Experts in Oncology Highlight Key Abstracts Presented at the 2019 ESMO Congress

Targeted Oncologyfollowers on Twitter shared their thoughts in a Twitter Poll on which area had the most important data come out during the meeting. There was a general agreement that ovarian cancer saw the most important updates, while lung and breast cancers also had some significant data presented. Experts also noted some key trials presented for gastrointestinal (GI) and genitourinary (GU) cancers.

ESMO POLL: In what area do you think the most important data came from at the 2019@myESMOCongress? Tell us in the comments what your favorite#ESMO19abstracts were and tag colleagues for their opinions, too!

Look back on some of the abstracts here, too:https://t.co/ZAnZXJRQYE

— Targeted Oncology (@TargetedOnc)October 1, 2019

Following the 2019 ESMO Congress, experts across various fields highlighted some next steps and how these treatment options will improve the treatment landscape for patients with ovarian, lung, breast, GI, or GU cancers. Overall, the abstracts presented at this year’s meeting will change the treatment paradigm in a number of patient populations.

“This year’s ESMO was the most impactful meeting for the treatment of first-line ovarian cancer in history,” David O’Malley, MD, professor and division director, Gynecologic Oncology, James Cancer Center and The Ohio State University, Columbus, toldTargeted Oncology. “The first-line trials presented at ESMO will shape the way we treat ovarian cancer for the next decade.”

Looking at the advances made in the field of breast cancer, Erika Hamilton, MD, medical oncologist, director, Breast and Gynecologic Cancer Research Program, Sarah Cannon Research Institute, said, “I think immunotherapy warrants further investigation in HER2-positive patients. We continue to see a trend that our patients with breast cancer seem to receive more benefit from immunotherapy the earlier they received it in their disease course. We have certainly seen this in the first line versus later lines in triple-negative breast cancer (TNBC) with a negative later-line pembrolizumab [Keytruda] presentation at ESMO as well.”

Ovarian Cancer:

David OMalley, MD

David OMalley, MD

“We have further confirmation that women who receive CDK4/6 inhibitors in combination with endocrine therapy live longer,” Hamilton added. “We often see increased progression-free survival [PFS] on trials, but overall survival [OS] is our gold standard and what we are really striving for.”VELIA Trial Shows Benefit for Combination of PARP Plus Chemotherapy in Ovarian Cancer

In the phase III VELIA trial, patients with advanced ovarian cancer were randomized to 1 of 3 arms, all of which included carboplatin plus paclitaxel as induction therapy. In the control arm, patients also received placebo maintenance; in the 2 experimental arms, patients received veliparib (ABT-888) at 150 mg twice daily in combination with chemotherapy, followed by maintenance with either placebo or veliparib at 400 mg twice daily. The primary endpoint was PFS.

“VELIA met its primary endpoint for the entire population,” said O’Malley. “VELIA was most impactful as the first phase III trial to show we could combine a PARP inhibitor with standard chemotherapy safely, which results in a significant impact in these frontline patients. Though it impacted the entire intent-to-treat population, the greatest impact appeared to be in theBRCAand HRD-positive patients.”

The addition of frontline veliparib plus carboplatin and paclitaxel followed by veliparib maintenance reduced the risk of progression or death by 32% compared with the control arm. The median PFS for this group of patients was 23.5 months versus 17.3 months in the control. However, the benefit was more pronounced in those with aBRCAmutation, where the median PFS was 34.7 months compared with 22.0 months for the control.

Overall, the adverse events (AEs) with veliparib remained consistent with what was noted for the chemotherapy combination. The most common grade 3/4 AEs with veliparib were neutropenia, anemia, thrombocytopenia, and leukopenia.

“The ability to combine chemotherapy with a PARP inhibitor could potentially move PARP inhibitors ahead of bevacizumab in the adjuvant and maintenance setting of first-line ovarian cancer,” O’Malley concluded. “These findings will be impactful for the treatment of this disease.”

Lead author Robert L. Coleman, MD, FACOG, FACS, professor in the Department of Gynecologic Oncology and Reproductive Medicine at the University of Texas MD Anderson Cancer Center, also discussedthe results from the VELIA trial in a video interviewwithTargeted Oncology.

PFS Improved With Frontline Niraparib Maintenance in Ovarian Cancer

Patients with newly diagnosed, advanced ovarian cancer received either niraparib (Zejula) or placebo in the phase III PRIMA trial. The median PFS was improved by 5.6 months with frontline niraparib versus placebo. The median PFS was 13.8 months with niraparib compared with 8.2 months with placebo, representing a 38% reduction in the risk of progression or death.

“PRIMA met its primary endpoint in maintenance therapy in the first-line setting for the entire population,” O’Malley commented. “This sub-analysis was also insightful with regard to the marked benefit in biomarker-positive patients as well as a modest benefit in biomarker-negative patients.”

The median PFS in patients who tested positive for homologous recombination deficiency (HRD) was 21.9 months with niraparib versus 10.4 months with placebo. Upon further analysis of the HRD group, the median PFS for patients harboring aBRCAmutation was 22.1 months versus 10.9 months with niraparib and placebo, respectively. For those that did not harbor a BRCAmutation, the median PFS was 19.6 with niraparib versus 8.2 with placebo. Niraparib also outperformed placebo for PFS in those with HRD-negative tumors, where the median PFS was 8.1 months versus 5.4 months.

Grade 3 or greater AEs were experienced by 65.3% of patients in the niraparib arm versus 6.6% in the placebo arm. The most common grade ≥3 for niraparib included anemia, thrombocytopenia, platelet count decrease, and neutropenia.

Olaparib Plus Bevacizumab Extends PFS as Frontline Maintenance in Ovarian Cancer

The phase III PAOLA-1 trial randomized newly diagnosed patients with advanced ovarian cancer to receive either 15 mg/kg of bevacizumab (Avastin) twice daily with 300 mg olaparib (Lynparza) tablets twice daily or matched placebo. The primary objective of this trial was to demonstrate a statistically significant improvement in PFS with olaparib plus the standard frontline bevacizumab.

“PAOLA-1 is in the upfront maintenance setting with a primary endpoint of PFS in all patients,” O’Malley said. “This is the first trial to show that PARP inhibitors and bevacizumab when combined as a first-line treatment was beneficial as compared with bevacizumab alone. This is the first phase III trial to show the benefit of PARP inhibitor maintenance compared to an active therapy, bevacizumab, rather than a placebo.”

The median PFS was improved by 5.5 months in the olaparib arm versus placebo. Median PFS was 22.1 months versus 16.6 months in the olaparib and placebo arms, respectively. This represents a 41% reduction in the risk of progression or death with the addition of olaparib. Additionally, median PFS was 37.2 months with olaparib versus 21.7 with placebo in patients who tested positive forBRCA1/2mutations (tBRCAm). In patients who were HRD-positive and notBRCA-mutated, the median PFS was 28.1 months versus 16.6 months, while those with HRD-positivity and tBRCAm had a median PFS of 37.2 months versus 17.7 months in the olaparib versus placebo arms, respectively.

Lung Cancer:

“This sub-analysis was very interesting and thought provoking, especially regarding the differences in outcomes of biomarker-positive (BRCA/HRD) versus biomarker-negative patients,” O’Malley concluded.Overall Survival Improved With Frontline Osimertinib inEGFR-Positive NSCLC

After randomizing 556 patients withEGFR-positive locally advanced or metastatic non—small cell lung cancer (NSCLC) to either frontline osimertinib (Tagrisso) or a standard TKI, including erlotinib (Tarceva) or gefitinib (Iressa), the updated findings from the phase III FLAURA trial showed an improvement in median OS with osimertinib in the frontline setting for patients with metastaticEGFR-mutant NSCLC.

The median OS was 38.6 months versus 31.8 months in the osimertinib and erlotinib or gefitinib arms, respectively. There was a 20% reduction in the risk of death with osimertinib as well. The FDA approved osimertinib in April 2019 as a frontline treatment of patients withEGFR-positive NSCLC based on earlier findings from this trial.

“Osimertinib is already an FDA-approved frontline treatment choice in the United States, and it’s also approved in many other parts of the world,” study author Suresh S. Ramalingam, MD, from the Winship Cancer Institute of Emory University, said. “These data confirm its position as the preferred frontline therapy agent with improvement in PFS and OS.”

The most common all-grade AEs with this agent included rash or acne, dry skin, paronychia, stomatitis, and decreased appetite, but AEs were less likely to lead to discontinuation in the osimertinib arm versus the control.

OS Improvement Seen in Updated Results for Atezolizumab Combo in ES-SCLC

In the international, randomized, placebo-controlled, double-blind phase III IMpower133 trial, 403 treatment-naïve patients with extensive-stage small cell lung cancer (ES-SCLC) were randomized to receive carboplatin and etoposide (CP/ET) with either atezolizumab (Tecentriq) or placebo followed by maintenance with atezolizumab or placebo. According to the updated findings presented at this year’s meeting, frontline atezolizumab plus CP/ET improved OS.

The median OS remained 12.3 months in patients randomized to atezolizumab at a median follow-up of 22.9 months versus 10.3 months in the placebo group (HR, 0.7;P= .007). This is the first trial to demonstrate a significant improvement in survival in the frontline setting for patients with SCLC since platinum-based chemotherapy in the 1990s, according to presenter Martin Reck, MD, PhD.

In the updated analysis, there was no change in tolerability. Approximately 38.9% of patients in the atezolizumab arm and 35.2% in the placebo arm had serious AEs. The most common immune-related AEs with the PD-L1 inhibitor included rash, hepatitis, changes in thyroid function, and infusion-related reactions.

Nivolumab and Ipilimumab Demonstrate OS Benefits Upfront in Advanced NSCLC, Regardless of PD-L1 Expression

The final analysis of part 1 of the phase III CheckMate 227 trial was presented at the 2019 ESMO Congress; these data showed that the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) led to survival benefits in treatment-naïve patients with advanced NSCLC, regardless of PD-L1 expression status.

The median OS was 17.1 months versus 14.9 months with the combination versus chemotherapy in patients with PD-L1 expression of 1% or greater (HR, 0.79; 97.72% CI, 0.65-0.96;P= .007). Additionally, the median OS of patients regardless of PD-L1 expression status was 17.1 months with the combination compared with 13.9 months with chemotherapy.

Survival Benefit With Atezolizumab in High PD-L1 NSCLC

The phase III IMpower110 trial randomized 572 patients with chemotherapy-naïve stage IV nonsquamous or squamous NSCLC with PD-L1 expression ≥1% to receive either 1200 mg of atezolizumab every 3 weeks (arm A), or 4 or 6 cycles of platinum-based chemotherapy (arm B). Interim survival results showed that the single agent improved OS in newly diagnosed patients with wild-type NSCLC who had ≥50% expression of PD-L1 on tumor cells or ≥10% expression on tumor-infiltrating immune cells.

The median OS was 20.2 months versus 13.1 months with atezolizumab and chemotherapy, respectively, at a median follow-up of 15.7 months (HR, 0.59; 95% CI, 0.40-0.89). Median PFS was 8.1 months in the atezolizumab arm versus 5.0 months in the chemotherapy arm, while the confirmed objective response rate (ORR) was 38.3% versus 28.6%, respectively.

Breast Cancer:

Erika Hamilton, MD

Erika Hamilton, MD

There were no new safety signals in arm A; 60.5% of patients in arm A and 85.2% in arm B experienced treatment-related AEs, while grade 3/4 treatment-related AEs occurred in 12.9% and 44.1% of patients, respectively.Prolonged pCR Rates Seen in TNBC With Neoadjuvant Pembrolizumab and Chemotherapy

The phase III KEYNOTE-522 randomized patients with early TNBC 2:1 to receive either pembrolizumab (Keytruda) plus chemotherapy or chemotherapy alone. In the combination arm, treatment resulted in an extension of the pathological complete response (pCR) by 13.6 percentage points compared with the chemotherapy-alone arm.

“This study showed a 13% improvement in pCR rates for women who received neoadjuvant chemotherapy in combination with pembrolizumab compared with those who received chemotherapy alone,” said Erika Hamilton, MD. “The benefit with pembrolizumab was seen irrespective of PD-L1 status. We care about increased pCR essentially because we hope this translates to improved cure rates for women.”

“The trial did report an early look at recurrence-free survival with an 18-month cutoff, and this was improved from 11.8% down to 7.4%,” Hamilton noted. “Seeing the improved pCR rate translate to improved disease-free survival is exactly what we want to see to think about offering our patients with higher-risk TNBC pembrolizumab in combination with chemotherapy.”

OS Improved in Advanced HR+/HER2- Breast Cancer With Ribociclib/Fulvestrant

In the phase III MONALEESA-2 trial, postmenopausal patients with hormone receptor (HR)—positive, HER2-negative advanced breast cancer were randomized 2:1 to ribociclib (Kisqali) at 600 mg daily in a 3-weeks-on/1-week-off schedule plus fulvestrant (Faslodex) at 500 mg daily or placebo.

“This was a trial that explored the benefit of adding ribociclib to fulvestrant for first- and second-line patients with ER-positive breast cancer,” Hamilton said. “The OS was 40 months with fulvestrant alone and was not reached with the addition of ribociclib (HR, 0.724; P= .00455).”

Overall, the data demonstrated a clinically significant OS benefit with the combination of ribociclib plus fulvestrant.

“At 3.5 years of follow-up, women had a 45.9% chance of being alive if they received fulvestrant alone and a 57.8% chance with both fulvestrant and ribociclib (an 11.9% improvement in survival). It also showed that the addition of ribociclib delayed time to first chemotherapy for patients, which can be a significant quality-of-life concern.”

Abemaciclib/Fulvestrant Demonstrates Overall Survival Benefit in HR+ Advanced Breast Cancer

The phase III MONARCH-2 trial enrolled patients with HR-positive, HER2-negative advanced breast cancer who progressed on prior endocrine therapy and randomized them to endocrine therapy in a 2:1 ratio to receive abemaciclib (Verzenio) plus fulvestrant or placebo/fulvestrant, where abemaciclib was administered at 150 mg twice daily on a continuous schedule and fulvestrant was given at 500 mg twice daily continuously.

“This trial examined fulvestrant with and without the addition of abemaciclib in an endocrine resistant setting (relapse within 1 year of adjuvant endocrine therapy or progressed on first-line therapy for metastatic disease),” said Hamilton. “The addition of abemaciclib showed an improvement of 9.4 months in survival.”

At a median follow-up of 47.7 months, the median OS with the combination was 46.7 months versus 37.3 months for placebo plus fulvestrant (HR, 0.757; 95% CI, 0.606-0.945;P= .0137) in patients with HR-positive, HER2-negative advanced breast cancer who previously progressed on endocrine therapy, according to the data from the randomized phase III MONARCH-2 trial.

The safety and tolerability of abemaciclib was consistent with what’s been previously reported in clinical trials, with the most common hematologic grade 3 or greater AEs being neutropenia, anemia, and leukopenia, and the most common nonhematologic AE being diarrhea.

“Abemaciclib also demonstrated delayed time to chemotherapy,” Hamilton noted. This agent has already been approved by the FDA in combination with fulvestrant in this patient population based on the PFS data from MONARCH-2.

GI Cancers:

Ghassan K. Abou-Alfa, MD

Ghassan K. Abou-Alfa, MD

George Sledge, Jr., MD, professor of medicine (oncology) at Stanford University Medical Center, alsospoke to the OS data from the MONARCH-2 trial in this video interviewwith Targeted Oncology.Risk of Progression or Death Reduced With Ivosidenib in Advanced Cholangiocarcinoma

In the phase III ClarIDHy trial, 185 patients withIDH1-mutant cholangiocarcinoma were randomized to receive either ivosidenib (Tibsovo) at 500 mg daily or matched placebo. The risk of progression or death was reduced by 63% with ivosidenib compared with placebo in patients withIDH1-mutant advanced cholangiocarcinoma. Median PFS was 2.7 months with this agent versus 1.4 months with placebo.

“ClarIDHy shows the clinical relevance and benefit of ivosidenib in mutatedIDH1cholangiocarcinoma,” Ghassan K. Abou-Alfa, MD, from the Memorial Sloan Kettering Cancer Center, told Targeted Oncologyfollowing the meeting. “It helped establish the role for genomic testing in cholangiocarcinoma and introduced the new paradigm of delineating different biliary tumors based on genetic alterations rather than the standard anatomical one.”

Additionally, this trial showed a non-statistically significant improvement in OS, and despite more than 50% of patients crossing over, there was a trend toward reduction in the risk of death with ivosidenib.

Grade 3 or greater treatment-emergent AEs were experienced in 46.2% of patients in the ivosidenib arm, while the most common included ascites, bilirubin increase, anemia, and AST increase.

Pemigatinib Induces Responses in Second-LineFGFR+Cholangiocarcinoma

In the open-label, single-arm phase II FIGHT-202 clinical trial, 147 patients with previously treated, locally advanced, or metastatic cholangiocarcinoma were enrolled, where 107 patients hadFGFR2fusions or rearrangements (cohort A), 20 patients had FGF/FGFRgenetic alterations (cohort B), and 18 patients had no FGF/FGFRalterations. Treatment with pemigatinib (INCB54828) induced an ORR of 35.5% in cohort A.

“An ORR of 35.5% [is] durable and with a median PFS of 6.9 months demonstrates the therapeutic benefit of pemigatinib for patients with cholangiocarcinoma andFGFR2fusions or rearrangements,” said Abou-Alfa. “FIGHT-202 also supports the use of fusion partner—agnostic testing.”

The higher ORR also translated into a prolonged median PFS in cohort A, where the median PFS was 6.9 months versus 2.1 months in cohort B and 1.7 months in cohort C. The AEs were manageable, while the most common AE was hyperphosphatemia, which occurred in 60% of patients with no cases of grade 3 or greater events.

For patients with cholangiocarcinoma harboringFGFR2fusions/rearrangements, a phase III trial is currently ongoing, comparing frontline pemigatinib with gemcitabine plus cisplatin, based on data from the FIGHT-202 trial.

Combination of Atezolizumab and Bevacizumab Shows Early Efficacy in Unresectable HCC

According to results from 2 small clinical trials, atezolizumab in combination with bevacizumab induced objective responses in patients with unresectable hepatocellular carcinoma (HCC). More than one-third of patients had clinically meaningful responses in an uncontrolled evaluation of the combination, whereas three-fourths were ongoing with a median follow-up of over 1 year.

“The 2 presented studies suggest VEGF inhibition to reverse VEGF-mediated immunosuppression along with anti—PD-L1 atezolizumab,” Abou-Alfa said. “We are all awaiting the outcome of the IMbrave150 phase III study.”

VEGF receptor tyrosine kinase inhibitors are the global standard of care for first-line treatment of patients with unresectable or metastatic HCC, offering a modest survival benefit with a cost of considerable toxicity. PD-1/PD-L1 immune checkpoint inhibitors have also demonstrated activity but have yet to show superiority in a randomized trial in advanced HCC. Evidence that many HCC tumors exhibit hypervascularity and over expression of VEGF and PD-L1 provided rationale for combining these 2 agents, according to presenter Michael Lee, MD.

GU Cancers:

This combination is being evaluated further in the phase III IMbrave150 study (NCT03434379).First-Line Atezolizumab/Chemotherapy Improves Outcomes in Metastatic Urothelial Cancer

Patients with locally advanced or metastatic urothelial carcinoma were randomized to receive either atezolizumab plus platinum-based therapy and gemcitabine, atezolizumab monotherapy, or placebo plus platinum-based therapy and gemcitabine in the international phase III IMvigor130 trial. This was the first trial to evaluate the combination of immunotherapy and chemotherapy in these patients.

Atezolizumab in combination with chemotherapy improved the median PFS by 1.9 months compared with placebo, but no OS benefit was found. After a median follow-up of 11.8 months, the final median PFS was 8.2 months in the atezolizumab combination arm versus 6.3 months with chemotherapy. This led to an 18% reduction in the risk of disease progression or death.

“I think the combination of atezolizumab plus chemotherapy will be added as a new treatment option for our patients with untreated metastatic urothelial carcinoma,” said lead study author Enrique Grande, MD, head of the Medical Oncology Service, head of Clinical Research of the MD Anderson Foundation Spain, MD Anderson Cancer Centre Madrid, Spain. “We have an exciting debate now to try to select which are the best patients to receive this combination.”

This combination was well tolerated, and the toxicity profile remained consistent with what’s been observed previously. “When we added atezolizumab to the chemotherapy arm, we did not see more toxicities than in the chemotherapy arm,” Grande concluded.

Olaparib Improves rPFS in Heavily Pretreated HRR+ mCRPC

The phase III PROfound trial enrolled 2 cohorts of patients with heavily pretreated metastatic castration-resistant prostate cancer (CRPC) who had homologous recombination repair (HRR) alterations. Cohort A included patients withBRCA1/2or ATMalterations, while cohort B consisted of those with alterations in BARD1,BRIP1,CDK12, CHEK1/2, FANCL, PALB2, PPP2R2A, RAD51B/C/D, orRAD54L. Patients in cohort A received either olaparib or abiraterone acetate (Zytida) plus prednisone or enzalutamide (Xtandi). Cohort B received either olaparib or physician’s choice of abiraterone acetate plus prednisone or enzalutamide.

“The benefit was actually pretty remarkable, in that radiographic PFS (rPFS) was significantly delayed in the primary cohort, cohort A,” said lead investigator Maha Hussain, MBChB, from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “It’s almost double [in the olaparib arm] of the control.”

The median rPFS was improved, according to blinded independent review. For cohort A, the rPFS was 7.39 months with olaparib versus 3.55 months with abiraterone or enzalutamide (HR, 0.34; 95% CI, 0.25-0.47;P<.0001). The 12-month rPFS rate was 40% with olaparib and 11% for physician&rsquo;s choice, while the ORR in this cohort was 33.3% versus 2.3%, respectively.

&ldquo;Overall, early trends on OS are very encouraging,&rdquo; said Hussain. &ldquo;We have not had adequate numbers yet in terms of deaths to declare it a final result, but the curves started separating very early in the process for the overall population, so it looks very promising.&rdquo;

FDA Grants Breakthrough Designation to Niraparib for Metastatic CRPC

Following the data from the ongoing multicenter, open-label phase II GALAHAD trial presented at the 2019 ESMO Congress, the FDA granted a breakthrough therapy designation to niraparib (Zejula) for the treatment of patients withBRCA1/2-mutant metastatic CRPC who have received prior taxane chemotherapy and androgen receptor targeted therapy.

According to the prespecified interim analysis, the ORR was 41%, including 1 complete response and 11 partial responses in patients withBRCAbiallelic DNA repair gene defects (DRD). Median rPFS was 8.2 months, while the median OS was 12.6 months in these patients. For those with non-BRCAbiallelic DRD, the ORR was 9% with 2 partial responses, the median rPFS was 5.3 months, and the median OS was 14.0 months.

See more fromthe 2019 ESMO Congress.

At least 1 AE was observed in 98% of all patients, while grade 3/4 AEs were experienced by 70% of the patients. The most common grade 3/4 AEs included anemia and thrombocytopenia.