Fixed-Duration Therapy Struggles to Find Footing Across Tumor Types

Chul Kim, MD

Investigators have explored fixed-duration systemic therapies as a way to provide patients the opportunity to alleviate toxicities, financial burden, and adherence issues often associated with continuous therapies without the risk of losing efficacy. These treatment options have gained some traction in hematologic malignancies, where advances in drug development and sequencing strategies have afforded invetigators the opportunity to conduct trials.

In relapsed chronic lymphocytic leukemia (CLL), for example, a high proportion of patients who receive venetoclax (Venclexta) and rituximab (Rituxan) achieve durable remissions, and those with deep responses have the same progression-free survival (PFS) rates whether they received continuous therapy or a fixed 2-year regimen.¹ In advanced melanoma, data show little benefit in remaining on checkpoint inhibitors for longer than 2 years, and in some patients just 1 year of therapy provides lasting PFS benefit.²

With other cancers, however, the search for treatments that can be stopped or paused after a relatively short period of time has been stymied by a lack of therapies that induce deep responses in significant numbers of patients. Additionally, few studies compare limited-duration and continuous therapies and investigators face challenges in terms of accruing patients in clinical trials.

In non–small cell lung cancer (NSCLC), a significant fraction of patients can safely pause their immunotherapy but creating a trial to determine the optimal duration would be difficult, said Chul Kim, MD, an assistant professor at Georgetown University and a physician at Georgetown Lombardi Comprehensive Cancer Center and MedStar Georgetown University Hospital in Washington, DC.

“There are patients who achieve good disease response and stabilization on immunotherapy for 2 years, but lung cancer in general is more aggressive. Response to immunotherapy and overall survival [OS] is much better in melanoma, for example,” Kim said. “We don’t see complete responses that often in lung cancer. It would be a great study to conduct, but that would require a pretty big effort. At individual centers there will not be a lot of people you can find to randomize to a study.”

Meanwhile, in some diseases such as multiple myeloma, the introduction of Shuo Ma, MD, PhD new agents shifted paradigms in the other direction, away from fixed-duration therapies and toward maintenance therapies that may be costly but provide better outcomes in the long term.

Fixed and Continuous Options in Hematologic Malignancies

Until a decade ago the typical treatment regimen for patients with CLL was a fixed course of chemoimmunotherapy that was repeated upon relapse and tended to become less effective over time, said Shuo Ma, MD, PhD, an associate professor of medicine at Northwestern University Feinberg School of Medicine and a physician at Robert H. Lurie Comprehensive Cancer Center of Northwestern University, in Chicago, Illinois. Standard treatments have shifted in the frontline setting and for patients with relapsed CLL, ushering in an era of continuous therapy with ibrutinib (Imbruvica) or another Bruton tyrosine kinase (BTK) inhibitor, and fixed-duration venetoclax with a monoclonal antibody, she said.

Ma coauthored a study in 2017 on the efficacy of venetoclax plus rituximab (VenR) in relapsed CLL, and results from a 5-year follow-up study were published in 2021. Patients in the phase 1b trial (NCT01682616) received daily oral venetoclax and a monthly injection of rituximab for 6 months followed by venetoclax monotherapy. Discontinuation of therapy was allowed for those who achieved a complete response (CR), CR with incomplete marrow recovery (CRi), or who had undetectable minimal residual disease (uMRD), defined as less than 10^–4 by flow cytometry. At the time of disease progression, patients could be retreated with VenR.¹

The evaluable population included 49 patients; the 5-year overall response rate was 86% (95% CI, 73%-94%), with 53% (95% CI, 38%-68%) achieving CR/CRi. Among responders, 29% achieved CR/CRi within in 1 year, 16% between 1 and 2 years, and 8% after 2 years. The median overall survival (OS) was not reached, and the 5-year OS rate was 86% (95% CI, 72%-94%). In terms of PFS the median was 5.6 years (95% CI, 3.1-6.6) and the 5-year rate was 56% (95% CI, 40%-70%). The median duration of response was 6.2 years (95% CI, 3.9-6.3) with a 5-year ongoing response rate of 58% (95% CI, 40%-73%).¹

Thirty-three patients achieved a deep response, defined by investigators as CR and/ or uMRD. Among these responders, 14 opted for continuous venetoclax monotherapy for a median of 5.6 years (range, 2.4-6.6) and 19 chose limited-duration therapy with venetoclax, which they received for a median of 1.4 years (range, 0.4-4.2).

Among the responders who received continuous venetoclax, 8 remained in ongoing remission and the 5-year PFS rate was 79% (95% CI, 47%-93%) with a median PFS of 6.6 years (95% CI, 4.4-6.6). The rates were similar for those who stopped treatment with venetoclax, with a median PFS of 6.5 years (95% CI, 3.6-6.5) and a 5-year PFS rate of 80.0% (95% CI, 49.4%-93.0%). The 5-year estimates for ongoing remission were 71% (95% CI, 39%-88%) for those receiving on continuous therapy vs 79% (95% CI, 49%-93%) for those receiving limited-duration therapy.¹

Ma noted that despite providing the opportunity to stop or pause therapy, fixed-duration VenR has not displaced continuous BTK inhibition in CLL, in part because patients do not find oral medications burdensome. “Most [patients] are tolerating [the drug] very well. They’re used to taking a chronic medication every day, just like they’re taking their blood pressure or cholesterol medication every day. For most patients it’s actually not a big problem, especially if they don’t have the high co-pay,” she said.

In addition, the venetoclax combination is not a cure. “Both classes of treatment are very widely used, and most likely a patient with CLL will be using both of those classes in their treatment history—one class is not going to be able to control the disease forever, so you have to go to the next one. It’s just a matter of sequence,” Ma said.

CLL trials continue to investigate optimal treatment duration, often in the context of combinations or sequences that might increase the frequency of deep responses, she continued. Investigators are also using markers, such as uMRD to trace the efficacy of regimens among responders. For example, in the phase 2 CAPTIVATE study (NCT02910583), venetoclax plus ibrutinib was evaluated in patients with treatment-naÏve CLL.³ After initial therapy, those with confirmed uMRD are randomly assigned to double-blind placebo or ibrutinib, and those without uMRD are assigned to open-label ibrutinib or ibrutinib plus venetoclax.

In the primary analysis, patients with confirmed uMRD who were randomly assigned to placebo or continued ibrutinib had similar 1-year diseasefree survival (DFS) at 95% and 100%, respectively. In an updated analysis presented at the 63rd American Society of Hematology Annual Meeting and Exposition, no new MRD relapses, instances of progressive disease, or deaths were reported among the 43 patients in either arm with confirmed uMRD. In this patient population the 2-year DFS rate in the MRD-guided placebo arm remained at 95.3% (95% CI, 82.7%-98.8%) and the 2-year DFS rate for patients who received ibrutinib remained at 100%; 3-year estimated PFS rates were 95% and 100%, respectively.

Cutoffs for Immunotherapy in Melanoma

Two years of immunotherapy is probably sufficient for most patients with melanoma, according to Geoffrey T. Gibney, MD, coleader of the Melanoma Disease Group at Georgetown Lombardi Comprehensive Cancer Center and MedStar Cancer Network. However, as is the case other solid tumors, the optimal duration remains a matter of debate given a lack of trials that stop treatment at a predetermined time or directly compare fixed and continuous regimens.

“We recognize, as a melanoma community, that we need more answers. How much treatment does a patient actually need?” Gibney said.

Table 1. MRD-Guided Outcomes in CAPTIVATE³

The 2-year consensus is based on results of studies which show durable responses in subsets of patients who reach that benchmark. Gibney cited KEYNOTE-006 (NCT01866319), in which 556 patients received pembrolizumab (Keytruda) and of whom 103 (19%) completed 2 years of the drug.⁴ Within that subgroup, 21 (20%) achieved a best overall response of CR, 69 (67%) achieved PR, and 13 (13%) had stable disease (SD).

Results of a 5-year follow-up analysis demonstrated ongoing responses in 76% of the patients who had completed 2 years of pembrolizumab and achieved CR. Ongoing responses were shown among 77% of patients with PR, and 54% of those with SD. Additionally, 23 patients who stopped pembrolizumab early, as allowed by the protocol, and who did not complete 2 years of the drug had a 24-month PFS rate of 86.4% (95% CI, 63.4%95.4%), which is similar to that in patients with CR who did complete 2 years.

Other relevant trials include KEYNOTE-001 (NCT01295827). In a 5-year follow-up analysis most patients (90%) who met the criteria for stopping pembrolizumab and entered observation maintained their responses.⁵ Of 655 enrolled participants, 72 met the criteria and entered observation. This population included 67 patients with a CR and 5 with a PR.

In a pooled analysis of CheckMate 067 (NCT01844505) and CheckMate 069 (NCT01927419), 56 of 96 patients who discontinued nivolumab (Opdivo) plus ipilimumab (Yervoy) in the first 12 weeks because of toxicity achieved an objective response. Further, investigators observed ongoing responses in 64% of the responding patients.⁶

To better identify patients who may safely discontinue immunotherapy, Gibney and his colleagues at Georgetown Lombardi Comprehensive Cancer Center conducted a study using PET/CT scans to assess for active disease. Investigators at the institution offered patients with advanced melanoma scans after approximately 12 months of therapy to determine whether tumor sites were metabolically active; if they were, the investigators used biopsies to evaluate active residual disease. The results of patients who had disease control and discontinued treatment as a result of toxicity were compared with those who stopped treatment after 12 months using a CT scan to identify CR.

Figure 1. Monitoring for Active Disease in Melanoma: PET-Stop Study Design⁷

Among 122 patients included in the retrospective study, 24 had no active disease and discontinued treatment by choice whereas 28 discontinued because of toxicity. The median treatment durations were 12 months and 4 months, respectively.⁷ The 3-year eventfree survival (EFS) rates among the 2 groups were 95% and 71%, respectively. The low rates of relapse among patients with no active disease via scan or biopsy led investigators to conclude that discontinuation of anti–PD-1 therapy at 12 months may be a viable option for these patients.⁷

Gibney is now leading PET-Stop (EA6192, NCT04462406), a phase 2 trial by the ECOGACRIN Cancer Research Group, to validate these results. Following 1 year of standard-of-care anti–PD-1 therapy, investigators will use fluorodeoxyglucose (FDG)-PET/CT scan and tumor biopsy to guide immunotherapy discontinuation decisions in patients with unresectable stage IIIb/ IV melanoma. Gibney said using scans helps overcome patient reluctance to stop treatment early.

“[Conducting] a standard trial, where you have a short duration compared with a long duration [of therapy], may not be very appealing to investigators at various centers or patients,” Gibney said. “Patients are probably going to f ind more appealing an approach that uses a biomarker-type driven [data], or some other signal that allows them to feel comfortable [so that] when they discontinue their therapy, their disease will hopefully remain in remission.”

Other trials that may illuminate the duration question in melanoma include DANTE (ISRCTN15837212), a randomized phase 3 trial in the United Kingdom evaluating the feasibility of stopping first-line anti-PD-1 monotherapy (nivolumab or pembrolizumab) at 12 months in patients who are progression free.8 Meantime, investigators of Safe Stop (NL7293), a singlearm prospective trial in the Netherlands, are evaluating early discontinuation of first-line anti–PD-1 therapy for patients with advanced or metastatic melanoma who have a confirmed CR or ongoing PR.⁹

In Canada, the phase 3 STOP-GAP trial (NCT02821013) is randomly assigning patients with unresectable stage III/IV melanoma to 2 years of standard therapy in the absence of disease progression, or treatment until maximal tumor response as determined by at least 2 radiologic measurements, with retreatment at time of progression.

Moving Away From Fixed-Duration Therapies

Until about a decade ago, fixed-duration therapies were the norm in multiple myeloma treatment. Patients would receive 4 cycles of an initial therapy followed by transplant, or 1 to 2 years of the therapy if they were ineligible for transplant, followed by observation, said S. Vincent Rajkumar, MD, a professor of medicine and consultant in the Division of Hematology, Department of Internal Medicine and in the Division of Hematopathology, Department of Laboratory Medicine and Pathology at Mayo Clinic in Rochester, Minnesota. Rajkumar is the 2019 Giants of Cancer Care^® award winner in Multiple Myeloma.

“We didn’t have any proof that treatment beyond that time was going to prolong life or improve quality of life. Once we had the data that treatment beyond that time, maintenance, prolongs life, we switched to that approach,” he said. “That principle should be the case for all cancers. The burden of proof is on us to show that you need to continue to treat.”

Multiple studies support the move to continuous therapy in multiple myeloma, including one coauthored by Rajkumar in 2021 on the optimal duration of lenalidomide (Revlimid) maintenance following autologous stem cell transplant.¹⁰ The retrospective study assessed the outcomes of 213 patients with myeloma who received treatment at Mayo Clinic from 2005 to 2016. The evaluable population consisted of 48 patients after excluding those who stopped lenalidomide maintenance within 3 years because of progression on maintenance therapy.

Those who had least 3 years of maintenance had a superior 5-year OS rate of 100% vs 85% among those who had less than 3 years of maintenance (n = 100; P = .011). The median PFS was 7.2 years (95% CI, 6.0-8.5) vs 4.4 years (95% CI, 4.3-4.5), respectively (P < .0001). The 5-year PFS rates were 86% and 35%, respectively. Investigators concluded that in this patient population, longer courses of lenalidomide maintenance generated ongoing responses, prolonging time to next treatment with other agents such as daratumumab (Darzalex).

Despite this finding, Rajkumar highlighted 2 features of toxicity associated with lenalidomide—the financial and physical costs and AEs. “You’re talking $15,000 to $20,000 per month for lenalidomide alone,” he noted. “[There is] risk of diarrhea, leg cramps, fatigue [and] there is the risk of [developing] second cancers long-term. We are always asking ourselves, are there patients who don’t need continuous therapy? Do we need to give it forever? Maybe 3 years is enough,” Rajkumar said. “It’s important that investigators keep asking those questions.”

Rajkumar is part of the ENDURANCE trial (NCT01863550), the second part of which is comparing 2 years of lenalidomide maintenance with continuous lenalidomide until disease progression or unacceptable toxicity. He said patient accrual is complete and analysis of the maintenance data is underway.

Unanswered Clinical Questions

Lung cancer investigators have noted the findings on stopping immunotherapy in melanoma, but results of duration studies in their field have been mixed.

Some trials have shown intriguing examples of durable responses. For example, a 5-year follow-up analysis of the phase 1 CA209-003 trial (NCT00730639) demonstrated that patients with NSCLC treated with 2 years of nivolumab may achieve long-term survival benefit. Among 129 patients with pretreated, advanced NSCLC the 5-year OS rate was 16%, which aligns with data from the 3-year follow-up that showed an OS rate of 18%. The median OS was consistent at 9.9 months (95% CI, 7.8-12.4).11 Investigators noted that the findings are encouraging, but that an optimal treatment duration has yet to be determined.

Results of other studies have not supported f ixed-duration treatments. In an exploratory analysis, the phase 3 CheckMate153 trial (NCT02066636) patients with pretreated, advanced NSCLC were randomly assigned to receive continuous nivolumab (n = 127) or 1-year fixed duration treatment (n = 125). Of the randomized population, the PFS populations included 89 and 85 patients, respectively. At 13.5 months’ follow-up the median PFS was 24.7 months (95% CI, 14.8-13.7) in the continuous therapy arm vs 9.4 months (95% CI, 5.6-13.0) in the fixed-duration arm (HR, 0.56; 95% CI, 0.370.84). At 1 and 2 years the PFS rates were 64.6% and 51.9% for continuous nivolumab vs 44.0% and 30.7% for fixed-duration therapy. For those who had SD, investigators noted that continuous and f ixed-duration therapy had similar outcomes with a median PFS of 11.8 months (95% CI, 7.0-21.8) vs 9.4 months (95% CI, 9.4-20.7), respectively (HR, 1.01; 95% CI, 0.51-2.01).¹²

Some critiques of the trial were that the analysis included only a small fraction of the initial CheckMate153 population and randomly assigned only nonprogressing patients and that the trial design did not mandate SD and durable disease response for this analysis.¹³ Additionally, outside of CheckMate153, several unanswered questions remain concerning retrospective-type studies, such as examinations of overtreatment with immune-checkpoint inhibitors and the presence of biomarkers that offer prognostic significance.¹³

Kim said he was not aware of any current trials looking at optimal duration of immunotherapy in NSCLC, as investigators tend to focus on novel agents or combinations, such as 4-drug regimens in first-line disease or a second immunotherapy added to pembrolizumab. For his patients who are receiving immunotherapy, his approach depends in part on what they are comfortable doing.

“After 2 years, if there’s good response, then I have a discussion with the patient. If they want to stop, we hold and watch it, and hopefully nothing happens. If something happens and there’s progression, then we put the patient back on the pembrolizumab,” he said. “But there are some patients who just don’t want to stop, especially when they feel great. They are a little concerned about the uncertainty about what would happen if the treatment were stopped. Some people don’t want to rock the boat.”

References

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