Megan Hollasch

Adding Lynparza (olaparib) to carboplatin and paclitaxel did not improve outcomes in the presurgical treatment setting for patients with basal-like 

 wild-type triple-negative breast cancer (TNBC).

Study findings — which were presented at the 2024 AACR Annual Meeting — compared pathologic complete response (pCR; lack of cancer found in tissue biopsies), event-free survival (EFS; time without complications from cancer) and overall survival (OS; time from treatment until death from any cause) among treatment groups.

The PARTNER trial showed no significant differences in pCR rates for patients treated with Lynparza compared with chemotherapy alone. Rates at surgery were 51.1% vs 52.4%, respectively. The 36-month EFS rates were 80% vs 79% and the 36-month OS rates were 90% vs 87%, respectively.

Adding Lynparza to certain presurgical chemotherapy drugs did not make a difference in how well treatment worked for certain patients with triple-negative breast cancer, according to a study.

The study looked at how well patients responded to treatment, how long they went without complications from cancer and how long they lived after treatment.

The study showed that the combination of Lynparza with chemotherapy did not improve outcomes compared to chemotherapy alone, and it caused more side effects for some patients.

The next steps include further research to understand why some patients respond differently to treatment and exploring new treatments, like immunotherapy, for TNBC.

“[When] looking at the survival endpoints by pCR in this triple-negative wild type cohort, pCR shows a strong association with long-term outcomes,” Dr. Karen Pinilla Alba, a medical oncologist and a clinical researcher in the Department of Oncology at the University of Cambridge Cancer Research, UK Cancer Centre, said in a presentation of the data. “Patients with a pCR achieved a 36-month PFS of 90% versus a 36-month PFS of 70% in those who did not achieve pCR. This difference was statistically significant. Similarly, researchers observed more deaths in the non-PCR group with a 36-month OS of 83% for those who did not achieve a pCR. This compared with 96% for patients who achieved pCR.”

Alba said the lack of improvement in pCR, EFS and OS were “in sharp contrast to the 

-mutated cohort.” However, “the gap schedule regimen provides a biologically relevant concept that should be considered when testing future PARP inhibitor combinations.”

Additionally, the pCR rates were 65% in tumor-infiltrating lymphocytes (TILs) of at least 60% group versus 47.9% in the TILs less than 60% group.

higher levels of TILs was associated with improved survival

The trial enrolled patients with TNBC with ER-negative, HER2-negative or germline 

 wild-type disease with any hormone status. Stage 1 evaluated safety in 75 patients. Stage 2 was the preplanned selection of the research arm examining safety, efficacy and compliance/convenience in 159 patients. Stages 1 and 2 randomly assigned patients to one of three groups: the control arm of carboplatin and paclitaxel; the combination gap-schedule arm of carboplatin and paclitaxel plus Lynparza on days 1 to 14; or the combination non-gap schedule arm of carboplatin and paclitaxel plus Lynparza on days 2 to 10. Anthracycline-based chemotherapy and surgery followed.

The combination non-gap schedule arm was stopped after the first two stages. Patients received the chemotherapy combination with or without Lynparza on days 3 to 14 followed by anthracycline-based chemotherapy and surgery. Patients enrolled also had TILs. Further, the primary endpoint of the study was pCR. Secondary endpoints included EFS and OS.

“PARTNER is the first clinical trial to test the combination of [Lynparza] in combination with platinum-containing chemotherapy in the [presurgical] setting of selected with basal-like 

“Subgroup analysis didn’t show any differences among age, tumor size, [and] histopathological involvement of lymph nodes and TILs. pCR by TILs was consistent with what has been reported previously,” Alba said. “[There were] no significant differences in pCR rates in each TILs group between the research and control [arms].”

Further, grade 3 or higher side effects occurred in 64.2% of patients in the Lynparza arm compared with 58.7% in the chemotherapy-alone arm. Serious side effects occurred at rates of 34.0% versus 34.6%. They were attributed to carboplatin (21.3% versus 18.2%), paclitaxel (22.3% vs 17.5%) and Lynparza(16.0% versus not applicable). In the Lynparza arm, 7.4% of patients discontinued treatment due to toxicity versus 8.2% in the chemotherapy arm. Additionally, red blood cell transfusion was required in 51.4% versus 30.5% of patients during chemotherapy, respectively.

“What are the next steps?” Dr. Hope S. Rugo, of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, asked in a discussion of the data. “For TNBC, it’s critical that we have further characterization of a potential set of biomarkers to determine response in this larger population where we run out of treatment options and face difficulties. Also, combinations with immunotherapy, potentially in the post-neoadjuvant setting, are quite intriguing.”

Alba added that TNBC heterogeneity is going to be further investigated by the PARTNER Trial Consortium.


For more news on cancer updates, research and education, don’t forget to 

Articles

The addition of Lynparza to presurgical chemotherapy did not improve outcomes for patients with basal-like BRCA wild-type triple-negative breast cancer.

Adding Lynparza to Presurgical Chemo May Not Boost TNBC Outcomes

Patients with clear cell renal cell carcinoma (ccRCC) experienced improved overall survival (OS; the time a patient lives after treatment regardless of disease status) when treated with adjuvant (postsurgical) Keytruda (pembrolizumab) as compared to patients treated with placebo, according to data from the third prespecified interim analysis of the phase 3 KEYNOTE-564 trial presented at the 2024 

Patients with clear cell renal cell carcinoma tended to live longer when treated with Keytruda after surgery compared to those who received a placebo.

The analysis also revealed a continued benefit in disease-free survival with adjuvant Keytruda, showing a reduction in the risk of disease recurrence. This benefit was observed across various patient subgroups.

The safety data for Keytruda remained consistent and manageable, with no significant increase in side effects observed even after an extended follow-up of 57.2 months. The overall safety profile aligns with previous findings, supporting the long-term use of Keytruda as an adjuvant treatment.

Key subgroups, including male patients, those with M1 no evidence of disease, and individuals younger than 65, experienced pronounced survival benefits with Keytruda. Additionally, patients in various risk categories and those with specific features, such as sarcomatoid features, also showed improved outcomes with Keytruda.

“This is the first study to show a statistically significant and clinically meaningful survival improvement with any adjuvant therapy in kidney cancer and this further supports adjuvant (Keytruda) as a standard of care after surgery in this disease setting,” Dr. Toni Choueiri, lead study author and the director of the Lank Center for Genitourinary Oncology, co-leader of the Kidney Cancer Program, and a senior physician at Dana-Farber Cancer Institute in Boston noted during the presentation. 

At a median follow-up of 57.2 months in the intention-to-treat population, the median OS was not reached (NR) in either the Keytruda (496 patients) or placebo (498 patients) arms (meaning more than half of the patients in both arms were still alive). Findings revealed OS rates were 98.6% versus 98% at 12 months, 96.3% versus 93.9% at 24-months, 93.9% versus 89.5% at 36 months and 91.2% versus 86% at 48 months in the Keytruda versus placebo arms, respectively.

“In patients with ccRCC at increased risk of recurrence following surgery (there was a) 38% reduction in the risk of death with adjuvant Keytruda (versus placebo) with a survival benefit seen across key subgroups. A continued disease-free survival (DFS; the time a patient lives without signs of disease) benefit was seen (as well),” Choueiri, who is also the Jerome and Nancy Kohlberg Chair and a professor of medicine at Harvard Medical School in Boston, added.

Data from the study’s first protocol-specified interim analysis demonstrated that patients experienced a significant DFS benefit with adjuvant Keytruda versus placebo (hazard ratio [HR; the chance of an event happening], 0.68). After the DFS primary end point was met at the first interim analysis, it has not been formally tested again.

At this third interim analysis, the median DFS was not reached in the Keytruda group or in the placebo group, meaning more than half of the patients in both groups did not have signs or symptoms of disease. DFS rates were as follows at 12 months (85.5% versus 76.1%), 24 months (78.2% versus 67.2%), 26 months (72.4% versus 62.9%) and 48 months (64.9% versus 56.6%), respectively, according to the updated data presented.

Examining Enrollment Criteria and Patient Characteristics

Patients with histologically confirmed ccRCC who had not received prior systemic therapy were randomly assigned to receive Keytruda 200 mg or placebo every three weeks for up to 17 cycles. Eligible patients underwent surgery up to 12 weeks prior to randomization and had post-nephrectomy intermediate-high risk of recurrence, defined as pT2 (grade 4 or sarcomatous, no disease in the lymph nodes) or pT3 (any grade, no disease in the lymph nodes), or post-nephrectomy high-risk of recurrence, defined as pT4 (any grade, no disease in the lymph nodes) or any pT (any grade, node-positive disease). Additional enrollment criteria included receival of post-nephrectomy as well as complete resection of metastasis. Patients also needed to have an ECOG performance status of 0 or 1, meaning they could perform daily tasks with little to no assistance.

As of December 2022, all patients completed or discontinued study therapy as patients were randomly assigned and treated with Keytruda (498 patients) or placebo (496 patients) from June 30, 2017 to Sept. 20, 2019. Of those who completed therapy with Keytruda (298 patients) versus placebo (366 patients), discontinuations (190 versus 130, respectively) occurred due to relapse (51 versus 101), side effects (105 versus 11), withdrawal by patient (21 versus 10), physician decision (nine versus six), noncompliance with protocol (three versus two) or protocol violation (one versus zero). The median time from random assignment to data cutoff was 57.2 months.

Baseline characteristics were generally well-balanced between the two arms; the median age in the Keytruda and placebo arms was 60 years versus 60 years. Most patients in both arms were male (70% versus 72.1%,), from outside the U.S. (77% versus 76.5%), had M0 disease rather than M1 (94.2% versus 94.4%) and had an ECOG performance status of 0 (84.9% versus 85.5%). Disease risk categories were M0 intermediate-high (85.1% versus 86.9%), M0 high risk (8.1% versus 7.4%) and M1 no evidence of disease (5.8% versus 5.6%), respectively.

Further, sarcomatoid features in patients given adjuvant Keytruda versus placebo were present (10.5% versus 11.8%, respectively), absent (83.5% versus 83.3%), or unknown (6% versus 4.8%) and regarding PD-L1 status, patients had a combined positive score of less than 1 (25% versus 22.7%), at least 1 (73.6% versus 76.9%) or missing (1.4% versus 0.4%).

Key subgroups achieved an OS benefit when treated with the PD-1 inhibitor vs placebo; patients who were male, had M1 no evidence of disease and were younger than 65 experienced the most pronounced benefit.

Additionally, all subgroups experienced a DFS benefit with Keytruda versus placebo. The most notable benefits were seen in those with M1 no evidence of disease, M0 high risk disease, sarcomatoid features and those 65 years or older.

Of patients who experienced recurrence in the Keytruda (161 patients) and placebo (210 patients) arms, 79.5% (128 patients) compared with 81.4% (171 patients) received subsequent therapy, respectively. Subsequent therapy included radiation (24.2% versus 19.3%), surgery (17.4% versus 13.3%), and systemic anticancer therapy (79.7% versus 84.8%) encompassing a PD-(L)1 inhibitor (41.2%), VEGFR/VEGFR inhibitor (92.2% versus 84.8%) or other therapy (31.4% versus 41.4%).

Safety Data Remains Consistent with That Previously Reported

“The question is after 57.2 months of follow-up is there any impact in terms of toxicity (from approximately) one year of (Keytruda treatment)?” Choueiri asked. “We showed the result in the prior analysis of 30.1 months (and) the numbers stayed the same — the steroid use, the grade 3 (side effects), the serious (side effects) are the same. With 27.1 (more months of) follow-up there was no difference.”

With an identical median duration of therapy for both arms as that of the prior analysis — 11.1 months in the Keytruda and in the placebo arm — no differences greater than 1% were observed regarding rates of any-cause side effects, serious side effects, treatment-related side effects or immune-mediate side effects and infusion reactions observed in the prior analysis versus this third prespecified interim analysis.

Serious side effects were reported in 20.7% of patients treated with Keytruda and 11.5% of those given placebo, leading to discontinuation in 10% versus 1% of patients, respectively, according to identical data from both analyses. Additionally, no treatment-related side effects led to death in either arm.

Patients with clear cell renal cell carcinoma had improved overall survival when treated with adjuvant Keytruda compared to placebo. 

Postsurgical Keytruda Boosts Survival in Clear Cell Renal Cell Carcinoma

Patients with chemotherapy-naïve, HER2-low hormone receptor-positive metastatic breast cancer experienced antitumor activity via combination therapy with Arimidex (anastrozole) or Faslodex (fulvestrant) plus Enhertu (fam-trastuzumab deruxtecan-nxki), according to data from the phase 1b DESTINY-Breast08 trial presented by Dr. Komal Jhaveri during the 

2023 San Antonio Breast Cancer Symposium (SABCS)

Findings from the study showed that the 21 patients in the Enhertu plus Arimidex arm achieved a confirmed objective response rate (ORR; patients whose disease responded partially or completely to treatment) of 71.4% versus 40% for the 20 patients in the Enhertu plus Faslodex; the median duration of response (DOR) was 9.8 months in the Enhertu plus Arimidex arm and not evaluable in the Enhertu plus Faslodex arm.

The median progression-free survival (PFS; the time a patient lives without their disease worsening) was 13.4 months in the Arimidex arm and not evaluable in the Faslodex arm; six-month PFS rates were 80.7% and 75.3%, and the 12-month PFS rates were 50.4% and 52.7%, respectively.

Jhaveri noted that efficacy results should be interpreted with caution due to the small number of patients in each arm. Additionally, 15% of patients in the Enhertu plus Faslodex arm withdrew consent, discontinuing treatment before disease progression. The median follow-up was also slightly shorter in the Enhertu plus Faslodex arm at 15.2 months compared with 20.2 months in the Enhertu plus Arimidex arm.

The study enrolled patients with locally assessed HER-low hormone receptor-positive advanced or metastatic breast cancer. Patients could have received a maximum of one prior line of endocrine therapy with or without a targeted agent for metastatic disease; however, no prior chemotherapy in the metastatic setting was allowed. Additionally, patients needed to have one measurable lesion and an ECOG performance status of 0 or 1 (meaning they could perform daily tasks with little or no assistance).

Results from the dose-expansion phase were presented from the Enhertu plus Arimidex arm and the Enhertu plus Faslodex arm. Enhertu was administered every three weeks, Arimidex daily and Faslodex every four weeks.

An additional two arms of the trial examined Enhertu plus capecitabine or Truqap (capivasertib) in patients with hormone receptor-negative disease but were not presented at SABCS.

At baseline, patients in the Enhertu plus Arimidex arm had a median age of 55 compared with 65.5 in the Enhertu plus Faslodex arm. Patients had a HER2 status of IHC 1+ (76.2% versus 65%) or IHC 2+/ISH- (23.8 versus 35%); endocrine receptor (ER)-positive and progesterone receptor (PR)-positive (66.7% versus 50%), ER-positive and PR-negative (33.3% versus 45%) or ER-positive and PR missing (0% versus 5%) disease and an ECOG performance status of 0 (57.1% versus 85%), 1 (38.1% versus 15%) or 2 (4.8% versus 0%) in the Enhertu plus Arimidex arm versus Enhertu plus Faslodex arm, respectively. 

“Safety evaluations were comparable to the safety (profile) of the individual agents alone,” Jhaveri, a breast oncologist and early drug development specialist at Memorial Sloan Kettering Cancer Center in New York, said during the presentation. “One patient (died) in (the) study and this was attributed to disease progression and drug-induced pneumonitis by the investigator, but per the adjudication committee, the interstitial lung disease (ILD) was not (determined) to be drug-induced. There were a total of five cases of drug-induced pneumonitis or ILD, all of which were grade 2. At the data cutoff, two had resolved, one was resolving and two were not resolved. Four of these five patients had at least one potential risk factor for developing ILD/pneumonitis.”

Regarding safety, common any-grade side effects observed in the Arimidex versus Faslodex arms included nausea (66.7% versus 95%), alopecia (42.9% versus 50%), fatigue (42.9% versus 15%), anemia (33.3% versus 25%), COVID-19 (33.3% versus 25%) and decreased appetite (33.3% versus 55%), among others. Side effects led to dose interruption (57.1% versus 45%), reduction (28.6% versus 20%) and discontinuation (19% versus 30%) of Enhertu, respectively.

Further, side effects of grade 3 or higher severity occurred in 47.6% versus 55% of patients in the Arimidex versus Faslodex arms, respectively.

The median actual treatment duration in the Arimidex arm was 10.4 months for Enhertu and 11 months for Arimidex. In the Faslodex arm, median actual treatment duration was 6.3 months for Enhertu and 8.3 months for Faslodex.

Additionally, 33.3% of patients in the Arimidex arm did not receive a prior line of treatment for metastatic disease compared with 30% of patients in the Faslodex arm. Investigators noted that as of Aug. 16, 2023, six patients were ongoing treatment in the Arimidex arm versus seven patients in the Faslodex arm; disease progression was the primary reason for treatment discontinuation.

“(Enhertu) in combination with (Arimidex) or (Faslodex) was active in chemotherapy-naive patients with HER2-low hormone receptor-positive metastatic breast, cancer demonstrating encouraging antitumor activity,” Jhaveri concluded. “However, these are small data sets that limit the interpretation of the efficacy results and further research to evaluate (Enhertu) in combination with endocrine therapies is warranted.”

Patients with chemotherapy-naïve, HER2-low hormone receptor-positive metastatic breast cancer experienced antitumor activity via combination therapy with Arimidex or Faslodex plus Enhertu, according to data from the phase 1b DESTINY-Breast08 trial.

Arimidex/Faslodex And Enhertu Has Metastatic Breast Cancer Antitumor Activity 

Adding Keytruda to chemotherapy improved progression-free survival in a subset of patients with cervical cancer.

Patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer experienced improvements in progression-free survival (the amount of time a patient lives without a disease spreading or worsening) due to the addition of Keytruda (pembrolizumab) to external beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy, when compared with placebo plus EBRT/chemoradiotherapy/brachytherapy, according to data from the phase 3 KEYNOTE-A18 study.

Findings from the first interim analysis of the trial, which were presented during the 2023 

, support adding Keytruda to chemoradiotherapy, which has been in place as standard of care (SOC) for this patient population since 1999, according to study principal investigator Dr. Domenica Lorusso an associate professor of obstetrics and gynecology at the Catholic University of Rome.

“This is a celebration for patients because we’re challenging a treatment paradigm that has stood for more than two decades,” Dr. Bradley J. Monk, a professor in the division of gynecologic oncology at the University of Arizona College of Medicine in Tucson and the medical director of the US Oncology Research Network–Gynecologic Program, noted in a discussion of Lorusso’s presentation at ESMO.

At a median follow-up 17.9 months, the median PFS was not yet reached (NR) for the 528 patients in the Keytruda plus chemoradiotherapy arm or the 530 patients in the placebo plus chemoradiotherapy arm. The 24-month PFS rates were 67.8% and 57.3%, respectively.

Data presented from protocol-specified subgroups suggested consistent benefit was observed with the addition of Keytruda to treatment; those with an ECOG performance status of 1 (a patient is limited in their ability to engage in strenuous activity), aged 65 years or older and with stage 3 to 4A disease at screening experienced the most pronounced benefit.

An increase in overall survival (OS) was reported in the Keytruda arm, however, median OS was NR in either arm. The 24-month OS rates was 87.2% in the Keytruda arm vs 80.8% in the placebo arm.

Improvements were seen regarding overall response rate (ORR, patients whose disease responded to treatment) in the Keytruda arm vs placebo arm as the ORR was 79.3% in the Keytruda arm, including a complete response (CR; disappearance of all signs of cancer) rate of 50.7% and a partial response (PR) rate of 28.6% vs 75.9% in the placebo arm, with a CR rate of 48.7% and a PR rate of 27.2%. The 12-month OS rates were 81.4% vs 77.3%, respectively.

KEYNOTE-A18 enrolled patients with treatment-naïve, stage 1B2 to 2B node-positive disease or stage 3 to 4A node-positive or node-negative disease.

Cisplatin chemotherapy was given weekly for five cycles with EBRT followed by brachytherapy in both arms; for five weeks those in the investigative arm received concurrent Keytruda and those in the control arm received concurrent placebo. Keytruda or placebo was then administered every six weeks for 15 cycles.

At the Jan. 9, 2023, data cutoff, patients in the investigative vs control arm were continuing treatment (57.8% vs 54.9%), completed treatment (11% vs 10.6%) or had discontinued the trial (31.3% vs 34.5%), respectively.

In both arms, patients received a median of five cycles of cisplatin and 11 cycles of Keytruda or placebo. The median overall radiation therapy treatment time was 52 days in the Keytruda and placebo arms; the median total physical cervix dose was 76 Gy and the total cervix EQD2 dose was 87 Gy in the Keytruda arm compared with 76 Gy and 87 Gy in the placebo arm, respectively.

Baseline characteristics were well balanced between the arms and most patients had a PD-L1 combined positive score of greater than 1 (94.9% vs 93.8%), squamous cell carcinoma (81.9% vs 84.9%) and planned to receive EBRT in the form of IMRT or VMAT (88.7% vs 88.5%) in the Keytruda vs placebo arms, respectively. Additionally, patients had an ECOG performance score of 1 (28.2% vs 25.2%), stage 1B2-2B (44.4% vs 42.7%) or stage 3-4A (55.6% vs 57.3%) disease at screening and planned to receive a total radiotherapy dose of 70 Gy or greater (91.1% vs 91.3%) or less than 70 Gy (8.9% vs 8.7%).

Lymph node involvement was positive pelvic only (61.6% vs 61.0%), positive para-aortic only (2.6% vs 1.9%), positive pelvic and para-aortic (19.8% vs 19.6%) or no positive pelvic/para-aortic (15.9% vs 17.5%) in the Keytruda vs placebo arms, respectively.

In a discussion of the trial, Monk noted that a diverse population was enrolled. “Fifty-one percent of the patients in this study were non-White, (which is) perhaps one of the highest non-White enrollments ever,” he said.

In the Keytruda vs placebo arm patients were White (48% vs 49.7%), Asian (29.3% vs 27.9%), multiple races (14.7% vs 16.2%), American Indian or Alaska Native (4.5% vs 4.1%), Black (2.6% vs 1.5%) and Native Hawaiian or other Pacific Islander (0.4% vs 0.2%), respectively.

Regarding safety, grade 3 or higher treatment-related side effects occurred in 67% of patients in the investigative arm vs 60.6% of those in the control arm and serious side effects were reported in 17.2% vs 12.3% of patients, respectively. Two patients in each arm died from side effects and five patients in the Keytruda arm compared with six patients in the placebo arm died from all-cause side effects. Any grade immune-mediated side effects occurred in 32.6% vs 11.7% of patients and at grade 3 or higher in 4.2% vs 1.1% of patients, respectively. No immune-mediated side effects led to death in either arm.

Any grade side effects in the Keytruda vs placebo arm included anemia (59.3% vs 55.1%), nausea (57.2% vs 59.4%), diarrhea (50.4% vs 51.1%), decreased white blood cell count (32.6% vs 34.2%), decreased neutrophil count (29.0% vs 27.9%), vomiting (25% vs 28.3%), leukopenia (23.7% vs 17.4%), decreased platelet count (22% vs 20.4%) and neutropenia (21.4% vs 17.4%), respectively. The most common immune-mediated side effects that occurred were hypothyroidism (19.3% vs 4.5%), hyperthyroidism (11.4% vs 2.1%) and colitis (2.7% vs 1.7%).

Merck previously announced that the Food and Drug Administration (FDA) has accepted a supplemental Biologics License Application for priority review seeking approval of Keytruda in combination with EBRT plus concurrent chemotherapy, followed by brachytherapy for the treatment of patients with newly diagnosed high-risk locally advanced cervical cancer.

The Prescription Drug User Fee Act (PDUFA) date has been set for Jan. 20, 2024 and the regulatory decision was supported by data from KEYNOTE-A18.

The addition of Keytruda to external beam radiotherapy and concurrent chemotherapy, followed by brachytherapy, resulted in statistically significant and clinically meaningful improvements in progression-free survival in patients with newly diagnosed, previously untreated, high-risk locally advanced cervical cancer.

Megan Hollasch

Adding Lynparza to Presurgical Chemo May Not Boost TNBC Outcomes

Postsurgical Keytruda Boosts Survival in Clear Cell Renal Cell Carcinoma

Arimidex/Faslodex And Enhertu Has Metastatic Breast Cancer Antitumor Activity

Keytruda Plus Chemo Improves Progression-Free Survival in Cervical Cancer

Latest News