Practical Questions on Checkpoint Agents Arise

Elizabeth Plimack, MD

Although the advent of checkpoint blockade immunotherapies has inspired more excitement among oncologists than any other recent anticancer therapeutic development,^1,2 researchers and clinicians alike are wrestling with an array of questions concerning how best to translate this new modality into practice.

Despite the promising developments in this arena, many patients with cancer respond inadequately to immune checkpoint monotherapy, and others develop serious (grade 3-4) toxicities that require treatment cessation.³ Understanding the evidence and questions concerning dosing, treatment schedules, efficacy, and safety of immune checkpoint inhibitors as monotherapy and in combination regimens is essential to optimize their use in clinical practice.

Monoclonal antibodies that inhibit the CTLA-4 and PD-1/PD-L1 pathways significantly extend survival compared with conventional treatment in patients with targetable malignancies. The list of immune-responsive cancers now spans melanoma, non—small cell lung cancer (NSCLC), urothelial bladder cancer, head and neck squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, Hodgkin lymphoma, Merkel cell carcinoma, renal cell carcinoma (RCC), and tumors with high mutational loads in patients with germline mutations involving DNA mismatch repair, particularly colorectal cancer (CRC).³

As of December 5, the FDA had approved 6 checkpoint inhibitors to treat 1 or more of these malignancies: ipilimumab (Yervoy), a CTLA-4 inhibitor; nivolumab (Opdivo) and pembrolizumab (Keytruda), both PD-1 inhibitors; and atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi), all PD-L1 inhibitors.

Table. FDA Recommendations for Checkpoint Immunotherapies^4-10

Dosing

Although these agents broadly share similar adverse event (AE) profiles, each has a unique dosing recommendation and schedule (Table^4-10) Several experts discussed relevant questions concerning the administration of these agents in interviews with OncologyLive^®.Historically, most monoclonal antibodies were dosed according to body weight because body size was thought to affect pharmacokinetics (PKs).¹¹ Early studies of pembrolizumab used the same approach, but as more PK data became available, researchers revisited the need for weight-based dosing. Pembrolizumab, nivolumab, and atezolizumab are now approved at fixed doses for treating several tumor types.

Evidence supports fixed checkpoint inhibitor dosing. In one recent study, researchers combined PK data on pembrolizumab with response data for patients with advanced melanoma or NSCLC.¹¹ Comparing individual areas under the exposure curve with exposure ranges from pembrolizumab doses in early trials, 2 mg/kg every 3 weeks (Q3W) and 10 mg/kg Q3W or every 2 weeks (Q2W) showed that a 200-mg fixed dose pharmacokinetically resembled weight-based dosing among patients with CRC, head and neck cancer, NSCLC, and urothelial cancer. Although patients weighing more than 90 kg had the lowest PK exposure, they still fell well within the range associated with near-maximum efficacy in prior studies.¹¹

Such findings make sense, according to Elizabeth Plimack, MD, MS, chief of genitourinary medical oncology and director of genitourinary clinical research at Fox Chase Cancer Center in Philadelphia. For inhibitors of the PD-1 pathway, “there’s no dose—response relationship,” she said. “We’re using much higher doses than are needed to saturate the receptors. An immune checkpoint inhibitor is training the immune system. The immune system has memory, and so we see that the durability of the antitumor effect continues after we stop treatment.”

Multiple studies’ findings have shown that dosing PD-1 agents above 1 mg/kg does not boost efficacy.¹² In one systematic review and meta-analysis of data on patients with advanced melanoma or RCC, nivolumab doses of 2 or 10 mg/kg yielded similar objective response rates (ORRs) but significantly better progression-free survival (PFS) and overall survival (OS) than 0.3 mg/kg.13 Nivolumab is approved at 3 mg/kg or 240 mg, depending on the indication.⁷

Patients who received pembrolizumab had similar outcomes at either 2 or 10 mg/kg.13 “[Past] a certain dose [of either agent], no further improvement was observed in patient outcomes,” the reviewers concluded. “Therefore, effective and minimum doses need to be determined so that patients can achieve maximum therapeutic benefit with minimum adverse effects.”¹³

The AEs of immune checkpoint blockade result from inflammatory effects of T-cell disinhibition.³ The PD-1/PD-LI inhibitors show no dose—toxicity relationship, which means that dose reduction is not an appropriate way to manage AEs, said Plimack. If patients develop grade 3-4 immunerelated AEs, they should stop treatment and receive high doses of corticosteroids.⁴

However, dose clearly affects both the efficacy and safety of the anti—CTLA-4 antibody ipilimumab.3,4,14 In a phase II dose-ranging study of patients with advanced melanoma, the ORR was highest among those who received 10 mg/kg ipilimumab (11.1%), intermediate at 3 mg/kg (4.2%), and lowest at 0.3 mg/kg (0%).14 The 10-mg/kg cohort experienced 21 grade 3-4 immune-related gastrointestinal AEs, while the 3-mg/kg group developed 3 such events and the 0.3-mg/kg had none.14

Phase III data also support dose—efficacy and dose–toxicity relationships for ipilimumab. In a trial of more than 700 patients with advanced melanoma, the median OS was 15.7 months in the 10-mg/kg ipilimumab cohort compared with 11.5 months in the 3 mg/kg group (HR, 0.84; 95% CI, 0.70 to 0.99).15 However, rates of serious treatment-related AEs, such as diarrhea and colitis, were 37% in the 10-mg/kg group and only 18% in the 3-mg/kg group.15 Immune-related gastrointestinal symptoms typically do not occur until nearly 6 weeks of ipilimumab therapy, when patients have received several doses.12 Only about 10% of treated patients develop grade 3-4 diarrhea at 3-mg/kg ipilimumab, but this AE been fatal fatal.12,16

Phase II data are sufficient to decide on clinical doses of checkpoint inhibitors, according to Plimack. She typically bases dosing on the FDA recommendations listed on the labels, but noted that the agency seems to be increasingly open to approving fixed doses of immune checkpoint inhibitors rather than requiring weight-based dosing.

Scheduling and Toxicities

“You waste less drug when you use fixed dosing, whereas with weight-based dosing, you have to waste a vial, so it saves not a trivial amount of money,” noted Jeffrey S. Weber, MD, PhD, deputy director of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center and co-director of its melanoma program.Schedule greatly affects ease of treatment, particularly in the maintenance or adjuvant setting, according to experts. “Schedule is more important than dose in terms of choice” of an immune checkpoint inhibitor, said Plimack. “It’s very inconvenient for patients to have to come every 2 weeks for treatment.”

Currently, pembrolizumab has a somewhat more convenient treatment schedule (Q3W) than nivolumab (Q2W),^6,7 but that will change if the FDA approves a supplemental biologics license application to add a second dosing schedule for nivolumab (480 mg every 4 weeks [Q4W]).

The pendulum will keep swinging back and forth in favor of one or another anti—PD-1/anti– PD-L1 agent as manufacturers seek approvals for extended dosing schedules, said Weber. He and other experts are comfortable with dosing nivolumab Q4W in stable patients. “At induction, you want to see them more frequently, but for patients on maintenance or adjuvant nivolumab, you don’t need to see them as often,” Weber said. Although anti–PD-1 and anti–PD-L1 agents do not show dose-related toxicity, treatmentassociated AEs appear to take longer to resolve than AEs stemming from anti–CTLA-4 therapy.⁴

Furthermore, the expanding population of patients on immune checkpoint inhibitors will include those with a higher risk of toxicities, heightening the need to educate patients about AEs and follow them closely, said Pavlos Msaouel, MD, PhD, chief fellow in hematology and oncology at The University of Texas MD Anderson Cancer Center. “If you are really concerned about toxicity, then you might want to start by seeing patients every 2 weeks to make sure the drug doesn’t stay in their system for too long without follow-up,” Msaouel said. “For most patients, follow-up every 3 to 4 weeks is fairly tolerable for this type of regimen, but there are always exceptions to that rule. For example, if patients have a history of autoimmune phenomena, I would be more suspicious of toxicities and would want more frequent follow-up.”

If a patient has very active, completely uncontrolled Crohn disease, or has psoriasis requiring a lot of immunosuppressive therapy, Msaouel tries to avoid immune checkpoint therapy entirely.

“But if a patient has a remote history of autoimmune disease that appears resolved or very well controlled, and that does not require immunosuppressive therapy, we would give an immune checkpoint inhibitor, but keep a closer eye on the patient.” That includes frequent visits regardless of approved dosing schedule, he said.

He added that patients tend to be far more accepting of frequent dosing early in treatment, but that twice-monthly treatment can become onerous over the longer term, such as during maintenance therapy. At MD Anderson, a trial of nivolumab and ipilimumab (NCT03274258) in patients with renal medullary carcinoma features a more spread-out dosing schedule for nivolumab (480 mg Q4W), he noted.

Combination Questions

Longer dosing intervals also save money, a key consideration in the current healthcare climate. During a plenary session at the 2015 American Society of Clinical Oncology Annual Meeting, experts estimated that widespread use of immunotherapy drugs could cost the United States $174 billion annually, exceeding $1 million per patient, and that switching from a schedule of Q2W to Q3W would save payers thousands of dollars per patient per month.¹⁷Questions persist about optimal dose, schedule, and treatment strategies for checkpoint inhibition. For example, many patients with immune-sensitive cancers often do not respond to checkpoint inhibitor monotherapy. Thus, researchers are investigating whether combination regimens can increase the probability and quality of treatment response.^3,18,19

So far, efficacy results are relatively promising. Compared with ipilimumab monotherapy, reduceddose nivolumab (1 mg/kg) plus standard-dose ipilimumab (3 mg/kg) produced significantly higher rates of objective response, OS, and PFS in the phase II CheckMate 069 trial and the phase III CheckMate 067 trials of patients with previously untreated advanced melanoma.20,21 The FDA has approved the regimen at a dosing schedule of Q3W for 4 doses, followed by nivolumab at 240 mg once Q2W.^22,7

However, combining checkpoint inhibitors can increase the risk of serious immune-related AEs.18 In a 3-year update of CheckMate 067, ipilimumab plus reduced-dose nivolumab led to grade 3-4 AEs more than twice as frequently (59%) as monotherapy with either nivolumab (21%) or ipilimumab (28%).²³

Therefore, researchers are experimenting with lowering the anti—CTLA-4 dose instead of the anti–PD-1 dose. In a large multicenter phase Ib trial of patients with advanced melanoma (KEYNOTE-029), reduced-dose ipilimumab (1 mg/kg) plus standard-dose pembrolizumab (2 mg/kg) showed favorable safety compared with separate data on standard-dose ipilimumab plus reduced-dose nivolumab.24 Rates of grade 3-4 AEs were 45% at a median of 17 months of follow-up compared with 55% at 9 months of follow-up among patients who received standard-dose ipilimumab plus reduced-dose pembrolizumab in CheckMate 067.^24,21

“This result was expected, since the occurrence of side effects with ipilimumab monotherapy is known to be dose dependent,” wrote Michael A. Postow, MD, of Memorial Sloan Kettering Cancer Center, in an editorial accompanying the KEYNOTE-029 report.19

Although adding reduced-dose ipilimumab to pembrolizumab produced higher rates of AEs than are observed with pembrolizumab alone, the ORR of 61% also was nearly 3 times higher, he added. The KEYNOTE-029 regimen was associated with more toxicity than has been reported for either pembrolizumab or ipilimumab monotherapy, particularly with regard to hypothyroidism, hyperthyroidism, pneumonitis, hepatitis, and hypophysitis.24 But crucially, reducing the dose of ipilimumab appeared to reduce the risk of anti— CTLA-4-associated colitis and diarrhea, which have been fatal in rare cases.24,19

Nonetheless, the work is far from over. The fact that 2-year OS rates were generally similar between CheckMate 067 and KEYNOTE-029 “stresses the need to continue to refine and improve the combination of ipilimumab with anti— PD-1,” Postow wrote. “The first obvious step will be completion of ongoing randomized trials testing various doses and schedules of the combination of reduced-dose ipilimumab with standard-dose pembrolizumab,” he noted.¹⁹ Lessons from these trials should help inform trials of additional anti— PD-1 combinations, he said.¹⁹

Reduced-dose ipilimumab plus standard-dose pembrolizumab is showing promise in other cancers besides melanoma. In September 2017, the phase III CheckMate 214 study was stopped early after nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) yielded superior OS compared with standard-of-care sunitinib (Sutent) in patients with treatment-naïve advanced or metastatic RCC.25 The findings also reinforced concerns about toxicity, however, since rates of treatment cessation for AEs were 24% with nivolumab-ipilimumab and 12% with sunitinib.26 Researchers also are experimenting with combining 2 lowered doses of checkpoint inhibitors. In an ongoing phase I/II trial (NCT02941744), they are testing low fixed doses of ipilimumab (50 mg) plus nivolumab (10 mg) as adjuvant therapy after resection of melanoma macrometastases. Safety findings are scheduled to be reported in 2018. Another study (NCT03233152) is evaluating a low fixed dose of nivolumab (40 mg/4 mL) in combination with intratumoral ipilimumab (50 mg/10 mL) after resection of recurrent glioblastoma.

Additional trials are examining various doses and schedules of other checkpoint inhibitor combinations, as well as combinations of checkpoint inhibitors plus other anticancer strategies such as vaccines, radiation, chemotherapy, IDO pathway inhibitors, cytokine-directed therapies, oncogenic pathway inhibitors, and T-cell therapies, among others.^19,27,18

Another question is how best to select doses and schedules for trials of new immune checkpoint inhibitors or new combinations. Early-phase studies usually evaluate objective antitumor activity, which can complicate the selection of doses and schedules for phase III trials that investigate a stricter OS endpoint.28 However, because agents such as nivolumab work by stimulating the immune system, the same dose might be appropriate across multiple tumor types.28

By incorporating clinical safety and efficacy data with analyses of relationships between dose and exposure response,28 one research team tested the hypothesis that nivolumab monotherapy is optimized at 3 mg/kg regardless of tumor type. Safety findings were similar at doses ranging from 0.1 to 10 mg/kg, regardless of tumor type. ORRs also were similar across doses in melanoma and RCC, but doses of 3 and 10 mg/kg yielded higher ORRs in NSCLC than doses of 1 mg/kg, even though peripheral receptors were saturated at dosesof 0.3 mg/kg and higher. The researchers emphasized the value of integrating dose-response and exposure-response data with efficacy and safety data in the immune-oncology setting.²⁸

In addition to dosing questions, the ideal scheduling of anti—PD-1 and anti–CTLA-4 antibodies remains unclear, experts have noted.¹² For example, therapies that target PD-1/PD-L1 usually are administered continuously, despite a lack of robust evidence that ongoing treatment is necessary. In terms of duration of immunotherapy, Weber said: “I’d be hard pressed to believe that maintenance therapy lasting more than a year is really going to make a difference.” Hopefully, future studies will help clarify these questions.

References

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