Allison Schepers, PharmD BCOP
Clinical Pharmacist Specialist, Medical Oncology
University of Michigan Medicine
Ann Arbor, MI

More than 42,000 healthcare providers, researchers, industry professionals, patient advocates, and other stakeholders gathered in Chicago May 31–June 4, 2019, for the American Society of Clinical Oncology (ASCO) Annual Meeting.

This diverse group was united by the theme “Caring for Every Patient, Learning from Every Patient.” In the presidential address, outgoing ASCO president Monica Bertagnolli, MD FASCO, highlighted efforts by ASCO members to provide high-quality care and access to clinical trials in underserved areas. She also introduced CancerLinQ, an ASCO data-sharing initiative that allows clinicians to access real-world data from thousands of deidentified patients with the goal of providing evidence-based recommendations for all patients, including those who are not typically represented in clinical trials.

Atul Gawande, MD MPH, author of The Checklist Manifesto and Being Mortal, delivered the keynote address. He encouraged the audience to consider what “a life worth living” means to individual patients and to discuss this concept with patients and caregivers early in the treatment course.

The plenary session summarized four potentially practice-changing studies, ranging from a population-based study on racial disparity in oncology to a negative phase 3 trial in soft tissue sarcoma. To start the plenary session, Amy Davidoff, PhD MPH, presented data that examined racial disparities in time to treatment of advanced cancer in 41 states.¹ Davidoff and colleagues compared states that expanded Medicaid through the Affordable Care Act to states that declined Medicaid expansion. Timely treatment initiation was defined as first-line treatment within 30 days of cancer diagnosis. In states that did not expand Medicaid eligibility, the difference in rates of timely treatment initiation between White and Black cancer patients was 4.8%. In states that expanded Medicaid, that racial disparity decreased to 0.8%—a statistically significant difference. This study showcased the effects that national healthcare policy can have on cancer outcomes and leveraged a large data set to quantify the national impact of a policy change.

Another notable study in the population health track was presented by R. Donald Harvey, PharmD BCOP FCCP FHOPA. Harvey and colleagues used the CancerLinQ database to examine the effects of expanding clinical trial eligibility for non-small-cell lung cancer (NSCLC) patients.² The investigators found that traditional clinical trial criteria excluded 48% of patients. The expanded criteria allowed patients with creatinine clearance 30–60 ml/min, brain metastases, and concomitant malignancies—thus excluding only 1.5% of patients. Using expanded inclusion criteria would nearly double the number of patients eligible to participate in oncology clinical trials and increase the external validity of these trials.

Christopher Sweeney, MBBS, presented the results of the ENZAMET trial, which compared frontline enzalutamide (with or without docetaxel) to nonsteroidal antiandrogen therapy in 1,125 patients with metastatic hormone-sensitive prostate cancer.³ All patients received standard androgen-deprivation therapy. Notably, 61% of patients with high-volume disease in this trial received concomitant docetaxel. Overall survival (OS) and progression-free survival (PFS) were improved in the enzalutamide arm compared to the standard-of-care arm. The hazard ratio (HR) for OS, the study’s primary outcome, was 0.67 (95% confidence interval [CI] 0.52–0.86, p = .002). The magnitude of OS benefit was decreased in patients who received early treatment with docetaxel and those with high-volume disease, though the study was not powered to detect differences in these subgroups. Other updates in prostate cancer included results of the TITAN trial, which showed a statistically significant OS advantage at 2 years (p = .005, number needed to treat = 12) with apalutamide versus placebo in metastatic hormone-sensitive prostate cancer.⁴ In contrast to ENZAMET, only 11% of the patients in the apalutamide arm received prior docetaxel, despite this group having high-performance status and 62% high-volume disease. The phase 3 Alliance A031201 trial showed no OS benefit with the addition of abiraterone and prednisone to enzalutamide in the metastatic castration-resistant setting.⁵ Finally, the phase 2 TOPARP-B trial examined response to olaparib in castration-resistant patients with DNA-damage repair mutations whose disease had progressed on taxane chemotherapy.⁶ Doses of both 300 mg twice daily and 400 mg twice daily of olaparib tablets were studied. Composite response rates were 39% in the 300-mg cohort and 54% in the 400-mg cohort, though 37% in the 400-mg cohort required dose reductions. Trials studying olaparib in combination or as maintenance therapy for metastatic prostate cancer are currently recruiting.

William Tap, MD, presented the phase 3 results of the ANNOUNCE trial, which examined olaratumab in combination with doxorubicin as frontline treatment of locally advanced or metastatic soft-tissue sarcoma.⁷ Olaratumab is a monoclonal antibody against platelet-derived growth factor receptor (PDGFR) that has been widely integrated into frontline treatment of sarcoma on the basis of the 11.8 month improvement in OS seen in the phase 2 clinical trial.⁸ However, in the international double-blind placebo-controlled phase 3 trial of 509 patients, OS did not differ between the olaratumab and placebo arms (OS 20.4 months vs. 19.7 months, HR 1.05, 95% CI 0.84–1.3, p = .69), despite a higher dose of olaratumab in the phase 3 trial. The phase 3 trial also used eight cycles of doxorubicin, mandatory dexrazoxane, and a placebo control on days 1 and 8, which may have contributed to longer-than-expected survival in the doxorubicin and placebo group. Interestingly, the PDGFR-positive subgroup performed worse than the PDGFR-negative subgroup in both trials. Eli Lilly and Company is in the process of withdrawing olaratumab from the market on the basis of the phase 3 results. The approval and subsequent withdrawal of olaratumab will certainly fuel debate regarding the appropriateness of the accelerated-approval pathway for expensive but potentially life-prolonging oncology drugs.

The final trial presented during the plenary session was the phase 3 POLO trial of olaparib for maintenance therapy in metastatic pancreatic cancer.⁹ Approximately 5% of pancreatic cancer patients have a germline BRCA mutation (gBRCAm). The POLO trial randomized 154 gBRCAm patients to maintenance therapy with either olaparib 300 mg twice daily or placebo following at least 4 months of frontline platinum-based therapy. Median PFS was 7.4 months in the olaparib group compared to 3.8 months with placebo (HR 0.53, p = .004). At 49% data maturity, median OS was not significantly different between the groups (18.9 months vs. 18.1 months, p = .68). Mature data showing an OS benefit are necessary before maintenance olaparib becomes the standard of care for this patient population. Additionally, questions remain regarding the appropriateness of a placebo control in patients who have not had disease progression on platinum-based chemotherapy.

A common thread throughout the meeting was the movement of immunotherapy to the frontline setting. In advanced or metastatic head and neck squamous cell carcinoma, KEYNOTE-048 examined three potential frontline treatment regimens: (1) pembrolizumab monotherapy, (2) the EXTREME regimen (cetuximab + platinum + 5-fluorouracil), and (3) pembrolizumab + platinum + 5-fluorouracil.¹⁰ Pembrolizumab monotherapy showed no OS advantage in the total patient population versus EXTREME, but patients with programmed death ligand-1 (PD-L1) combined positive scores (CPS) ≥1 and ≥20 showed a significant OS benefit compared to EXTREME. The pembrolizumab + chemotherapy arm showed a significant OS benefit in the total population and both CPS subgroups compared to EXTREME. Hazard ratios and median OS were numerically improved in the CPS-positive subgroups for both comparisons, but it is unclear how much of the benefit is being driven by the CPS ≥20 subgroup. Pembrolizumab monotherapy was not compared to pembrolizumab + chemotherapy in this analysis. Nevertheless, KEYNOTE-048 is a practice-changing trial for advanced or metastatic head and neck cancers.

Late-breaking abstract KEYNOTE-062 studied pembrolizumab monotherapy, platinum doublet chemotherapy, and pembrolizumab + platinum doublet in frontline metastatic gastric and gastroesophageal junction (GEJ) cancers with CPS ≥1 and negative for HER2.¹¹ Pembrolizumab has previously failed in the second-line setting for gastric cancer.¹² Pembrolizumab monotherapy showed noninferiority to chemotherapy for OS with the upper bound of the CI at 1.18, just below the 20% noninferiority margin. Pembrolizumab + chemotherapy did not show a significant benefit in OS compared to chemotherapy alone. Though pembrolizumab monotherapy met its primary noninferiority endpoint, the 20% noninferiority margin drew criticism, as well as the practicality of using pembrolizumab monotherapy in a highly symptomatic patient population. Updated OS results in the frontline metastatic setting from the KEYNOTE-001 trial in NSCLC and ImPASSION-130 in triple negative breast cancer were also presented.^13,14

In the targeted-therapy arena, investigators reported results from the phase 2 trial of enfortumab vedotin (EV) in patients with 3+ lines of treatment for advanced urothelial carcinoma.¹⁵ EV is a monoclonal antibody against Nectin-4 conjugated with monomethyl auristatin E. At the time of data analysis for the ASCO meeting, the overall response rate (ORR) was 44% in this heavily pretreated population, with 12% of patients achieving complete response (CR). Notable grade 3-4 side effects were neuropathy, neutropenia, rash, and hyperglycemia. A phase 3 trial of EV versus physician’s choice of chemotherapy (paclitaxel, docetaxol, or vinflunine) is currently recruiting.

In metastatic breast cancer, the MONALEESA-7 trial reported the first OS benefit for cyclin-dependent kinase 4/6 (CDK4/6) inhibitors over endocrine therapy alone in breast cancer.¹⁶ The MONALEESA-7 trial compared ribociclib + endocrine therapy to endocrine therapy alone in peri- or premenopausal patients with hormone receptor positive HER2-negative advanced breast cancer. Fourteen percent of patients had received one prior line of chemotherapy in the metastatic setting, and 40% had received prior endocrine therapy. Median OS in the ribociclib arm was not reached, compared to 40.9 months in the endocrine therapy arm (HR 0.712, 95% CI 0.54–0.95, p = .00973). Grade 3-4 neutropenia occurred in 68% of patients on ribociclib.

Abstracts from the 2019 meeting can be accessed at https://abstracts.asco.org/239/CatView_239_B.html.

The 2020 ASCO Annual Meeting will be held May 29–June 2, 2020, in Chicago, IL.

References

1. Adamson BJS, Cohen AB, Estavez M, et al. Affordable Care Act (ACA) Medicaid expansion impact on racial disparities in time to cancer treatment. J Clin Oncol 2019, 37 (suppl; abstr LBA1).
2. Harvey RD, Rubinstein WS, Ison G, et al. Impact of broadening clinical trial eligibility criteria for advanced non-small cell lung cancer patients: real-world analysis. J Clin Oncol 2019, 37 (suppl; abstr LBA108).
3. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. New Engl J Med 2019 (epub ahead of print).
4. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. New Engl J Med 2019 (epub ahead of print).
5. Morris MJ, Heller G, Bryce AH, et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol 2019, 37 (suppl; abstr 5008).
6. Mateo J, Porta N, McGovern UB, et al. TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations. J Clin Oncol 2019, 37 (suppl; abstr 5005).
7. Tap WD, Wagner AJ, Papai Z, et al. ANNOUNCE: a randomized, placebo (PBO)-controlled, double-blind, phase (Ph) III trial of doxorubicin (dox) + olaratumab versus dox + PBO in patients (pts) with advanced soft tissue sarcomas (STS). J Clin Oncol 2019, 37 (suppl; abstr LBA3).
8. Tap WD, Jones RL, VanTine BA, et al. Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 2016; 388:488-497.
9. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. New Engl J Med 2019 (epub ahead of print).
10. Rischin D, Harrington KJ, Greil R, et al. Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). J Clin Oncol 2019, 37 (suppl; abstr 5000).
11. Tabernero J, Van Cutsem E, Bang YJ, et al. Pembrolizumab with or without chemotherapy versus chemotherapy for advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: the phase III KEYNOTE-062 study. J Clin Oncol 2019, 37 (suppl; abstr LBA4007).
12. Shitara K, Özgüroğlu M, Bang YJ, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018; 392(10142):123-133.
13. Garon EB, Hellmann MD, Costa EC, et al. Five-year long-term overall survival for patients with advanced NSCLC treated with pembrolizumab: results from KEYNOTE-001. J Clin Oncol 2019, 37 (suppl; abstr LBA9015).
14. Schmid P, Adams S, Rugo HS. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2019, 37 (suppl; abstr 1003).
15. Petrylak DP, Balar AV, O’Donnell PH. EV-201: results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors. J Clin Oncol 2019, 37 (suppl; abstr LBA4505).
16. Hurvitz SA, Im SA, Lu YS, et al. Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ± ribociclib: overall survival (OS) results. J Clin Oncol 2019, 37 (suppl; abstr LBA1008).