Wayne Kuznar

Acalabrutinib (Calquence), whether used as a single agent or in combination with obinutuzumab (Gazyva), led to an improvement in survival adjusted for quality over chlorambucil and obinutuzumab in patients with treatment- naive chronic lymphocytic leukemia (CLL). The results were from a post hoc quality-adjusted time without symptoms of disease and toxicity (Q-TWiST) analysis of patient-level data from the randomized, open-label phase 3 ELEVATE-TN trial (NCT02475681).

A Q-TWiST analysis assesses the balance of risk (toxicity) and benefit (prolonged survival without symptoms of progression or adverse events) of oncologic treatments. It incorporates both the benefits and risks of the drug’s effect, capturing the toxicity and mortality effects of treatment over the follow-up of a clinical trial.

The findings were presented at the 2021 International Workshop on Chronic Lymphocytic Leukemia by Jeff P. Sharman, MD, director of research at Willamette Valley Cancer Institute and Research Center and medical director of hematology research for The US Oncology Network, and colleagues.

Patients treated with acalabrutinib monotherapy had a significantly longer mean duration of time spent without toxicity compared with those treated with chlorambucil plus obinutuzumab at 24.94 months vs 19.53 months, respectively (

 < .0001). They also experienced a significantly shorter duration of relapse (1.39 vs 5.64 months; 

 < .0001). Additionally, the acalabrutinib- monotherapy arm had a numerically shorter time with toxicity at 1.11 vs 1.65 months with chlorambucil plus obinutuzumab (

 = .126). Overall, Q-TWiST duration was significantly longer with acalabrutinib monotherapy compared with chlorambucil plus obinutuzumab at 26.20 vs 23.18 months, respectively (

Patients treated with the acalabrutinib plus obinutuzumab combination, compared with chlorambucil plus obinutuzumab, had a significantly longer duration of TWiST at 25.10 vs 19.53 months, respectively (

 < .0001) and a significantly shorter time spent in relapse (0.14 vs 5.64 months; 

 < .0001). They also had a significantly longer Q-TWiST duration (26.14 vs 23.18 months; 

 < .0001) and a numerically longer duration of time spent with toxicity (1.94 vs 1.65 months; 

“The relative gain in Q-TWiST is equivalent to 11.3% and 11.0% of OS [overall survival] time in acalabrutinib monotherapy and acalabrutinib plus obinutuzumab, respectively; the gains were considered clinically important as they met the criterion of 10% used to determine clinically important Q-TWiST improvement,” the study authors wrote.

Previously in ELEVATE-TN, acalabrutinib plus obinutuzumab and acalabrutinib monotherapy significantly improved progression-free survival (PFS) compared with obinutuzumab plus chlorambucil, with tolerable safety in patients with treatment-naïve CLL.

Patients in the study were randomized 1:1:1 to receive oral acalabrutinib (100 mg twice daily continuously) alone or combined with intravenous obinutuzumab (1000 mg on days 1, 2, 8, and 15 of cycle 2, and day 1 of subsequent 28-day cycles for a total of 6 cycles), or obinutuzumab plus oral chlorambucil (0.5 mg/kg on days 1 and 15 of each 28-day cycle for 6 cycles). Crossover to acalabrutinib was allowed for patients who progressed on obinutuzumab plus chlorambucil.

At a median follow-up of 28.3 months (range, 25.6-33.1), the median PFS was not reached with acalabrutinib or acalabrutinib plus obinutuzumab compared with 22.6 months for chlorambucil plus obinutuzumab (HR, 0.1; 95% CI, 0.06-0.17; 

 < .0001). A lower or similar incidence of grade 3/4 adverse events was also reported for the acalabrutinib- based combination as compared with the chlorambucil-based regimen. The PFS rate at 2 years was estimated to be 93% (95% CI, 87%-96%) with acalabrutinib plus obinutuzumab, 87% (95% CI, 81%-92%) with single-agent acalabrutinib, and 47% (95% CI, 39%-55%) with obinutuzumab plus chlorambucil.

With the acalabrutinib and obinutuzumab combination, the most common grade 3 or higher adverse event was neutropenia in 30% of patients, and infections were reported in 21%. For the Q-TWiST analysis, the restricted mean duration for each health state was derived from the area under the Kaplan- Meier survival curve.

A limitation of the analysis was the use of immature clinical trial data, according to the investigators. “Given the indolent nature of CLL and acalabrutinib as a chronic treatment, maturity of clinical trial data can be achieved in long-term follow-up only; therefore, an updated analysis from ELEVATE-TN with longer-term follow-up [median of 47 months] is planned to validate the findings presented herein,” they wrote.

1. Sharman JP, Emeribe U, Cai L, Gaitonde P. A quality-adjusted survival (Q-TWiST) analysis of acalabrutinib with or without obinutuzumab in patients with treatment-naïve chronic lymphocytic leukemia (CLL). Poster presented at: 2021 International Workshop on CLL; September 17-20, 2021; Virtual. Abstract 1083755.

2. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naïve chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278- 1291. doi:10.1016/S0140-6736(20)30262-2

Articles

Patients treated with acalabrutinib monotherapy had a significantly longer mean duration of time spent without toxicity compared with those treated with chlorambucil plus obinutuzumab in the phase 3 ELEVATE-TN trial.

Frontline Acalabrutinib Improves Quality-Adjusted Survival in CLL

The benefit o first-line atezolizumab (Tecentriq) over chemotherapy in patients with non–small cell lung cancer (NSCLC) was not predicted with Blood-based tumor mutational burden (TMB) in the analysis of cohort C in the Blood First Assay Screening Trial (BFAST), according to a presentation given during the ESMO Congress 2021.

Data showed that, in a population selected for high TMB, which was defined as at least 16 mutations/megabase (mut/Mb) using the clinical trial assay (CTA), progression-free survival (PFS), the primary endpoint of cohort C of BFAST, was not significantly improved with atezolizumab, said lead study author Rafal Dziadziuszko, MD, PhD, in a virtual presentation during the meeting.

At a median follow-up of 18.2 months, PFS events occurred in 82% of the atezolizumab arm versus 85% of the chemotherapy arm in the high-TMB cohort (stratified HR, 0.77; 95% CI, 0.59-1.00; 

 = .053).The median PFS was 4.5 months in the atezolizumab arm vs 4.3 months in the chemotherapy arm.

“Progression rates were initially higher in the atezolizumab vs the chemotherapy arm. The curves crossed around 4 months and then a PFS benefit was observed with atezolizumab after 4 months,” said Dziadziuszko, deputy head and national consultant in radiation oncology, Medical University of Gdansk in Poland.

Overall survival (OS) was not different between the 2 arms in the high-TMB population, with the median OS being 13.3 months with atezolizumab and 10.3 months with chemotherapy (stratified HR, 0.87; 95% CI, 0.64-1.17; 

 = .035). The OS events were 57% with atezolizumab and 60% with chemotherapy.

TMB, while a promising biomarker for immunotherapy in NSCLC, is largely supported by data from retrospective analyses, with none reported from prospective phase 3 trials.

“Importantly, up to 30% of patients with NSCLC may have insufficient tissue [at diagnosis] for PD-L1 expression analysis and other biomarker testing

BFAST is a global, open-label, multicohort trial investigating the safety and efficacy of targeted therapies or immunotherapy in patients with advanced or metastatic NSCLC, who identified using a blood-based next-generation sequencing assay. Cohort C from BFAST is the first prospective study to evaluate blood-based TMB as a predictive biomarker for immunotherapy.

Eligible patients for BFAST Cohort C had untreated unresectable stage IIIB or IV NSCLC with a blood-based TMB of at least 10 mut/Mb and an absence of an 

 genetic alteration. Two TMB cutoffs were used: at least 10 mut/Mb to 15 mut/Mb to define moderately high TMB, and at least 16 mut/Mb to define high TMB. Patients were randomized to atezolizumab given at 1200 mg every 3 weeks until progressive disease or loss of clinical benefit, or platinum-based chemotherapy every 3 weeks for 4 or 6 cycles, with maintenance pemetrexed permitted for patients with nonsquamous NSCLC.

A preplanned bridging study comparing blood-based TMB clinical trial assay and the approved FoundationOne Liquid CDx was conducted to enable the FoundationOne assay data to be used for a companion diagnostic filing in the event that the trial was positive.

In cohort C of the BFAST study, 471 patients were enrolled overall, and 291 in the cohort had blood-based TMB at least 16 mut/Mb. Baseline characteristics were well balanced between the atezolizumab and chemotherapy arms. Brain metastases were present in 14.1% and 19.4%, respectively.

The confirmed objective response rate in the high-TMB population was 25.5% (95% CI, 18.7-33.4)for atezolizumab vs 17.8% (95% CI, 12.0%-25.0%) for chemotherapy.

In the high-TMB cohort, PFS was significantly higher with atezolizumab in patients with nonsquamous histology (5.3 vs 4.2 months; HR, 0.65; 95% CI, 0.48-0.88; 

Grade 3/4 treatment-related adverse events (TRAEs) occurred in 45.7% of the atezolizumab arm vs 57.5% of the chemotherapy arm. Serious TRAEs of any grade occurred in 44.4% of patients on the atezolizumab vs 37.1% of those on the chemotherapy arm.

An exploratory analysis of PFS and OS in the population with TMB of at least 13.6 mut/Mb by the FoundationOne Liquid CDx found a median PFS of 4.9 months in the atezolizumab arm compared with 4.2 months in the chemotherapy arm (stratified HR, 0.71; 95% CI, 0.52-0.96; 

 = .028). The median OS was 15.4 months vs 10.6 months, respectively (stratified HR, 0.75; 95% CI, 0.53-1.08; 

The assays were highly concordant for positive percentage agreement (82.9%), positive predictive value (89.4%), negative percentage agreement (91.5%),, and negative predictive value (86.0%).

1. Dziadziuszko R, Peters S, Gadgeel SM, et al. Atezolizumab (atezo) vs platinum-based chemo in blood-based tumour mutational burden-positive (bTMB+) patients (pts) with first line (1L) advanced/metastatic (m)NSCLC: results of the Blood First Assay Screening Trial (BFAST) phase 3 cohort C. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1281O3.

2. Carbone DP, Reck M, Paz-Ares L, e al. First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. 

 2017;376(25):2415-2426. doi:10.1056/NEJMoa1613493

3. Herbst RS, Giaccone G, de Marinis F, et al. Atezolizumab for first-line treatment of PD-L1-selected patients with NSCLC. 

 2020;383(14):1328-1339. doi:10.1056/NEJMoa1917346

4. Kris MG, Johnson BE, Berry LD, et al. Using multiplexed assays of oncogeneic drivers in lung cancers to select targeted drugs. 

. 2014;311(19):1998-2006. doi:10.1001/jama.2014.3741

Blood-based tumor mutational burden was hypothesized to be predictive of benefit on atezolizumab treatment in patients with non–small cell lung cancer, but a study has shown otherwise.

Blood-Based Tumor Mutational Burden Not Prognostic for Atezolizumab Use in NSCLC

The use of targeted therapy and immunotherapy in the adjuvant setting is emerging in several settings. After success in malignant melanoma and non–small cell lung cancer, adjuvant treatments are demonstrating improvements in disease-free survival (DFS) in other cancers, including renal cell carcinoma (RCC), esophageal/gastroesophageal cancer, and breast cancer.

Most recently, pembrolizumab (Keytruda) was granted priority review by the FDA for a new supplemental biologics license application for the adjuvant treatment of patients with RCC at intermediate- high or high risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions.

Extrapolating From Efficacy in Metastatic Disease

Targeted/immunotherapy in the adjuvant setting is used to treat micrometastatic disease before cancer cells become well established.

“The holy grail for any kind of cancer is a reduction in the number of recurrences and an increase in the number of patients who are completely cured of their disease [and never have a recurrence],” Naomi B. Haas, MD, said in an interview with 

™. “The way we define success of adjuvant therapy or neoadjuvant therapy, however, is often based on lower bars such as improvement in DFS, defined as a delay in recurrence. That’s a pretty well-established approach in a lot of diseases [eg, breast cancer, colon cancer, lung cancer, melanoma]. A lot of us wish the bar would be a little bit higher. Sometimes it’s an improvement of only 10% or 6%, and sometimes it’s much higher than that.”

Activity in the advanced disease setting provides the rationale for investigation of these therapies in earlier disease states, said Rana R. McKay, MD, in an email correspondence with 

™. “While pembrolizumab is not approved as a single agent for metastatic disease, the activity of single-agent use was demonstrated in the KEYNOTE-427 trial1 [NCT02853344] [in patients with locally advanced/metastatic RCC],” she wrote. “Additionally, the activity of single-agent nivolumab [Opdivo] has also been demonstrated for patients with metastatic disease.”

The adoption of adjuvant targeted therapy and immunotherapy requires a balance that tilts toward benefit and quality of life over the burden of adverse events (AEs), said Haas, director of the Prostate and Kidney Cancer Program at Penn Medicine’s Abramson Cancer Center in Philadelphia, Pennsylvania.

The best example is the exploration of adjuvant VEGF receptor tyrosine kinase inhibitors (TKIs) in the treatment of RCC, a setting in which numerous clinical trials have been conducted. The largest trial, ASSURE (ECOG-ACRIN E2805; NCT00326898),

was a 1-year blinded trial of adjuvant sorafenib (Nexavar), adjuvant sunitinib (Sutent), or 1 year of placebo. No improvement in DFS or overall survival (OS) was observed with adjuvant treatment. The ATLAS trial (NCT01599754),

 which examined the use of adjuvant axitinib (Inlyta) vs placebo for up to 3 years, was terminated early due to futility. Furthermore, adjuvant pazopanib (Votrient) did not show improvements in DFS or OS in this setting 

Adjuvant sunitinib in the S-TRAC study (NCT00375674) showed an improvement over placebo on the end point of DFS in a more restricted high-risk clear cell RCC population, but the benefit to DFS did not translate into an OS advantage.

More than 60% of patients in each of these trials had a grade 3 or 4 toxicity, and most TKI recipients required dose reductions to manage AEs. “If you’re giving a patient treatment for a year, even with sunitinib in S-TRAC, you delay recurrence by a year but the patient spent that year being miserable,” Haas said.

Based on the results from S-TRAC, sunitinib was approved by the FDA for use in the adjuvant setting. However, its use was downgraded to category 3 in the National Comprehensive Cancer Network guidelines due to a lack of OS benefit, Haas pointed out.

The data with immune checkpoint inhibitors in RCC are more exciting, Haas said. The supplemental Biologics License Application for pembrolizumab was accepted for review by the FDA on the basis of results from the KEYNOTE-564 study (NCT03142334),5 which were presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.6 Adjuvant pembrolizumab induced a significant and clinically meaningful improvement in DFS compared with placebo in patients with locoregional RCC who underwent nephrectomy.


Following nephrectomy, almost half of such patients eventually have recurrence of their disease. “The data represent a paradigm shift as the first positive phase 3 study of adjuvant immunotherapy in RCC,” said McKay, a medical oncologist and associate professor of medicine at UC San Diego Health, a discussant of the ASCO session. “Ultimately, this is a quantum leap forward for our patients and provides additional options for individuals with RCC.”

KEYNOTE-564 enrolled 994 patients with histologically confirmed clear cell RCC who had undergone nephrectomy no more than 12 weeks prior to being randomized to pembrolizumab 200 mg every 3 weeks for up to 17 cycles (approximately 1 year) or placebo.

The primary end point of DFS in the intention-to- treat population favored pembrolizumab, with an HR of 0.68 (95% CI, 0.53-0.87; 

 = .0010). At 12 months, the DFS rates were 85.7% in the pembrolizumab arm and 76.2% in the placebo arm. DFS rates at 24 months were 77.3% and 68.1%, respectively. 

The benefit favoring pembrolizumab extended to intermediate-high risk, high risk, and M1 no evidence of disease categories.

An interim OS analysis favored pembrolizumab (HR, 0.54; 95% CI, 0.30-0.96; 

 = .0164), with an OS rate at 12 months of 98.6% in the pembrolizumab arm and 98.0% in the placebo arm. The 24-month OS rates were 96.6% and 93.5%, respectively.

“What was really uplifting was that there was less grade 3 and grade 4 toxicity reported [compared with trials of sunitinib],” Haas said.

No new safety signals were observed with adjuvant pembrolizumab in KEYNOTE-564. Grade 3 to 5 treatment-related AEs occurred in 18.9% of patients in the pembrolizumab arm and in 1.2% in the placebo arm, with AEs leading to treatment discontinuation in 17.6% and 0.6%, respectively. There were no deaths attributed to treatment-related AEs.

Immune-mediated AEs in the pembrolizumab arm included hypothyroidism (21.1% vs 3.6% in the placebo group), hyperthyroidism (11.9% vs 0.2%, respectively), and pneumonitis (2.3% vs 1.0%).

However, the irreversible nature of some of the treatment-related AEs associated with pembrolizumab (eg, diabetes, adrenocortical insufficiency, panhypopituitarism) and\ severe AEs such as myocarditis and encephalitis could be cause for concern, Haas said, as opposed to adjuvant TKIs, with treatment- related AEs that are mostly reversible.

Given the signal for improved OS with pembrolizumab, unlike with the TKIs used in the adjuvant setting, “the results of KEYNOTE-564 are definitely going to change the way we approach adjuvant therapy for patients with RCC,” McKay said. “Use in the clinical setting is going to be dependent on multiple factors, including patients’ calculated risk of recurrence, age, comorbidities, treatment [AEs], and other variables.”

Although subset analyses demonstrated consistent benefit across all subgroups, additional studies investigating DFS by TNM stage, presence of sarcomatoid features, and other subsets are warranted, McKay said.

The FDA has set a Prescription Drug User Fee Act date of December 10, 2021, for pembrolizumab for this indication.

Will Perioperative Nivolumab Be Effective in PROSPER?

The PROSPER RCC trial (NCT03055013) is a phase 3 global study sponsored by the National Cancer Institute designed to determine if perioperative nivolumab can supplant postsurgical surveillance as the standard of care in patients scheduled to undergo radical or partial nephrectomy for high-risk RCC (ie, clinical stage ≥ T2 or T

N+ RCC of any histology). Haas is the medical oncology study monitor for this study.

The trial is investigating immunotherapy in both neoadjuvant and adjuvant settings. Patients in PROSPER RCC assigned to the investigational arm receive a single 480-mg dose of nivolumab 7 to 28 days prior to partial or radical nephrectomy (when the study was initiated, patients received two 240-mg doses prior to surgery). Following recovery from surgery, patients then receive 9 adjuvant doses of nivolumab every 4 weeks. Those in the control arm will undergo immediate nephrectomy followed by surveillance.

The nivolumab regimen was selected from findings obtained in mouse models, Haas said. “The hypothesis behind it was that you might need more tumor in place to better prime T lymphocytes to do their work,” she said. “If you give just adjuvant immune checkpoint inhibitor when there’s no cancer around, it might not be as effective. The other reason is that if you give patients treatment and then take the tumor out, you can look for pathologic complete responses, immune signatures, and the degree of tumor-infiltrating lymphocytes that are present in kidney tumor after treatment.”

She cited work from Motzer et al8 showing that clusters based on RNA print signatures can stratify patients to predict improved outcomes from VEGF inhibitors or immune checkpoint inhibitors. The 3 main types of signatures are high angiogenesis signatures that respond to antiangiogenic agents such as VEGF inhibitors, immune-mediated signatures that benefit from immune checkpoint inhibitors, and mixed signatures that may respond to both or neither.

“What we’re doing in PROSPER RCC, and I imagine will be done in some of the industry trials, is retrospectively looking at these signatures in the populations to see, based on the response, who had these signatures, who didn’t, and can we better home in on our population,” Haas said.

Adjuvant Immunotherapy in Gastroesophageal Cancer

On May 20, 2021, the FDA approved nivolumab for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy. The basis for this regulatory decision was a significant improvement in median DFS obtained with adjuvant nivolumab in the phase 3 double-blind Check-Mate 577 study (NCT02743494).

Adjuvant nivolumab doubled median DFS compared with placebo, at 22.4 months vs 11.0 months, corresponding to a 31% relative reduction in the risk of disease recurrence or death (HR, 0.69; 95% CI, 0.56-0.86; 

For patients with stage II or stage III esophageal and GEJ cancers, neoadjuvant chemotherapy followed by surgery, also called trimodality therapy, is a widely used standard of care.

“Unfortunately, risk of recurrence following trimodality therapy remains high, particularly in the 70% to 75% of patients who do not achieve a pathologic complete response,” said lead CheckMate 577 investigator Ronan J. Kelly MD, director of oncology for the Baylor Scott & White Charles A. Sammons Cancer Center in Dallas, Texas. “There is no established adjuvant treatment, with close observation as [the] standard approach. In the CheckMate 577 trial, we saw a doubling in median DFS compared [with] placebo, which suggests that [nivolumab] could become a new standard of care for these patients.”

CheckMate 577 enrolled 794 patients with stage II/III esophageal or GEJ cancer, adenocarcinoma, or squamous cell carcinoma to 240 mg of nivolumab once every 2 weeks for 16 weeks followed by 480 mg once every 4 weeks (n = 532) or placebo every 2 weeks for 16 weeks and then once every 4 weeks (n = 262) for up to 1 year. To be eligible for enrollment, patients had to have received neoadjuvant chemoradiation, undergone surgical resection, and had residual disease.

The favorable effect of nivolumab on DFS was consistent regardless of PD-L1 status, and subgroup analysis showed equal benefit in patients with stage II and III disease.

Data from an exploratory analysis in 563 patients with adenocarcinoma showed that the median DFS with nivolumab was 19.4 months vs 11.1 months with placebo (unstratified HR, 0.75; 95% CI, 0.59-0.96). Among 230 patients with squamous cell carcinoma, the median DFS with nivolumab was 29.7 months vs 11.0 months with placebo (unstratified HR, 0.61; 95% CI, 0.42-0.88).

Patient-reported quality of life was equivalent between the 2 arms, Kelly reported. “The majority of patients were not at all bothered by treatment-related [AEs] in both the nivolumab and placebo arms.” Additionally, a quality-of-life analysis showed a trend toward improvement in both arms and in maintenance quality of life after treatment was stopped, Kelly said.

In the breast cancer setting, 1 year of adjuvant treatment with the PARP inhibitor olaparib (Lynparza) following the completion of local treatment and standard adjuvant or neoadjuvant chemotherapy significantly improved both invasive DFS and distant DFS in patients with high-risk, HER2-negative, early-stage breast cancer harboring germline 

Results from the OlympiA trial (NCT02032823),11 which randomized 1836 patients to continuous olaparib (300 mg twice daily) or placebo, showed that olaparib reduced the risk of invasive breast cancer recurrence, second cancers, or death by 42% (

 < .0001) and the risk of distant disease recurrence or death by 43% (

 < .0001) at a median follow-up of 2.5 years, reported Andrew Tutt, PhD, FMedSci, at the 2021 ASCO meeting. The study was terminated early based on a prespecified event-driven interim analysis.

The absolute difference between arms in the 3-year invasive DFS rate was 8.8 percentage points and the difference in invasive DFS in the mature cohort (median follow-up, 3.5 years) was 8.6 percentage points.

The 3-year difference between arms in distant DFS rate was 7.1 percentage points. 

Fewer deaths were reported in the olaparib arm, but OS data from OlympiA are not yet mature at a median of 2.5 years. The stratified hazard ratio for death was 0.68 (

 = .024) but was not significant based on a level of

 < .01. The absolute different in 3-year OS rates between arms was 3.7 percentage points.

Tutt, head of the Division of Breast Cancer Research at Guy’s Hospital, King’s College, in London, England, said: “I think most of us would agree that the development of metastatic disease is a fatal event in HER2-negative breast cancer. At a median follow-up of 2.5 years, we’ve just not seen the inevitable OS events. The number of deaths was 86 in the placebo arm and 59 in the treatment arm. But the statistical boundary was incredibly rigorous at this point because we’re saving statistical power for more appropriate follow- up time points. I think that’s why it’s not statistically significant.”

 sequencing “is an important biomarker in early breast cancer,” he concluded. “I think it also speaks to the need to consider genetic testing of patients in a slightly different way now. It was already beginning to be considered as a patient selection for treatment, as opposed to a risk assessment test for risk of developing 

-associated cancers and managing family risk.”

“I think everyone agrees that these results are practice-changing,” said Nadine Tung, MD, director of the Cancer Risk and Prevention Program at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “I agree with Dr Tutt completely; we really need to get comfortable with this because it’s not just about future cancer risk at this point. It’s about optimal treatment of the cancer. At the very least, anyone who would meet the eligibility for OlympiA should be tested.”

Head and Neck: Adjuvant Pembrolizumab Being Studied

Adjuvant therapies are continuing to be investigated in more solid tumors.

The KEYNOTE-689 (NCT03765918) trial is a randomized, open-label phase 3 study evaluating pembrolizumab as neoadjuvant and adjuvant therapy to radiotherapy with or without cisplatin in the previously untreated, resectable locally advanced head and neck squamous cell carcinoma.

Patients will be randomized to neoadjuvant pembrolizumab followed by surgical resection then standard of care plus 15 cycles of adjuvant pembrolizumab or surgical resection followed by adjuvant standard of care. Dual primary end points are major pathologic response and event-free survival.

1. McDermott DF, Lee JL, Ziobro M, et al. Open-label, single-arm phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma

. 2021;39(9):1029-1039. doi:10.1200/JCO.20.02365

2. Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomized, phase 3 trial. 

 2016;387(10032):2008-2016. doi:10.1016/S0140-6736(16)00559-6

3. Gross-Goupil M, Kwon TG, Eto M, et al. Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma: results from the phase III, randomized ATLAS trial. 

2018;29(12):2371-2378. doi:10.1093/annonc/mdy454

4. Ravaud A, Motzer RJ, Pandha HS, et al; S-TRAC Investigators. Adjuvant sunitinib in high-risk renal-cell carcinoma after nephrectomy. 

 2016;375(23):2246-2254. doi:10.1056/NEJMoa1611406

5. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: randomized, double-blind, phase III KEYNOTE-564 study. 

 2021;39(suppl 18):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5

6. FDA grants priority review to Merck’s supplemental biologics license application for KEYTRUDA (pembrolizumab) as adjuvant therapy in certain patients with renal cell carcinoma (RCC) following surgery. News release. Merck; August 10, 2021. Accessed August 21, 2021. 

7. Allaf ME, Kim SE, Master VA, et al. PROSPER: phase III randomized study comparing perioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143). 

 2021;39(suppl 15):TPS4596. doi:10.1200/JCO.2021.39.15_suppl.TPS4596

8. Motzer RJ, Banchereau R, Hamidi H, et al. Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. 

020;38(6):803-817.e4. doi:10.1016/j.ccell.2020.10.011

9. FDA approves nivolumab for resected esophageal or GEJ cancer

 FDA. May 20, 2021. Accessed August 21, 2021. 

10. Kelly RJ, Ajani JA, Kuzdzal J, et al; CheckMate 577 Investigators. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. 

. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125

11. Tutt A, Garber JE, Kaufman B, et al. OlympiA: A phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline 

 mutations and high-risk HER2-negative early breast cancer. 

 2021;39(suppl 18):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1

After success in malignant melanoma and non–small cell lung cancer, adjuvant treatments are demonstrating improvements in disease-free survival in other cancers, including renal cell carcinoma, esophageal/gastroesophageal cancer, and breast cancer.

Targeted Agents, Immunotherapies Are Advancing to the Adjuvant Setting in Solid Tumors

Improved progression-free survival (PFS) in heavily pretreated patients with relapsed ovarian cancer was seen with ith maintenance olaparib (Lynparza) rechallenge following response to platinum-based chemotherapy, according to results of the phase 3 OReO/ENGOT Ov-38 (NCT03106987) study that were presented during the 2021 ESMO Congress.

Data showed that 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.

PFS in Relapsed Ovarian Cancer Previously Treated With PARP Inhibition Improved with Olaparib Rechallenge

Compared indirectly with real-world data of patients treated with standard of care, mobocertinib (Exkivity), a novel EGFR tyrosine kinase inhibitor (TKI), exhibited clinically meaningful activity in patients with non–small cell lung cancer (NSCLC) who harbor 

 exon 20 insertion mutations following frontline platinum-based chemotherapy, according to findings from a multicenter, open-label clinical trial that were presented during the 2021 ESMO Congress.

Results showed that the weighted response rate was nearly 3 times higher with mobocertinib vs standard of care, and both progression-free survival (PFS) and overall survival (OS) were significantly prolonged with mobocertinib compared with treatment options used in the real-world setting, according to Sai-Hong I. Ou, MD, PhD, from the Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, and colleagues who presented the results in a poster presentation.

After propensity score weighting, the confirmed ORR for 114 patients treated with mobocertinib in the study was 35.1% (95% CI, 26.4%-44.6%) vs 11.9% (95% CI, 5.8%-18.0%) in the real-world group, an absolute difference of 23.2% (odds ratio [OR], 3.75; 95% CI, 2.05-6.89; 

The weighted median PFS was longer in mobocertinib-treated patients in the trial, at 7.3 months (95% CI, 5.6-8.8) compared with 3.3 months (95% CI, 2.2-7.3) in the real-world group (HR, 0.57; 95% CI, 0.36-0.90; 

After weighting, the median OS for the mobocertinib group and RWD group was 24.0 months (95% CI, 14.6-28.8) and 12.4 months (95% CI, 7.1-16.6), respectively (HR, 0.53; 95% CI, 0.33-0.83; 

 for the treatment of adult patients with locally advanced or metastatic 

 exon 20 insertion–mutant metastatic NSCLC, as detected by an FDA-approved test, and who have received prior platinum-based chemotherapy.

“Among platinum-pretreated patients with 

 NSCLC, mobocertinib demonstrated significantly higher ORR, prolonged PFS and OS compared with treatment options used in the real-world setting, even after propensity score weighting,” the investigators noted.

 exon 20 insertion mutations are present in 4% to 12% of patients with 

-mutant NSCLC. Standard frontline treatment in this setting is platinum-based chemotherapy, but outcomes are poor, representing an unmet need, according to the investigators. Mobocertinib is designed to selectively target in-frame 

In an ongoing phase 1/2 trial (NCT02716116), mobocertinib demonstrated clinically meaningful benefit in platinum-pretreated patients with 

 exon 20 insertion–mutant metastatic NSCLC, which was the basis for the September 2021 FDA approval in this setting.2

The study presented during the 2021 ESMO Congress compared clinical outcomes for platinum-pretreated patients with 

 exon 20 insertion–mutant metastatic NSCLC who were treated with mobocertinib at 160 mg daily, as part of the phase 1/2 trial, vs standard of care in the post-platinum second- or later-line setting using data from 50 patients identified from the Flatiron Health electronic record database.

Because of the rarity of patients with NSCLC who have 

 exon 20 insertion mutations, conducting a controlled clinical trial with a comparator arm is difficult; therefore, the investigators chose to use real-world data as a comparator.

The median age of participants was 60.0 years in the mobocertinib group and 64.0 years in the real-world group. Females represented 65.8% and 68.0% of the groups, respectively. A smoking history was present in 28.9% and 42.0%, respectively, and 35.1% and 34.0%, respectively, had brain metastases at baseline.

In the real-world group, second- or later-line standard-of-care treatment consisted of an EGFR TKI in 20.0%, immunotherapy alone in 40.0%, and chemotherapy with or without immunotherapy or monoclonal antibody in 40.0%.

The analysis was conducted in an unadjusted data set and in a set using propensity score modeling with inverse probability of treatment weightings to balance prognostic factors for NSCLC between patients in the mobocertinib and real-world data groups.

In the unweighted dataset, the confirmed ORR (

 = .0053) were all significantly superior in patients on the mobocertinib arm compared with the real-world group, and notable differences remained following propensity weighting.

“Despite differences between controlled trial data and real-world data, in the absence of direct head-to-head trial data, real-world can be used as a comparator for single-arm clinical trials,” the investigators added.

OuS-H I, Lin HM, Hong J-L, et al. Indirect comparison of mobocertinib and standard of care in platinum-pretreated patients with NSCLC with EGFR exon 20 insertion. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1211P. 

Compared indirectly with real-world data of patients treated with standard of care, mobocertinib, a novel EGFR tyrosine kinase inhibitor, exhibited clinically meaningful activity in patients with non–small cell lung cancer who harbor EGFR exon 20 insertion mutations following frontline platinum-based chemotherapy. 

Wayne Kuznar | Authors

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