid events despite the placebo treatment, suggesting that even in the background for normal patients in this monitoring period of a clinical trial a rate of about 4% to 5% of thyroid-based events would be expected,” Luke said.

Regarding the exploratory end point, global health status/QOL scores were similar between the pembrolizumab and placebo arms at all timepoints.

1. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: efficacy and safety results from the KEYNOTE-716 double-blind phase 3 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA3_PR.

2. FDA approves pembrolizumab for adjuvant treatment of melanoma. News release. FDA. February 15, 2019. Accessed September 18, 2021. https://bit.ly/3jTx0c5

3. Eggermont AMM, Blank CU, Mandalà M, et al. Adjuvant pembrolizumab versus placebo in resected stage III melanoma (EORTC 1325-MG/KEYNOTE-054): distant metastasis-free survival results from a double-blind, randomised, controlled, phase 3 trial. 

 2021;22(5):643-654. doi:10.1016/S1470-2045(21)00065-6

The use of adjuvant pembrolizumab resulted in a recurrence-free survival benefit for patients with resected high-risk stage II melanoma. 

Reduction In Disease Recurrence, Death With Adjuvant Pembrolizumab Noted in Resected High-Risk Stage II Melanoma

Results of the phase 3 OReO/ENGOT Ov-38 trial (NCT03106987) showed that rechallenge with maintenance olaparib (Lynparza) after platinum-based chemotherapy response resulted in longer progression-free survival (PFS) for patients with relapsed ovarian cancer, regardless of their 

 status, according to data presented at the 

2021 European Society for Medical Oncology Congress

The median PFS improved from 2.8 months in patients who received placebo to 4.3 months in those randomized to rechallenge with olaparib among the cohort of patients with 

-mutant ovarian cancer (HR, 0.57; 95% CI, 0.37-0.87; 

-mutant cohort, the median PFS improved similarly with olaparib rechallenge from 2.8 months in the placebo arm to 5.3 months in the olaparib arm (HR, 0.43; 95% CI, 0.26-0.71; 

The data are the first to demonstrate a benefit to PARP inhibitor rechallenge in patients with platinum-sensitive relapsed ovarian cancer, said Eric Pujade-Lauraine, MD, PhD, of ARCAGY-GINECO in Paris, France, in a virtual presentation during the meeting.

-mutant cohorts, a proportion of patients derived clinically relevant long-term benefit from maintenance olaparib rechallenge,” he said.

Although most patients with newly diagnosed or platinum-sensitive relapsed ovarian cancer achieve long-term responses to PARP inhibitors as maintenance therapy, the majority of them will relapse. It has been unknown whether patients who relapse on PARP inhibition will have a benefit from rechallenged PARP inhibitor therapy following responde to platinum-based chemotherapy.

OReO/ENGOT Ov-38 is a phase 3, randomized, double-blind trial that enrolled 220 patients with nonmucinous platinum-sensitive relapsed ovarian cancer who received 1 prior line of PARP inhibitor maintenance and were in response to their most recent platinum-based chemotherapy. Two cohorts were enrolled, a 

-mutant cohort (n = 108), both of which were randomized 2:1 to olaparib at 300 mg (or 250 mg if 300 mg was not previously tolerated) or placebo until progression.

Eligible patients must have had a complete response (CR) or partial response to their most recent platinum regimen or no evidence of disease after surgery without a rise in their CA-125 level. The 

-mutant cohort must have had prior PARP inhibitor exposure for at least 18 months after first-line chemotherapy, or at least 12 months after second-line or later chemotherapy. For the non–

-mutant cohort, prior PARP inhibitor exposure for at least 12 months after frontline chemotherapy or at least 6 months after second- or later-line chemotherapy was required.

Patients were stratified by prior bevacizumab (Avastin) and 3 or fewer or at least 4 prior lines of platinum-based chemotherapy. The primary end point was investigator-assessed PFS; secondary end points were time to RECIST/CA-125 progression or death, time to first and second subsequent therapy or death, time to treatment discontinuation or death, overall survival, health-related quality of life, and safety.

-mutant cohort, the median age was 58.5 years (range, 37-80) in the olaparib arm and 61.5 years (range, 44-87) in the placebo arm. Forty-two percent of patients in each arm had 3 prior lines of any chemotherapy, and 23% and 21% in the olaparib and placebo arms, respectively, had exposure to more than 4 prior lines. Thirty-five percent of the olaparib arm and 42% of the placebo arm had exposure to more than 4 prior lines of platinum-based chemotherapy. The best response to platinum-based chemotherapy prior to study entry was a CR in 20% and 34% of the olaparib and placebo arms, respectively.

-mutant cohort, the median age was 66.5 years (range, 29-81) in the olaparib arm and 62.5 years (range, 43-77) in the placebo arm. Twenty-eight percent and 22%, respectively, had more than 4 lines of any prior chemotherapy, and 32% and 31%, respectively, had at least 4 prior lines of platinum-based chemotherapy. Best response to platinum-based chemotherapy prior to study entry was a CR in 26% of the olaparib group and 31% of the placebo group.

The median duration range of prior PARP inhibitor therapy was 18.3 to 21.2 months in the 

-mutant cohort and 12.4 to 12.6 months in the non–

-mutant cohort. Sixty-one percent of the 

-mutant cohort had a duration of prior PARP inhibitor exposure of at least 18 months, and 53% to 57% of the non–

-mutant cohort had a duration of prior PARP inhibitor exposure of at least 12 months.

-mutant cohort was olaparib (91% vs 21.5%, respectively), niraparib (Zejula; 4.5% vs 61%), rucaparib (Rubraca; 3% vs 13.5%), veliparib (0% vs 2%), blinded therapy (0% vs 3.5%), and placebo (1.5% in each).

Homologous recombination deficiency (HRD) status was positive in about 40% of the non–

-mutant cohort, with HRD status unknown in up to one quarter of patients in this cohort.

-mutant cohort, treatment is ongoing in 9% of patients on the olaparib arm and 3% of the placebo arm; in the non–

-mutant cohort, these percentages are 29% and 17%, respectively. About 60% of patients on the 

-mutant cohort discontinued the study, 90% of which were due to death. Twenty-eight percent of those in the non–

-mutant cohort discontinued, with 67% (olaparib arm) and 73% (placebo arm) discontinuing due to death.

“A proportion of patients derived long-term benefit in the olaparib arm,” said Pujade-Lauraine, as the PFS rates in the 

-mutant cohort at 12 months after randomization were 19% in the olaparib arm vs 0% in the placebo arm.

-mutant cohort, “long-term benefit was again observed—14% of patients in the olaparib arm being free of disease progression [at 12 months] vs 0% in the placebo arm,” he added. In exploratory analyses, the benefit of olaparib in the non–

-mutant cohort appeared consistent, irrespective of HRD status.

In both cohorts, the PFS benefit to olaparib was observed across subgroups, and was irrespective of HRD status. No new safety signals were observed and the rate of discontinuations due to adverse events was low, said Pujade-Lauraine.

Clare L. Scott, MBBS, PhD, chair of Gynecological Cancer at University of Melbourne, Australia, who served as a discussant on the abstract, said that the results from OReO/ENGOT Ov-38 provide some rules to identify patients who would benefit based on prior PARP inhibitor exposure.

“All clinical groups appear to benefit except for patients who had a short time on treatment prior to coming on to study, but really we need to define the molecular groups who benefit from alternative therapies or combination PARP inhibitor therapies,” Scott said.

Pujade-Lauraine E, Selle F, Scambia G, et al. Maintenance olaparib rechallenge in patients (pts) with ovarian carcinoma (OC) previously treated with a PARP inhibitor (PARPi): phase IIIb OReO/ENGOT Ov-38 trial. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA33.

Patients previously treated with PARP inhibitors showed an improvement in median progression-free survival when rechallenged with olaparib maintenance. 

PFS Enhanced With Olaparib Rechallenge in Relapsed Ovarian Cancer After Prior PARP

The phase 2 ZENITH20 trial (NCT03318939) examining a daily dose of poziotinib (NOV 120101) at 16 mg showed a 35% median tumor reduction in patients with previously untreated 

 exon 20–mutant non-small cell lung cancer, according to data that were presented at the 

“Most patients, 88%, show tumor reduction and a median tumor reduction of 35%,” said lead author Robin Cornelissen, MD, PhD, a pulmonologist with Erasmus MC Cancer Institute in Rotterdam, The Netherlands. “There are 3 patients with 100% decrease of the target lesions, however, 2 of those patients also had nontarget lesions and therefore were deemed as partial response.”

At a median follow-up of 13.5 months, the objective response rate (ORR) was 43.8% (95% CI, 29.5%-58.8%) with 1 (2.1%) complete response and 20 (41.7%) partial responses. Fifteen patients (31.3%) had stable disease and 7 (14.6%) had progressive disease; 5 patients (10.4%0 were not evaluable.

The disease control rate was 75%. The ORR, including unconfirmed response, was 47.9% (95% CI, 33.3%-62.8%). The median duration of response was 5.4 months (range, 2.8 to >19.1). The 6- and 1-year response duration rates were 42% and 24%, respectively.

The median progression-free survival (PFS) was 5.6 months (range, 0 to >20.2). The 6-month PFS rate was 42%; the 1-year PFS rate as 26%.

At present, there is no approved treatment for patients with 

 exon 20 mutations, Cornelissen said. Studies exploring efficacy with current treatments—chemotherapy with our without immune checkpoint inhibitors and tyrosine kinase inhibitors (TKIs)—show ORRs from 6.9% to 35% and median PFS outcomes of 3 to 7 months. Furthermore, none of these current options are specific to exon 20 mutations.

In March, the FDA granted a fast track designation to poziotinib for use in previously treated patients with 

ZENITH20 is a multicohort, multicenter, open-label trial examining the efficacy, safety, and tolerability of poziotinib, an oral, irreversible TKI targeting 

 exon 20 insertion mutations. In cohort 4 of the study, 48 patients with untreated locally advanced or metastatic NSCLC with 

 exon 20 insertion mutations were assigned to 16 mg of poziotinib daily or 8 mg twice daily. Dose reductions were allowed if treatment-emergent adverse events (TEAEs) occurred. Patients were treated until intolerable toxicity, disease progression, or death.

Eligible patients must have an ECOG performance status of 0 or 1. Prior adjuvant or neoadjuvant therapies were permissible if treatment ended at least 15 days prior to study entry. Those who had received previous treatment with poziotinib or any other 

 exon 20 insertion mutation–selective TKI or who had 

The primary end point was ORR; secondary end points were DCR, DOR, and safety and tolerability.

In the daily dosing cohort, most patients were White (75%), female (54%), nonsmokers (69%), and had an ECOG performance status of 1 (65%). The median age was 60.5 years (range, 34-87).

All 48 patients were evaluable for safety and all experienced treatment-related adverse events (TRAEs). Five (10%) experienced serious TRAEs. Six (13%) left the trial due to adverse events (AEs), 88% required dose interruptions, and 77% required dose reductions.

The most common grade 3 TRAEs were rash (35%), stomatitis/mucosal inflammation (21%), and diarrhea (15%). There were no grade 4/5 AEs observed.

The cohort is still recruiting patients for an 8-mg, twice-daily group (n = 23).

Xiuning Le, MD, PhD, an assistant professor of thoracic/head and neck medical oncology, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center, presented safety and efficacy data from cohort 5 (n = 19) during the 2021 AACR Annual Meeting.

 In this cohort, patients with locally advanced or metastatic NSCLC with 

 exon 20 insertion mutations were randomly assigned to either 10 mg, 12 mg, or 16 mg of poziotinib daily, or 6 mg or 8 mg of the drug twice daily.

The ORRs were 31.6% at 8-mg twice-daily, 15.8% at 16-mg daily, 15.8% at 12-mg daily, and 5.3% at 6-mg twice-daily doses. All were partial responses.

Prior findings from cohort 3 of ZENITH20 presented at the 2021 ESMO TAT Virtual Congress showed that a 16-mg daily dose of poziotinib elicited clinically meaningful activity in treatment-naïve patients with metastatic NSCLC with 

Cornelissen R, Sun S, Wollner M, et al. Efficacy and safety of poziotinib in treatment-naïve NSCLC harboring HER2 exon 20 mutations: a multinational phase II study (ZENITH20-4). Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA46.

FDA grants fast track designation to Spectrum Pharmaceuticals’ poziotinib. News release. Spectrum Pharmaceuticals. March 11, 2021. Accessed September 18, 2021. http://bwnews.pr/3tf1PuO

Le X, Shum E, Suga J, et al. Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutant NSCLC (ZENITH20-5). Presented at: 2021 AACR Annual Meeting 2021; April 10-15, 2021; virtual. Abstract CT169.

Sacher A, Le X, Cornelissen R, et al. Safety, tolerability and preliminary efficacy of poziotinib with twice daily strategy in EGFR/HER2 exon 20 mutant non-small cell lung cancer. 

. 2021;32(suppl_1):S14-S19. doi:10.1016/annonc/annonc459

Daily poziotinib in patients with untreated HER2 exon 20-mutant non-small cell lung cancer resulted in tumor reduction. 

ZENITH20 Trial Shows Positive Results With Poziotinib in Untreated HER2 Exon 20-Mutant NSCLC

The combination of relatlimab and nivolumab (Opdivo) led to an a longer treatment-free interval (TFI), as well as a reduction in risk of progression or death following the next line of therapy vs nivolumab alone in patients with previously untreated metastatic or unresectable melanoma, according to findings from the phase 2/3 RELATIVITY-047 trial (NCT03470922), which were presented during the 

The new efficacy results, which were, demonstrated that those who received the doublet and discontinued treatment (n = 167) experienced a longer TFI vs single-agent nivolumab (n = 151), with a median TFI of 3.22 (range, 0.1-30.4) vs 1.41 (range, 0.1-25.6), respectively.

Relatlimab plus nivolumab also reduced the risk of progression following the next line of systemic therapy (PFS2), per investigator assessment, or death compared with nivolumab alone. The median PFS2 in the investigative arm had not yet been reached (95% CI, 21.75–not reached) vs 20.04 months (95% CI, 15.44-25.13) with nivolumab alone (hazard ratio [HR], 0.77; 95% CI, 0.61-0.97).

“Patients on relatlimab/nivolumab experienced prolonged benefit beyond initial treatment and first progression. Among those who discontinued study therapy, those treated with relatlimab/nivolumab had a long TFI vs nivolumab alone,” F. Stephen Hodi, MD, lead study author, director of the Melanoma Center, director of the Center for Immuno-Oncology, and Sharon Crowley Martin Chair for Melanoma at Dana-Farber Cancer Institute, said in a presentation on the data. “A greater proportion of patients treated with relatlimab/nivolumab remained without subsequent systemic therapy and [the combination] reduced the risk of progression after the next line of systemic therapy, per investigator assessment, or death vs nivolumab alone.”

It is known that LAG-3 and PD-1 are distinct immune checkpoints, but they are often co-expressed on tumor infiltrating lymphocytes and are known to play a role in tumor-mediated T-cell exhaustion, according to Hodi, who is also a professor of medicine at Harvard Medical school.

Relatlimab is a human LAG-3–blocking antibody that was designed to restore the effector function of T cells that have been exhausted.

RELATIVITY-047 is the first global randomized, double-blind, phase 2/3 registrational study to evaluate the combination of LAG-3 and PD-1 inhibition with relatlimab and nivolumab as a novel fixed-dose combination vs nivolumab alone in patients with previously untreated metastatic or unresectable melanoma.

To be eligible for enrollment, patients needed to have previously untreated metastatic or unresectable melanoma and an ECOG performance status of 0 or 1.

A total of 714 patients were enrolled to the trial, and were randomized 1:1 to receive either the fixed-dose combination of relatlimab at 160 mg plus nivolumab at 480 mg every 4 weeks (n = 355) or nivolumab alone at 480 mg every 4 weeks (n = 359).

Participants were stratified based on LAG-3 and PD-1 expression status, 

 mutational status, and American Joint Committee on Cancer version 8 metastatic stage.

The primary end point of the trial was progression-free survival (PFS) by blinded independent central review (BICR), and key secondary end points included overall survival and objective response rate by BICR. Exploratory end points of interest included TFI and PFS2.

Data from RELATIVITY-047 previously reported at the 2021 ASCO Annual Meeting showed that the doublet resulted in a median PFS of 10.12 months (95% CI, 6.37-15.74) vs 4.63 months (95% CI, 3.38-5.62) with nivolumab alone (HR, 0.75; 95% CI, 0.62-0.92; 

= .0055).2 The 12-month PFS rates in the investigative and control arms were 47.7% (95% CI, 41.8%-53.2%) and 36.0% (95% CI, 30.5%-41.6%), respectively.

“The PFS benefit was seen at the time of the first scan, which was 12 weeks, and continued thereafter,” Hodi noted. “Relatlimab plus nivolumab demonstrated superior PFS, with more than a doubling of improvement compared with nivolumab alone. We also consistently saw the PFS benefit [of the combination] across key subgroups, including [disease] subtypes such as acral and mucosal melanoma.”

The HR for PFS for cutaneous acral melanoma was 0.84 (95% CI, 0.50-1.39), 0.73 (95% CI, 0.57-0.93) for cutaneous non-acral disease, 0.72 (95% CI, 0.36-1.45) for mucosal disease, and 0.77 (95% CI, 0.44-1.36) for other subtypes.

During the 2021 ESMO Congress, Hodi shared data on the exploratory end points TFI and PFS2. TFI was defined as the time from the end of study therapy to subsequent systemic treatment or last known alive date in patients who discontinued study therapy; this excluded those who died before receiving subsequent systemic therapy. Investigators defined PFS2 as the time from randomization to progression following the next line of systemic therapy, per investigator assessment, or death.

The median duration of treatment with relatlimab/nivolumab was 5.6 months (minimum, 0.0; maximum, 31.5) vs 4.9 months (minimum, 0.0; maximum, 32.2) with nivolumab alone. Slightly more patients on the investigative arm discontinued treatment vs those on the control arm, at 66.8% and 64.9%, respectively.

The most common reason for discontinuation on the doublet and monotherapy arms was progressive disease (36.3% vs 46.0%, respectively), followed by treatment-related toxicity (17.7% vs 8.9%), patient request (5.4% vs 3.3%), and an adverse effect (AE) that was not related to treatment (3.4% vs 3.9%).

More patients on the nivolumab-alone arm received subsequent therapy compared with the relatlimab/nivolumab arm, at 37.3% vs 35.5%, respectively; 29.8% vs 27.9% of patients, respectively, received systemic therapy.

Subsequent treatments received in the investigative and control arms included PD-1 and/or CTLA-4 inhibitors (9.0% vs 12.8%, respectively), BRAF and/or MEK inhibitors (11.5% vs 13.9%), or other systemic options (10.7% vs 12.3%). Moreover, 11.5% of those on the investigative arm vs 10.0% of those on the control arm went on to receive radiotherapy; 5.1% vs 7.2% of patients, respectively, went on to receive surgery.

Among the off-treatment patients included in the TFI analysis, 40.7% of those who received relatlimab/nivolumab did not receive subsequent systemic therapy vs 29.1% of those who received single-agent nivolumab. In the investigative and control arms, 31.1% and 37.7% of patients, respectively, went on to receive subsequent treatment.

“This analysis included patients who were alive and off therapy or who died following subsequent systemic therapy,” Hodi said. “Of note, more patients on the relatlimab/nivolumab arm who discontinued study treatment did not receive subsequent therapy at the time of this analysis as compared with nivolumab alone.”

Regarding PFS2, the separation between the curves was seen at about 6 months and continued, according to Hodi, indicating the potential benefits of the combination regimen beyond initial treatment.

Relatlimab plus nivolumab was found to have a manageable toxicity profile and did not showcase any unexpected safety signals. Any-grade AEs were reported in 97.2% of those on the investigative arm vs 94.4% of those on the control arm; 40.3% and 33.4% of patients, respectively, reported grade 3 or 4 AEs.

Treatment-related AEs (TRAEs) were reported by 81.1% of those who received the doublet vs 69.9% of those who were given the monotherapy; grade 3 or 4 TRAEs were experienced by 18.9% and 9.7% of patients, respectively. Any-grade TRAEs resulted in discontinuation in 14.6% and 6.7% of those on relatlimab/nivolumab and nivolumab monotherapy, respectively. Grade 3 or 4 TRAEs led to discontinuation in 8.5% of those on the investigative arm vs 3.1% of those on the control arm.

Five treatment-related deaths occurred: 3 in the combination arm (includes hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis) and 2 in the monotherapy arm (includes sepsis and myocarditis and worsening pneumonia).

Hodi FS, Tawbi HA, Lipson EJ, et al. Relatlimab (RELA) + nivolumab (NIVO) versus NIVO in previously untreated metastatic or unresectable melanoma: additional efficacy in RELATIVITY-047. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract 1036O.

Lipson EJ, Tawbi HA, Schadendorf D, et al. Relatlimab (RELA) plus nivolumab (NIVO) versus NIVO in first-line advanced melanoma: primary phase III results from RELATIVITY-047 (CA224-047). 

. 2021;39(suppl 15):9503. doi:10.1200/JCO.2021.39.15_suppl.9503

Patients with previously untreated metastatic or unresectable melanoma achieved promising benefit following treatment with relatlimab/nivolumab combination therapy.


Addition of Relatlimab to Nivolumab Yields Longer TFI and Improved PFS2 in Metastatic or Unresectable Melanoma

Treatment with pembrolizumab (Keytruda) and olaparib (Lynparza) could help to improve prostate-specific antigen (PSA) response rates in patients with metastatic castration-resistant prostate cancer (mCRPC) regardless of homologous recombination repair (HRR) mutation status, according to findings from the KEYNOTE-365 trial (NCT02861573) that were presented at the 

The investigators also found high concordance between the Guardant Health (360 or Omni) assays and FoundationOne CDx for the detection of 

The study included patients from cohort A of the KEYNOTE-365 trial, which investigated pembrolizumab at 200 mg IV every 3 weeks plus olaparib at 400 or 300 mg twice daily in patients with molecularly unselected, docetaxel-pretreated mCRPC.

For the current study, the investigators sought to “evaluate the prevalence of 

mutations and other HRR mutations and their association with antitumor activity with pembrolizumab plus olaparib,” according to the study’s poster.

Primary end points included PSA response rate (50% or greater reduction from baseline), and objective response rate (ORR) per RECIST v1.1 by central review. Secondary end points included radiographic progression-free survival and overall survival.

The investigators assessed mutations in ctDNA using Guardant360 or GuardantOMNI assays. Guardant360 was used for detecting 

mutations. FoundationOneCDx was used to assess mutations in DNA isolated from formalin-fixed, paraffin-embedded tumor samples.

mutations were detected in 3 of 98 patients using Guardant360 or GuardantOMNI, and in 4 of 41 patients using FoundationOneCDx. HRR mutations were found in 14 of 59 patients using Guardant360 or GuardantOMNI and 12 of 41 patients using FoundationOneCDx.

mutation (2 of 4 patients; 95% CI, 6.8%-93.2%) and 14% in patients without a 

mutation (13 of 95 patients; 95% CI, 7.5%-22.3%). In patients with an HRR mutation, PSA response was 22% (4 of 18 patients; 95% CI, 6.4%-33%) vs 13% in patients without an HRR mutation (7 of 52 patients; 95% CI, 5.6%-25.8%). ORR was 33% in patients with a 

mutation (1 of 3 patients; 95% CI, 0.8%-90.6%) and 6% in patients without a 

mutation (3 of 53 patients; 95% CI, 1.2%-15.7%). ORR was 8% in patients with an HRR mutation (1 of 12 patients; 95% CI, 0.2%-38.5%) and 3% in patients without an HRR mutation (1 of 30 patients; 95% CI, 0.1%-17.2%).

“There was high concordance between [Guardant360 or GuardantOMNI] assays and [FoundationOneCDx] for determination of 

 (98% agreement) and HRR (87% agreement) mutational status,” the authors wrote in the study’s abstract.

“Caution should be used when interpreting these results because of small sample sizes,” they added.

Yu E, Piulats JM, Gravis G, et al. Association between homologous recombination repair mutations and response to pembrolizumab (pembro) plus olaparib (ola) in metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 Cohort A biomarker analysis. Paper presented at 2021 European Society for Medical Oncology Annual Congress; September 16-21, 2021; virtual. Abstract 73P.

Patients with metastatic castration-resistant prostate cancer experienced an improvement in prostate-specific antigen following treatment with pembrolizumab and olaparib.

Pembrolizumab/Olaparib Combo May Yield Better Responses in mCRPC Regardless of HRR Status

Results of a phase 2 trial that were presented during the 

 reveal potential clinical activity with the combination regimen of olaparib (Lynparza) and bipolar androgen therapy (BAT) for patients with castration-resistant prostate cancer (CRPC).

Almost half (47%) of patients had a PSA50 response, defined as a ≥50% decline in their PSA level. At a median follow-up of 22.7 months, the median progression-free survival (PFS) was 12.6 months.

“BAT plus olaparib is associated with high response rates and long PFS. Clinical benefit was observed regardless of homologous recombination repair (

) gene mutational status. Treatment was well tolerated, although caution should be taken in using this in men with a history of cardiovascular disease. Larger studies evaluating this regimen are warranted,” lead study author Michael Schweizer, MD, assistant professor, Division of Medical Oncology, University of Washington School of Medicine; associate professor, Clinical Research Division, Fred Hutchinson Cancer Research Center; and Physician, Seattle Cancer Care Alliance, and coinvestigators wrote in their abstract conclusion.

The single center (Fred Hutch) phase 2 study (NCT03516812), which officially launched on August 29, 2018, enrolled 36 patients (median age, 70 years; range, 51-88) with CRPC, as shown by PSA progression (PCWG3 criteria) and castrum serum testosterone level (≤50 mg/dL). Patients also had to have a PSA level that was ≤1 ng/ml and rising on 2 sequential measurements occurring ≥2 weeks apart. Prior abiraterone acetate (Zytiga) and/or enzalutamide (Xtandi) was required. Among 30 evaluable patients, 13 had prior abiraterone, 7 had prior enzalutamide, and 10 had received both.

Docetaxel in the hormone-sensitive prostate cancer setting was allowed; however, enrollment was prohibited for patients who received docetaxel for metastatic CRPC. Patients with cancer-related pain were also excluded from enrollment.

All patients received olaparib at 300 mg orally twice daily plus BAT. The BAT treatment consisted of 400 mg of testosterone enanthate or cypionate every 28 days while continuing androgen deprivation to suppress endogenous testosterone. The treatment cycles repeated every 28 days unless there was disease progression or unacceptable toxicity.

The primary end points were safety and the PSA50 response rate at a maximum of 12 weeks after starting treatment. The investigators officially measured the PSA50 end point in the entire study population; however, they also conducted an exploratory analysis of outcomes in patients stratified by 

 gene mutational status. The study required that at least half of the enrolled patients had ≥1 

Secondary outcome measures included radiographic response rate, PSA progression rate, overall survival, radiographic PFS, and quality of life.

Among 30 evaluable patients, 14 (47%) reached a PSA50 response, including 7 of 15 patients harboring an 

Notable declines in prostate-specific antigen levels were seen in patients with castration-resistant prostate cancer who received olaparib coupled with bipolar androgen therapy.

ONCOLOGY Vol 35, Issue 8 | September 2021

Perspective

Evolving Role of Autologous Stem Cell Transplantation for Light Chain Amyloidosis in the Modern Era

Clinical Quandaries

Sjögren Syndrome Induced by Immune Checkpoint Inhibitors in a Patient with Advanced Renal Cell Carcinoma

Case Study

A 64-Year-Old Man With Germline BRCA2-Mutated Breast Cancer: Known and Unknown Aspects of Male Breast Cancer

Review Article

The Role of Autologous Stem Cell Transplantation in Amyloidosis

Interview

Lung Cancer Investigators Expand Upon Indications of Standard Therapeutic Agents

Editorial

The Unhappy Intersection of Cancer and COVID-19

Clinical Trials in Progress

Clinical Trials in Progress: ROADS Trial