Monthly Dosing of Consolidation Durvalumab Is Key in Stage III NSCLC

Sandip P. Patel, MD

The approval of durvalumab (Imfinzi) for an additional dosing option, a fixed dose of 1500 mg every 4 weeks, in the existing indication of unresectable stage III non–small cell lung cancer (NSCLC) has made it easier for eligible patients to receive the standard-of-care regimen following completion of concurrent chemoradiation, said Sandip P. Patel, MD, who added that proactive toxicity management, including every-3-month scans, and timely initiation of the PD-L1 inhibitor are critical to deriving the maximum benefit from the curative intent–treatment.

“The biggest barrier to consolidation durvalumab that I’ve seen in my clinic is that patients are tired after several weeks of concurrent chemoradiation, and to come in once a month, makes it a little easier than the previous dosing per the [PACIFIC (NCT02125461)] study, which was every 2 weeks. So, that’s a huge benefit. Patients may have to commute back and forth, or they have childcare duties, and family responsibilities; some of them even work while they’re going through [treatment], which is a testament to their endurance. Every-4-week dosing is really meaningful to patients,” said Patel.

In an interview with OncLive^®, Patel, an associate professor of medicine, co-leader of Experimental Therapeutics, deputy director of the San Diego Center for Precision Immunotherapy, and director of the Clinical Trials Office at the University of California San Diego, discussed the real-world application of the phase 3 PACIFIC trial in unresectable stage III NSCLC.

OncLive^®: How can the benefit of durvalumab be optimized among patients with unresectable stage III NSCLC who complete concurrent chemoradiation?

Patel: It’s important to understand the type of patient that’s best suited for the PACIFIC regimen, which is consolidation durvalumab for 1 year [following concurrent chemoradiation]. [Eligible] patients are those who responded to concurrent chemoradiation, which is over 95% [of patients], and those who don’t have an underlying autoimmune condition, particularly interstitial lung disease with an autoimmune component, such as [idiopathic pulmonary fibrosis], which would be of concern.

Many patients who have completed over a month of concurrent chemoradiation have toxicities, such as esophagitis. However, the data seem to suggest, and whether it’s the demographic or whether it’s true that there’s some synergy between radiation and immunotherapy [we don’t know, but] beginning [durvalumab] within 2 weeks of completion of chemoradiation may confer better benefit. In my practice, I’ll try to start patients on durvalumab about 2 weeks after they complete chemoradiation for the most part. If you use weekly carboplatin [and] paclitaxel, you do not do consolidative chemotherapy with 2 cycles of every-3-week-dosing of carboplatin [and] paclitaxel, you go straight into durvalumab to complete 1 year [of therapy].

What is your experience with immune-related adverse effects (irAEs) with durvalumab? Do they prohibit patients from completing the full year of durvalumab?

Every patient is unique and one of the aspects about precision medicine in oncology is understanding where a drug fits overall into a patient’s life. Although the goal is 1 year of durvalumab as consolidative therapy, not every patient will get to 1 year. Some patients may start to get autoimmune toxicity. These [toxicities] range from immune-mediated pneumonitis to colitis to endocrinopathies. It’s important to assess for these toxicities because they can be generally successfully intervened upon with immunosuppressives, such as steroids.

Every-4-week-dosing of durvalumab relative to every-2-week-dosing solves one of the logistical hurdles in terms of infusion visits, but for those patients who develop irAEs and severe irAEs, many of them will not need to complete 1 year of therapy. This is because the development of that irAE sometimes portends a more favorable course for that patient in terms of anticancer effect.

What can be done to ensure that patients are able to receive durvalumab?

There are several challenges in the setting of stage III unresectable NSCLC. Especially in an older patient, concurrent chemoradiation can be tough even if one utilizes pemetrexed-based therapy or weekly carboplatin [and] paclitaxel. Esophagitis and pneumonitis can lead to a detrimental performance status, such that a patient may just not feel like coming in once a month for immunotherapy.

There’s also the recovery from their concurrent chemoradiation. Do we push too hard on the chemotherapy part [and] the radiation part? [We have to] ensure that like a symphony, each instrument isn’t playing too loud and drowns everyone else out. If we’re able to titrate everything to an appropriate level that patients can really do well, and continue to do well, [that’s important] because this is a curative intent–therapy. We really are trying to cure these patients who are in a high-risk place with stage III NSCLC. One of the places that we have really moved the needle in favor of patients has been in this setting to the appropriate use of concurrent chemotherapy and radiotherapy, but now [with] consolidative immunotherapy as well.

The key is to not push too hard on the chemotherapeutic component. If someone is having trouble with cisplatin, feel free to substitute carboplatin if that’s appropriate, especially with weekly paclitaxel, and adjust your chemotherapy doses such that the patient can run the whole marathon not just that initial sprint of concurrent chemoradiation. It’s a long journey for the patient. If you mention it’s 1 year of therapy, they’ll have that sense and they’ll undergo as much of that [treatment] as they think appropriate for their needs and as their body can safely tolerate.

What is the optimal time to scan patients following concurrent chemoradiation?

In PACIFIC, a scan was done after radiation was completed but before initiation of durvalumab, and it’s a tight window to complete your radiation, complete your chemotherapy, get a scan, and then start durvalumab in 2 weeks. That’s part of the reason that [window] got stretched to 6 weeks. In my practice, if someone’s having clinical symptoms, I’ll get a CT scan before starting immunotherapy and that’s to get a baseline on how their cancer is doing [and to see] if they’re having any pneumonitis that may be of concern that may be compounded with an immune-based [therapy]. For the most part while patients are on treatment, I’ll typically get scans every 3 months or so to see how they’re doing.

All of us who treat patients who are put on concurrent chemoradiation understand that the scans don’t tell the full story. It’s very hard to see any changes in the primary tumor [and] the lymph nodes after radiation and definitely after chemoradiation and immunotherapy. The most important scans tend to be those that are triggered by a new symptom, such as weight loss or cough, or after we’ve completed 1 year of therapy, but typical protocol is [to scan] every 3 months.

Do you envision a time where patients might not need chemoradiotherapy?

Concurrent chemoradiation for the treatment of patients with stage III NSCLC really has been a revelation for patients. Even in the control arm of PACIFIC, almost half of patients were alive at the end of the study years out from their initial therapy. We know that we can move the needle favorably for patients with some cures even just with chemoradiation, but by adding the consolidative durvalumab, we add anywhere from 10% to 15% to that rate.

It is possible that in a biomarker-selected cohort, we may be able to omit chemotherapy or even radiation. However, to throw out modalities that have curative potential, we would really want to ensure that we know that what we’re substituting in has equal or better potential in helping patients. Now that we’ve hit this high watermark with consolidation durvalumab after concurrent chemoradiation, we would want to ensure that any substitution we make has similar efficacy without worsening the adverse effect [AE] profile of an otherwise reasonably tolerable regimen.

Are patients still receiving consolidation chemotherapy post chemoradiation? What patients do you consider this approach in?

For the management of stage III NSCLC, if a patient undergoes concurrent chemoradiation, historically, if carboplatin and paclitaxel are used in weekly doses, there are 2 cycles of full-dose, every-3-week-chemotherapy given at the end of concurrent chemoradiation. However, with PACIFIC and the utilization of consolidative durvalumab, the 2 full doses of chemotherapy every-3-weeks of carboplatin [and] paclitaxel are not necessary anymore. There was always a question about whether those 2 full doses just added toxicity without improving survival. In my practice, when I utilize weekly carboplatin [and] paclitaxel, which is more commonly in [patients with] squamous histology, I’ll typically utilize durvalumab starting about 2 weeks afterwards and go straight from weekly concurrent chemoradiation with the weekly carboplatin and paclitaxel to durvalumab without those 2 full doses of high-dose systemic therapy.

How do you personalize when to initiate durvalumab after concurrent chemoradiation?

We don’t know if the potential benefit of starting durvalumab within 2 weeks of completion of concurrent chemoradiation is a bonafide survival benefit vs patient selection, in that those patients that can smoothly go from concurrent chemoradiation to immunotherapy may just have a better survival. Given that this isn’t something that we’re going to be able to figure out anytime soon, for those patients that are safe to initiate immunotherapy, I’ll typically recommend [starting] it within 2 weeks [after completing concurrent chemoradiation] to try to capture any of that potential synergy that may exist between radiation and immunotherapy, although it very well may just be [because of] patient selection and [a] statistical effect of the study as opposed to a biologic effect. [However,] without knowing that, given the magnitude benefit [of consolidative durvalumab we saw in PACIFIC], it’s hard for me to ignore and so I’ll try to offer my patients initiation of immunotherapy within 2 weeks of the conclusion of their radiation.

What guidelines do you refer to for toxicity management?

Immunotherapies really have revolutionized our ability to take care of patients with cancer. However, they don’t come toxicity free. Most of the autoimmune AEs are immune-related or immune-mediated AEs [imAEs]. There is a high index of suspicion because these AEs can happen at the end of treatment, meaning you could finish 1 year of durvalumab and the patient’s first endocrinopathy can be 4 months after their last dose of therapy. Having that high index of suspicion is key.

In terms of resources to help make the diagnosis and facilitate management, multiple guidelines are available, including [those from the] National Comprehensive Cancer Network, American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer, for example. All 3 organizations have guidelines that roughly converge on prompt diagnosis and early intervention with corticosteroids. Typically, 1 mg/kg of prednisone or an equivalent [is recommended], and the key aspect there is it must be [given in] a slower taper, typically, over multiple weeks. Five days of prednisone is not going to be enough to prevent or mitigate an imAE. Multiple guideline resources are available to help assist doctors and their caregivers in the management of these toxicities, which can occur, albeit rare. It’s important for us to be able to intervene because these therapies are so potent that these patients with AEs can have durable remissions lasting years if we’re able to keep them safe from the potential toxicities of these treatments.