ASCO 2020: Clinical Updates

July 20, 2020

Featuring findings from the KEYNOTE-177, ARAURA, ASPEN, and CITYSCAPE trials, and new results from MURANO.

Pembrolizumab as First-Line Treatment Doubles PFS in Certain Patients With Colorectal Cancer

Using Biomarkers to connect the right patients with the right treatment at the right time is the mantra for deciding when to use immunotherapy in cancer care. Results presented virtually at the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting proved that point for certain patients with metastatic colorectal cancer (mCRC).

The interim analysis of the phase 3 KEYNOTE-177 trial, presented during ASCO’s plenary session on May 31, showed that using pembrolizumab as a first-line therapy in mCRC patients with specific genetic mutations—microsatellite instability high/mismatch repair defi cient (MSI-H/dMMR) tumors—doubled progression-free survival (PFS) compared with chemotherapy (16.5 vs 8.2 months).1

FDA approval for pembrolizumab in this setting came less than a month later, on June 29, 2020, as Evidence-Based Oncology™ went to press.2

Lead study author Thierry André, MD, professor of medical oncology, the Sorbonne Université and Hôpital Saint Antoine in Paris, said during the plenary session that the results would change clinical practice. “No medical treatment has shown such an improvement,” he noted.

“Pembrolizumab works in nonrandomized studies in this group of patients with advanced disease,” André said. “This randomized study demonstrates a huge benefi t in fi rst-line [treatment] with pembrolizumab and should be the new standard of care.”

Michael Overman, MD, of the University of Texas MD Anderson Cancer Center, a discussant for KEYNOTE-177, agreed. “These results should change clinical practice,” he said, noting that the type of tumors being treated in the study are particularly good candidates for immunotherapy. Going forward, Overman said, “It is critical that we test all colorectal cancer patients for mismatch repair or microsatellite status.”

The only caveat, Overman explained, might involve patients for whom near-term survival is the highest priority, because results show that the benefit of immunotherapy over chemotherapy does not start to appear until about the 6-month mark. About 5% of mCRC patients’ tumors are MSI-H/dMMR, and these patients do not fare as well with conventional chemotherapy.

Pembrolizumab’s effectiveness when this mutation is present is well recognized, and it led to FDA’s first tissue-agnostic approval in 2017.3 “These data represent another step forward for biomarker-driven studies,” André said.

The data cutoff for the interim analysis was February 19,¨2020; at that time, the study included 307 mCRC patients with MSI-H/dMMR. Patients were randomized to receive first-line pembrolizumab for up to 2 years, or the investigator’s choice of 6¨diff erent standard chemotherapy regimens. Primary end points were PFS and overall survival (OS), while secondary end points included objective response rate (ORR) and safety.

An independent data monitoring committee had¨previously found statistically signifi cant and clinically meaningful improvement, and it called for the trial to continue without changes to the second co-primary end point of OS.4

Patients in the chemotherapy group who progressed were allowed to cross over into the pembrolizumab group.

Results

At 12 months, PFS was 55.3% with pembrolizumab vs 37.3% with chemotherapy; at 24 months, PFS was 48.3% with pembrolizumab vs 18.6% with chemotherapy.

The ORR, a measure of how much patients’ tumors shrank, was also better for the patients treated with pembrolizumab: 43.8% compared with 33.1% for chemotherapy. The data also show:

• 11% of the pembrolizumab patients had a complete response, meaning no detectable cancer, compared with 3.9% treated with chemotherapy

• 32.7% of the pembrolizumab patients had a partial response, compared with 29.2% in the chemotherapy group

• 30.9% taking pembrolizumab had stable disease, compared with 42.2% in the chemotherapy group.

• 83% in the pembrolizumab group had responses lasting longer than 2 years, compared with 35% in the chemotherapy group.

Adverse Events

Severe events, grade 3 or above, were less common among patients in the pembrolizumab group: 22%, compared with 66% in the chemotherapy group. The most common toxicities in the immunotherapy group were colitis and hepatitis, while the most frequent chemotherapy-related toxicities were diarrhea, neutropenia, fatigue, nausea, stomatitis, alopecia, and neurotoxicity. Merck funded the study.

References

1. André T, Shiu K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3, KEYNOTE-177 study. J Clin Oncol. 2020;38(18 suppl; abstr LBA4). doi:10.1200/JCO.2020.38.18_suppl.LBA4

2. Caffrey M. Pembrolizumab approved for first-line treatment of patients with colorectal cance and key mutations. The American Journal of Managed Care® website. www.ajmc.com/newsroom/pembrolizumab-approved-for-firstline-treatment-of-patients-with-colorectal-cancer-and-key-mutations. Published and accessed June 29, 2020.

3. FDA grants accelerated approval to pembrolizumab for first tissue/site agnostic indication. FDA. May 23, 2017. Updated May 30, 2017. Accessed June 6, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pembrolizumab-first-tissuesite-agnostic-indication

4. Merck announces KEYTRUDA (pembrolizumab) significantly improved progression-free survival as first-line treatment for advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. News release. Merck; April 2, 2020. Accessed June 6, 2020. https://investors.merck.com/news/press-release-details/2020/Merck-Announces-KEYTRUDA-pembrolizumab-Significantly-Improved-Progression-Free-Survival-as-First-Line-Treatment-for-Advanced-Microsatellite-Instability-High-MSI-H-or-Mismatch-Repair-Deficient-dMMR-Colorectal-Cancer/default.aspx

Osimertinib After NSCLC Surgery Keeps Cancer at Bay for Patients With Key Mutation

Osimertinib, already the first choice to treat patients with advanced EGFR-mutated non—small cell lung cancer (NSCLC), should become the treatment of choice for patients with this mutation who are treated after surgery for early-stage, localized disease, according to the lead investigator who outlined results virtually at the American Society of Clinical Oncology Annual Meeting.1

A remarkable 90% of the patients with stage II or stage IIIA NSCLC who received the targeted therapy osimertinib after surgery were alive after 2 years without cancer recurring, compared with 44% of those patients who received placebo, according to fi ndings presented during the May 31, 2020, plenary session. In patients at these stages, the risk of death or recurrence was reduced by 83%. Median disease-free survival (DFS) for osimertinib was not reached (NR) while for placebo, it was

20.4 months (HR, 0.17; 95% CI, 0.12-0.23; P˜<˜.0001).

The full study, called ADAURA, was unblinded in April after the overwhelming effi cacy became evident.2 AstraZeneca, maker of osimertinib (Tagrisso), a third-generation EGFR tyrosine kinase inhibitor, sponsored the study.

Roy S. Herbst, MD, PhD, the lead study author and chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital, called the trial a “home run” and said the results clearly pointed to giving osimertinib to patients earlier in course of treatment.

”Collectively, these data support the use of osimertinib as an appropriate treatment in the long-term adjuvant setting,” Herbst said, with safety and tolerability being important considerations. “Looking ahead, future considerations for ADAURA include investigation of local versus distant recurrence; sites of disease recurrence, including incidence of [central nervous system] metastases; subsequent therapy; and quality of life.”

with disease ranging from stage IB to IIIA, treatment with osimertinib reduced the risk of death or recurrence by 79% compared with placebo. Overall, DFS at the 2-year mark was 89% with osimertinib vs 53% for placebo.

Of note, Herbst pointed to data showing that patients who had adjuvant chemotherapy alongside osimertinib fared about the same as those who did not. Among patients who received chemotherapy, the median DFS for osimertinib was NR, compared with 22.1 months for those on placebo (HR, 0.18; 95% CI, 0.11-0.29).

Among those without chemotherapy, median DFS for osimertinib was NR, compared with 33.1 months for placebo (HR, 0.23; 95% CI, 0.13-0.38).

Data for overall survival are not yet mature, and both Herbstand a discussant, David Spigel, MD, chief scientific officer of the Sarah Cannon Research Institute, acknowledged that this might be challenging to evaluate going forward, now that the trial has been unblinded.

Other questions remain, including what happens after 3 years, when patients would be scheduled to stop taking the daily 80-mg tablets. Still, Spigel said if asked the question he hears in the clinic—which treatment would he give a family member?—he would choose osimertinib.

The results have important implications for managed care. Currently, patients with stage IB to stage III NSCLC who have surgery to remove the tumor typically have chemotherapy, but Herbst said rates of recurrence are high: Cancer returns in about half of patients with stage IB disease, and rates are higher at later stages.

In addition, the ability to more eff ectively treat patients with early-stage EGFR-mutated NSCLC tumors raises new questions about the need to screen more patients for lung cancer—and catch more cancers at earlier stages. Spigel said it is unclear at this point whether osimertinib is eliminating disease or “simply controlling and deferring disease that cannot be eradicated.” But the safety and tolerability of the targeted therapy are important, given a planned 3-year treatment course. And, he said, the results were consistent across subgroups.

Paradigm Shift?

Adrian Kilcoyne, MD, MBA, MPH, AstraZeneca’s vice president for US Medical Affairs and Health Economics Outcomes Research in Oncology, said the results should be paradigm shifting. “What we’ve been able to demonstrate is compelling,” Kilcoyne said. Any time a study is stopped early the results are important, but ADAURA “is important in a number of ways.”

“One, it’s telling us that if you hit [the disease] early, you can have very compelling results in lung cancer,” Kilcoyne said. “Second, in some of these patients, while they all had surgery, not all of them had adjuvant chemotherapy—half didn’t—and regardless of that, you’re seeing a signifi cant benefit. “It may drive people to want to identify disease earlier, which is&bsp;really important, too.”

When asked if the results might reopen discussion about current US Preventive Services Task Force guidelines on who should be screened or lung cancer,3 Kilcoyne said, “You’ve asked the million dollar question.”

Current guidelines are based on a mix of factors that include a person’s age, smoking history, and how long ago they quit smoking. Some study results suggest that the guidelines do not cast a wide enough net, but a CDC study found earlier this year that even under the current standards, very few people eligible for screening are tested.

”We’re at a point where we just can’t just focus on smoking,” Kilcoyne expressed. “ I think we should look at screening in a far more broad way. It’s not just screening patients who would have been smoking, how many pack years, age, etc.…How we screen is going to be incredibly important. We need to embrace newer

technology” that takes a personalized medicine approach.4

References

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(18 suppl; abstr LBA5). doi:10.1200/JCO.2020.38.18_suppl.LBA5

2. Tagrisso phase III ADAURA trial will be unblinded early after overwhelming efficacy in the adjuvant treatment of patients with EGFR-mutated lung cancer. News release. AstraZeneca; April 10, 2020. Accessed June 6, 2020. https://www.astrazeneca.com/media-centre/press-releases/

2020/tagrisso-phase-iii-adaura-trial-will-be-unblinded-early-after-overwhelmingefficacy-in-the-adjuvant-treatment-of-patients-with-egfr-mutated-lung-cancer.html

3. Richards TB, Soman A, Thomas CC, et al. Screening for lung cancer—10 states, 2017. MMWR Morb Mortal Wkly Rep. 2020;69(8):201-206. doi:10.15585/mmwr.mm6908a1

4. Francis Crick Institute. New lung cancer trial will use personalized monitoring to help predict relapse. Technology Networks. May 26, 2020. Accessed June 6, 2020. https://www.technologynetworks.com/tn/news/new-lung-cancer-trial-will-use-personalizedmonitoring-to-help-predict-relapse-335275

Zanubrutinib Pulls Away From Ibrutinib in Update, Shows Durable Responses in WM Patients Lacking Key Mutation

Zanubrutinib, the Bruton tyrosine kinase (BTK) inhibitor approved by the FDA to treat mantle cell lymphoma, showed a clear advantage over its competitor in new data presented virtually on May 29, 2020, during the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting.

The BTK inhibitor also produced meaningful and durable responses in certain patients with Waldenström macroglobulinemia (WM), even though they lacked a key mutation that has signaled successful treatment, according to updated results of the ASPEN trial.1

MYD88 mutations are present in 95% of patients with WM, a rare form of lymphoma,‘and BTK inhibitors have been effective in treating WM patients who have them. Prior research showed poorer response rates and shorter progression-free survival (PFS) among those who lack the mutations. Complicating matters is the fact that diagnosing mutations in WM can be tricky.

Results from ASPEN released in December 2019, and updated at ASCO,2 compared zanubrutinib with ibrutinib in WM patients with the MYD88 mutation. Early reactions were mixed. Some analysts noted that the ASPEN trial missed the goal of doubling ibrutinib’s rate of complete or very good partial responses, but

others pointed to the fact that data showed zanubrutinib numerically outperformed ibrutinib, with 28.9% of relapsed or refractory patients achieving this mark, compared with 19.8% for ibrutinib. Results for all patients, including those starting treatment, were comparable—28.4% vs 19.2%.

In an interview, lead investigator Constantine Tam, MBBS, MD, a clinical hematologist and professor at the Peter MacCallum Cancer Centre in Victoria, Australia, noted there were “some imbalances” in the randomization; more patients in the zanubrutinib arm were older than 75 years and more were anemic.

Updated Data at ASCO

ASPEN did more follow-up in January, accruing another 5 months of data. “This is important,” Tam said during the interview. “The longer you take the drug, the better your responses become.” So, while the study technically did not meet its end point, Tam said the lines separating zanubrutinib and ibrutinib have diverged since the first results were announced.‘Data presented online May 29, 2020, showed the following3:

• Complete response plus very good partial response as assessed by investigators for zanubrutinib was 30.4% compared with 18.2% for ibrutinib (exploratory analysis;

2-sided descriptive P = .0302).

• Adverse events (AEs): Compared with ibrutinib, zanubrutinib had less atrial fibrillation/flutter of any grade (3.0% vs 18.4%), bleeding of any grade (50.5% vs 60.2%), major hemorrhage (5.9% vs 10.2%), diarrhea (21.8% vs 32.7%), and hypertension (12.9% vs 20.4%). Patients taking zanubrutinib did have more neutropenia (31.7% vs 15.3%).

• Rates of grade ≥3 neutropenia were higher in the zanubrutinib arm (22.8% vs 8.2% for ibrutinib); however, rates of infection were comparable among patients in both arms (any grade: 69.3% vs 71.4%; grade ≥3: 18.8% vs 23.5%).

• No additional patients stopped treatment due to AEs in the zanubrutinib arm, compared with 5 patients in the ibrutinib arm (4.0% vs 14.3%). Neither arm had additional patients with an AE leading to death‘(1.0% vs 4.1%).

Data From Patients Without Key Mutation

The data presented in December did not include patients without MYD88 mutations. At enrollment in ASPEN, patients were assigned to cohorts based on mutation status. Data presented at ASCO covered 28 patients, including 26 who were WM with MYD88 wild type, enrolled in the cohort for patients lacking the mutation. Their median age was 72 years; 5 were not previously treated and 23 were relapsed/refractory. With a median follow-up of 17.9 months, results were the following:

• Two patients stopped treatment due to adverse events.

• Six patients experienced disease progression.

• The overall response rate (ORR) was 80.8%.

• The ORR featured a major response rate of 50.0%, including a very good partial response rate of 26.9%.

• PFS event-free rate at 12 months was 72.4%.

• Common AEs were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection.

Importance of Safety Data

The early ASPEN results showed that zanubrutinib produced fewer serious AEs and fewer AEs that led to discontinuation. Patients taking zanubrutinib were also signifi cantly less likely to experience atrial fibrillation (2.0% vs 15.3%), hypertension (10.9% vs 17.3%), or major bleeding (5.9% vs 9.2%). Those taking zanubrutinib did

experience more neutropenia (29.7% vs 13.3%).

But overall, do the results point to zanubrutinib for certaingroups of patients with WM?

“At the moment, there aren’t a whole lot of data about which patients get these other vascular [AEs],” Tam said. ASPEN did not set out to study examine which drug was better for patients who have hypertension or related risk factors, and Tam noted the event rates were fairly low.

However, Tam said, “One may come away from the study and say, ‘Well, those patients who potentially have a history of hypertension or have a history of atrial fibrillation—or have an abnormal electrocardiogram or abnormal echocardiogram—maybe they’re the ones who would be better off on [zanubrutinib]

compared with ibrutinib.’”

When asked if this second-generation BTKinhibitor would produce fewer cardiac AEs, Tam said, “We think it’s [related to] how clean the targeting is.”

The updated data presented at ASCO showed even greater diff erences between the 2 drugs in toxicity and atrial fibrillation, he said. “It is nice to have a drug that is fairly clean,” Tam said. Zanubrutinib does have to be taken twice a day, but there is no fasting requirement. “From [an AE] profi le, it’s worth it,” he said.

Zanubrutinib, sold in the United States as Brukinsa by BeiGene, last year received the first FDA approval from data gathered mostly in China.

References

1. Garcia-Sanz R, Dimopoulos MA, Lee H-P, et al. Updated results of the ASPEN trial from a cohort of patients with•MYD88•wild-type (MYD88WT)

Waldenström macroglobulinemia (WM). J Clin Oncol 2020;38(15 suppl; abstr e20056). doi:10.1200/JCO.2020.38.15_suppl.e20056

2. Tam CSL, Opat S, D’Sa S, et al. ASPEN: results of a phase III randomized trial of zanubrutinib versus ibrutinib for patients with Waldenström

macroglobulinemia (WM). J Clin Oncol.•2020;38(15 suppl; abstr 8007). doi:10.1200/JCO.2020.38.15_suppl.8007

3. BeiGene presents updated head to head results from phase 3 trial of zanubrutinib vs. ibrutinib in patients with Waldenström’s

macroglobulinemia at the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program. News release. BeiGene; May 29,

2020. Accessed May•29, 2020. http://ir.beigene.com/news-releases/news-release-details/beigene-presents-updated-head-head-resultsphase-3-trial?loc=US

Taking Aim at TIGIT: A New Immunotherapy Approach to Non—Small Cell Lung Cancer

The 2020 annual meeting of the American Society of Clinical Oncology (ASCO) featured the first results from CITYSCAPE, a trial involving a novel immunotherapy approach in non—small cell lung cancer. This phase 2 trial is the first to combine the immunotherapy tiragolumab with atezolizumab (Tecentriq), the monoclonal antibody that targets PD-L1.

Tiragolumab off ers a brand-new way to fight cancer: It binds to TIGIT, an immune checkpoint protein present on some T cells and also some natural killer cells. Like the better-known protein PD-L1, TIGIT plays a role in immune suppression, and blocking both the PD-L1 and TIGIT pathways at once could create a powerful tumor-fighting regimen:

• Results after 6 months of follow-up presented at ASCO show that the combination met both co-primary end points among patients with high levels of PD-L1. In an exploratory analysis among 135 randomized patients with tumor proportion score ≥50%, those taking the combination (n = 67) compared with those taking atezolizumab alone (n = 68) showed clinically meaningful improvement in objective response rate (ORR), 66% vs 24%, respectively, as well as a 70% reduction in the risk of disease worsening or death after 6 months.

• Median progression-free survival (PFS) for those taking the combination was not reached vs 4.1 months for patients taking atezolizumab alone (HR, 0.30; 95% CI, 0.15-0.61).

• After an additional 6 months of follow-up since the primary analysis, improvement in ORR and median PFS was maintained in the intent-to-treat population taking the combination.

• In the intent-to-treat population, the improvement in ORR was 37% for the combination compared with 21% for atezolizumab alone, and median PFS was 5.6 months vs 3.9 months, respectively (HR, 0.58; 95% CI, 0.38-0.89).

• The updated results showed no new or delayed safety events; grade 3 or above treatment-related adverse events (AEs) occurred in 14.9% of those taking the combination, compared with 19.1% of those taking atezolizumab alone.

AEs of grade 3 or above for any cause were 48% for the combination and 44% for atezolizumab alone. In a statement emailed to Evidence-Based Oncology™, a Genentech spokesperson said its scientists discovered TIGIT while researching innovative approaches to harnessing a patient’s immune system to fight cancer.

“Tiragolumab is our novel cancer immunotherapy designed to bind to TIGIT,” the statement said. “Although TIGIT is expressed on immune cells in multiple tumor types, it is highly expressed in lung cancer.”

CITYSCAPE coauthor•Melissa L. Johnson, MD, associate director for lung cancer research at the Sarah Cannon Research Institute and a partner at Tennessee Oncology, explained that TIGIT works similarly to PD-L1, in that it can blunt the immune response. “So, in a similar way to how blocking PD-1 or PD-L1 works, when you block TIGIT with the anti-TIGIT antibody,” she said, “you can restore the antitumor response and activate the infl ammatory cells to fi ght the cancer.”

The new combination “may be useful for patients and doctors who are looking for a chemotherapy-free option,” Johnson said. There is work directed toward exploring TIGIT as a second biomarker, but “right now, it appears to be expressed in many of the same cells as PD-L1.”

According to the statement from Genentech, “Both TIGIT and PD-L1 play an important role in immune suppression, and by blocking both pathways simultaneously we hope to deepen patient responses to immunotherapy and broaden the number of people who may benefit.

Identifying the right treatment for the right patient is very important, especially as each person’s cancer is diff erent. We’re investigating the predictive and prognostic value of PD-L1 as a biomarker for tiragolumab, as well the potential roles of TIGIT and poliovirus receptor, in clinical trials. We will look for further insights as part of our late-stage program.”

Johnson said the heart of her research involves the hunt for new compounds that can help patients who have developed resistance “to the standard FDA-approved agents.”

Johnson discussed the fi ndings within the context of the advances in lung cancer since her arrival at Sarah Cannon in 2014. “Thinking back over the last 5 years, some of the biggest gains in lung cancer research include the recognition of the importance of our immune system for the care of patients with lung cancer,” she said. “Now all patients with lung cancer will receive immunotherapy as part of their first line of treatment in the metastatic setting, and that wasn’t happening 5 years ago.”

Physicians—and patients—now have multiple options for PD-1 and PD-L1 inhibitors, not just from a single company but several, Johnson added. “We have learned so much because of the cumulative knowledge and wisdom gained across all those trials,” she said.

The second major advance, Johnson described, has been the recognition of the importance of molecular profiling, in the form of next-generation sequencing (NGS). Ideally, she said, this occurs in the first-line setting before treatment is given. “In the past, we have done hotspot panels or isolated analyte testing for single mutations. We know that not only is NGS testing better, but it’s more eff ective and more likely to identify rare mutations and unique alterations. It’s also more cost-eff ective to do it that way, as opposed to piecemeal testing, 1 mutation at a time. It has led to many, many diff erent therapy options for our patients that we wouldn’t otherwise know about.”

A third major advance is the way clinical trials are conducted. “Five years ago, we were still trying to compare each new therapy with platinum-based chemotherapy for lung cancer patients,” Johnson explained. “We now know that if you can design trials with selection for particular mutations up front, and you can show a benefit north of 50% in terms of response rates, then you have an active drug.”

The ability to combine data sets from many small subsets of patients, across lung and other tumor types, has allowed not only for advances that lead to new drug approvals, pointed out Johnson, but advances “in the way that we take care of patients.”

Reference

Rodriguez-Abreu D, Johnson ML, Hussein MA, et al. Primary analysis of a randomized, double-blind, phase II study of the anti-TIGIT antibody tiragolumab (tira) plus atezolizumab (atezo) versus placebo plus atezo as first-line (1L) treatment in patients with PD-L1-selected NSCLC (CITYSCAPE). J Clin Oncol.

2020;38(15 suppl; abstr 9503). doi:10.1200/JCO.2020.38.15_suppl.9503

MURANO Shows Worse Outcomes in R/R CLL When Venetoclax Is Stopped Early

When the first results from MURANO were published in the New England Journal of Medicine in 2018,1 they showed that the combination of venetoclax (Venclexta) with rituximab produced superior progression-free survival (PFS) in patients with relapsed or refractory chronic lymphocytic leukemia, compared with bendamustine/rituximab, if patients took venetoclax for 2 years.

Unfortunately, a significant number of the patients who begin taking venetoclax interrupt their treatment course or stop it completely. A fresh look at the MURANO data, released May 29 at the American Society of Clinical Oncology (ASCO) 2020 Annual Meeting,2 shows the poor outcomes that result when patients halt treatment for good. The data highlight the need to manage doses carefully to avoid toxicity.

MURANO data on discontinuation of venetoclax, featured in a poster released on May 29, 2020, were part of a Virtual ASCO 2020 highlights session on hematologic malignancies.

Venetoclax, taken by mouth, inhibits BCL-2, a key protein that regulates cell death. The protein is overexpressed in several blood cancers and can make them resistant to chemotherapy.

The poster’s data show that among the 194 patients in the venetoclax—rituximab arm of MURANO through May 8, 2019, 54 patients, or 28%, stopped the drug completely for the following reasons:

• adverse events (AEs): 29

• disease progression: 12

• study withdrawal: 5

• physician decision: 3

• death: 2

• other: 2

• nonadherance: 1

The median time on venetoclax before stopping due to AEs was 11.3 months (range, 0.5-24.6); for disease progression, it was 17.1 months (range, 4.6-25.1). According to the trial results, “greater cumulative exposure” to venetoclax signifi cantly reduced the risk of either a PFS or overall survival (OS) event (PFS: HR, 0.93; 95% CI, 0.88-0.99; P = .0168; and OS: HR, 0.85; 95% CI, 0.79-0.92; P < .0001).

A table included in the abstract gave statistics for patients who discontinued venetoclax for any reason (PFS: HR, 5.98; 95% CI, 3.31-10.82; P¦<¦.0001) and for those who discontinued due to AEs (PFS: HR, 5.82; 95% CI, 2.39-11.57; P < .0001).

Treatment interruption for AEs was seen in 134 of the 194 patients, mostly due to neutropenia (84/194, or 43%). The median time of treatment interruption was relatively short at 9 days, and short interruptions did not affect PFS or OS.

The authors reported, “These data highlight the importance of effective control of toxicity to realize the full benefit of [venetoclax/rituximab] treatment.”

The key to management of venetoclax has been the development of the 5-week dose-escalation schedule, as well as dosing adjustments, both of which help prevent tumor lysis syndrome (TLS). Data reported in 2019 by the American Association of Cancer Research on 297 patients “provide insights into current use of venetoclax in clinical practice, including TLS rates observed.…We identified opportunities for improved adherence to TLS risk stratifi cation and prophylaxis,

which may improve safety.”3

Genentech and AbbVie supported the study.

References

1. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax—rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976

2. Mato AR, Sharman JP, Biondo J, et al. Impact of premature venetoclax (ven) discontinuation/interruption on outcomes in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): phase III MURANO study results. J Clin Oncol. 2020;38(15 suppl; abstr 8028). doi:10.1200/JCO.2020.38.15_suppl.8028

3. Roeker LE, Fox CP, Eyre TA, et al. Tumor lysis, adverse events, and dose adjustments in 297 venetoclax-treated CLL patients in routine clinical practice. Clin Cancer Res. 2019;25(14):4264-4270. doi:10.1158/1078-0432. CCR-19-0361