Consolidation Immunotherapy Following Chemoradiation for Stage III NSCLC Is Standard of Care for Most Oncologists

Corey J. Langer, MD

During a Targeted Oncology Case Based Peer Perspective event, Corey J. Langer, MD, director, Thoracic Oncology, Abramson Cancer Center, professor of Medicine, Hospital of the University of Pennsylvania in Philadelphia, PA, discussed options for a 63-year-old patient with stage III non–small cell lung cancer.

Targeted Oncology™: Can you discuss the presentation of this patient with stage III non–small cell lung cancer?

LANGER: This is a classic case of stage III, or apparent stage III [locally advanced lung adenocarcinoma]; we don’t have the biopsy results yet. Transbronchial lung biopsy of the left upper lobe mass and node sampling showed adenocarcinoma at the primary site and in 4L and level 7 nodes. Level 7 subcarinal and level 4R contralateral were negative, so this patient is T2aN2M0 stage IIIA. Based on the bulk and extent of mediastinal disease, active emphysema, and borderline PFTs [pulmonary function tests], the patient’s cancer was deemed unresectable. Even if it had been resectable, he might have been deemed medically inoperable. He was referred for consideration of concurrent chemotherapy and radiation [cCRT].

The rule of thumb [with cCRT] is, preexisting interstitial lung disease [ILD] is at least a relative contraindication, as is any preexisting inflammatory disease above and beyond random episodes of pneumonia. Patients with progressive disease will often have a fair amount of interstitial markings, so you have to be careful. My other rule of thumb is, if they’ve got lousy PFTs, FEV1 [forced expiratory volume in 1 second] less than 1, I’m not sure that’s somebody you’re going to treat concurrently. That may be someone you treat sequentially and use different forms of radiation.

What are the recommended cCRT options from the National Comprehensive Cancer Network (NCCN) guidelines?

The current NCCN guidelines for cCRT include cisplatin plus etoposide and weekly paclitaxel plus carboplatin. In this COVID-19 [coronavirus disease 2019] era, when I’m trying to cut down on the number of institutional contacts, I’ve [increasingly] been giving [2 other NCCN guideline-recommended regimens], carboplatin/pemetrexed [Alimta] and cisplatin/pemetrexed, in stage III disease.1 We have data from the PROCLAIM trial [NCT00686959] showing cisplatin/pemetrexed is at least equivalent to older etoposide/platinum regimens.2 As far as I’m concerned, these are the standard regimens, and I’m hardpressed to show any major differences in outcome using any of these regimens. There’s always been this prejudice against carboplatin-based regimens that somehow they’re inferior. But we have data…that refute that supposition.

When is it best to initiate immunotherapy following radiation in a patient such as this?

I think 6 months is beyond the window of opportunity. I’ve done it at 2 months. I have to say that’s outside of the window of PACIFIC [NCT02125461]. It should be noted the Hoosier Oncology Group trial, which used pembrolizumab in the same setting, did extend the interval. They didn’t mandate a 2- to 6-week window, and they did go up to 8 weeks.

Which data support durvalumab in a patient with a partial response (PR) to cisplatin/pemetrexed and cCRT?

The PACIFIC trial was started before we had much data for durvalumab [Imfinzi] in stage IV recurrent disease. Randomization was 2:1, durvalumab versus placebo, for up to a year, every 2 weeks, [with randomization occurring] up to 6 weeks after cCRT. To be enrolled, patients had to have performance status 0 or 1. If patients’ status was 2 or 3 they weren’t eligible. Many patients are 1.5 or 2 and I’m sure some sneaked on, but by definition patients should have had a decent performance status. We don’t know the extent of their tumors or their PET status prechemoradiation. Those data were not tracked. Primary end points were overall survival [OS] and progression-free survival [PFS], and the key secondary end points [were overall response rate, duration of response, safety and tolerability, and patientreported outcomes].³

The PFS curves were unprecedented. The hazard ratio was 0.51 [95% CI, 0.41-0.63]; [the durvalumab arm PFS of 17.2 months was] essentially triple the PFS of the placebo arm of 5.6 months and far better than we’ve seen historically. The benefit was persistent over time, which was reported in the supplement to Scott Antonia’s first paper.⁴ Updates have shown that this benefit persists. There was a plateau at 2 to 3 years in the durvalumab arm. There was a plateau, as well, in the placebo arm, but far lower than for durvalumab. There was about a 23%\ [difference in] improvement in 18- to 24-month PFS [between the 2 arms].⁴

PFS benefits were seen across the board. They were independent of histology, although a bit more pronounced in the nonsquamous group. The HR [in the nonsquamous group] was 0.45 [95% CI, 0.33-0.59] versus 0.68 [95% CI, 0.50-0.92] for the squamous group. [PFS benefit was independent of] age group, gender, smoking status, and stage IIIA or IIIB. Even the PD-L1 less than 25% and PD-L1 unknown subgroups had a PFS benefit [HR, 0.59; 95% CI, 0.43-0.82 and HR, 0.59; 95% CI, 0.42-0.83, respectively]. Only 43 patients [across both arms] had EGFRmutant tumors, about 5% of all enrollees. The corresponding confidence interval was wide but overlapping unity [HR, 0.76; 95% CI, 0.35-1.64].³

In the subgroup analysis of about a quarter of all those enrolled who were able to complete radiation and be randomized within 14 days, the HR was relatively superior, 0.39 [95% CI, 0.26-0.58], compared with 0.63 [95% CI, 0.49-0.80] for those who were randomized between 14 and 42 days, which is the more typical HR. Patients in the first category probably had lower volume tumors, fewer complications, no overt [adverse] effects, and were ready and motivated to go. There may have been other variables that conspired to result in this superior PFS benefit… but these results have been used to argue for more rapid institution of durvalumab.⁵

The updated survival benefit was presented by Jhanelle Gray, MD, last year at ASCO [American Society of Clinical Society].⁶ I don’t think there’s a more recent curve, but I was a skeptic until the OS results came out. Once they came out, I embraced this approach wholeheartedly. There was [nearly] a 14% [difference in] improvement [between the 2 arms] at 3 years…and, again, a plateau in the OS curves. The median OS in [the durvalumab arm]—patients who completed cCRT without progression and went on to durvalumab—had not been reached. More than 50% of patients in that arm were alive at 3 years. The placebo group, compared to historic controls, was doing fairly well, with OS of about 43%, which was inferior to durvalumab. The durvalumab arm benefit was not just a statistically significant but [also] a clinically meaningful improvement.⁶

For patients who had PD-L1 less than 1% in the post hoc analysis, the HR at the time of the second paper was 1.36 [95% CI, 0.79-2.34]. In the other PD-L1 groups, there was a survival benefit [greater than or equal to 1% (HR, 0.53; 95% CI, 0.36-0.77); less than 25% (HR, 0.92; 95% CI, 0.63-1.34); greater than or equal to 25% (HR, 0.46; 95% CI, 0.27-0.78)]. For patients with EGFR-mutant tumors, so few events occurred [durvalumab, 10 events in 29 patients; placebo, 6 events in 14 patients] that there were no survival data for the 5% or so of patients with EGFR-mutant tumors on durvalumab.⁴

Less than 60% of patients enrolled had adequate tissue for PD-L1 assessment. Only about 20% of patients enrolled had a PD-L1 status of 0.4 An update on survival at 3 years [showed] the HR had dropped from 1.36 [95% CI, 0.79-2.34] to 1.14 [95% CI, 0.71-1.84] and the confidence intervals were clearly overlapping unity.⁵ The EU [European Union] has taken this seriously. In an effort to limit cost, their approval for durvalumab is restricted to patients with tumors that are PD-L1 positive, 1% or higher.⁷ In the US, the approval is a blanket approval, independent of PD-L1 status.⁸

Should durvalumab be started in a patient with PD-L1 less than 1% or patients with known EGFR tumor mutations?

There may be priming by radiation that can actually induce PD-L1. PD-L1 status was tested for on the original diagnostic specimen; it was not tested postchemoradiation…so we don’t know the [PD-L1 tumor status of patients] at the time durvalumab was started in PACIFIC.

In the dark ages, it was radiation alone and, until 2017, it was just cCRT. Every attempt to improve upon that with rituximab [Rituxan], with expanding the dose of radiation to 74 Gy, with empiric use of TKIs [tyrosine kinase inhibitors] independent of EGFR status, all of those—or more chemo, 3 cycles of docetaxel— all those studies were consistently negative. There wasn’t a hint of PFS or OS benefit.

We know a lot in metastatic disease…but we don’t have a lot of data for this scenario for people who received cCRT in stage III and then went on to a TKI. How can the dose of durvalumab be adjusted for those who are concerned about reducing potential exposure to coronavirus disease 2019 (COVID-19)?

Standard dosing is every 2 weeks; that’s the FDA approval. However, the current PACIFIC trials are looking at dosing every 4 weeks. I think many are moving to [this] regimen. It’s not the standard, but in light of COVID-19 it can make sense.

What are some of the relevant safety data from PACIFIC?

In PACIFIC, any-grade pneumonitis occurred in about a third of patients [in the durvalumab arm] compared with a quarter of patients in the placebo group; rates of grade 3 and 4 [pneumonitis] were low…3.4% [for the durvalumab arm] versus 2.6% [for the placebo arm]. There was no major difference in grade 5 [pneumonitis, 1.1% for durvalumab vs 1.7% for placebo]. The discontinuation rates were a bit higher for the durvalumab group [15.4%] compared with the placebo group [9.8%]. Any-grade pneumonia, and this didn’t include just pneumonitis but infectious pneumonia, was double [the rate] in the durvalumab arm [13.1% compared with 3.8% in the placebo arm]. For immune-mediated adverse events [imAEs], there was a 3-fold difference, 24% versus 8% [for durvalumab vs placebo], but they were mostly grade 1 or 2. The grade 3 and 4 [imAE] rates were 3.4% [for durvalumab] vs 2.6% [for placebo].⁴

The NCCN Guidelines now include consolidated durvalumab: every 2 weeks for up to 12 months; it’s a category 1 designation.¹ category 1 designation.¹

The NCCN deleted its earlier recommendation for an additional 2 cycles of full-dose chemotherapy if patients have not received full-dose cCRT, based on concerns that the risk of pneumonitis will go up if they subsequently receive durvalumab.¹ This was not included in the PACIFIC study and, in that setting, durvalumab was substituting for and probably doing better than chemotherapy. I still give 2 cycles to patients who are not candidates for durvalumab, but if they’re going to get durvalumab, I do not give it.

Are there patients who should not receive durvalumab?

Patients with immune-mediated diseases, collagen and vascular diseases, inflammatory bowel disease, and organ recipients [are not good candidates for durvalumab]. I’ve given it to a patient who had renal transplant, figuring that if things got bad, they could go on dialysis. I have not been brave enough to give it to people who had heart or liver transplants. It really depends on the circumstances. In patients with preexisting ILD or poor PFTs, I usually hold off.

This patient received durvalumab after cycle 8. He developed fatigue, mild shortness of breath, and cough, but…no chest pain. He had no fever, no recent sick contacts, or flu. His vaccines were up-to-date, and his chest CT showed reticular nodular interstitial markings on both sides, but particularly the left.

How should immune-related pneumonitis be managed in patients on durvalumab?

Patients with grade 3 or 4 pneumonitis, I will not rechallenge. For patients with grade 1, I will. I start right off the bat with milligrams per kilogram if it’s severe enough to cause an interruption in therapy. Depending on how quickly they improve, I’ll taper accordingly. In some cases, I rechallenge with steroids on board. Many studies now will allow up to 10 mg of prednisone baseline, figuring that they may have needed this for COPD [chronic obstructive pulmonary disease] or other issues. If I do rechallenge, I don’t do it without at least some steroid. I’ll give the patient 5 or 10 mg. You really have to be very selective about the patient. If they develop pneumonitis on rechallenge, they’re done.

ASCO guidelines for management of immune-related pneumonitis state that…for grade 1, hold the [immune] checkpoint inhibitor [ICI]. Repeat scans in 3 to 4 weeks…and consider PFTs. If there’s radiographic evidence of improvement, you can rechallenge. Even in this group, I might give some steroids. Monitor these patients closely, with exams and pulse oximetry. For grade 2, the ASCO guidelines say to hold the ICI…and start prednisone, 1 to 2 mg/kg per day. I don’t do 2 mg/kg unless the patient is very sick, and if that’s the case, they’re usually in the hospital. There can be other conditions causing the pneumonitis…so consider bronchoscopy with BAL [bronchoalveolar lavage] and, if they’ve got fever, empiric antibiotics. If there’s no improvement after 2 to 3 days [on steroids], treat as grade 3.⁹

In this age of COVID[-19], the work-up would include a COVID-19 test, as well as sputum cultures, blood cultures if they’re febrile, and bronchoscopy if you have the suspicion that there’s some other agent involved.

Per the ASCO guidelines, with grade 3 or 4 pneumonitis, stop the ICI permanently. The patient doesn’t need oxygen if they’re that sick. Use a higher dose of steroids, and if steroids

aren’t working, there are some other options, including infliximab and mycophenolate. I’ve used both. I’ve also used IVIG [intravenous immunoglobulin] as the ASCO guidelines suggest. I’ve not used cyclophosphamide or cyclosporine. Taper steroids slowly over 4 to 6 to 8 weeks.⁹ Frequently, you have a devil of a time getting these patients below 10 to 20 mg. In this sort of situation, it’s absolutely essential there be multidisciplinary management. Pulmonologists are an integral part of the team. If these patients end up in the hospital, the infusion team are an integral part of the team. There are 4 players: medical oncologists, radiation oncologists, pulmonologists, and [the infusion team].

References:

1. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 6.2020. Accessed September 26, 2020. https://bit.ly/2EAH60w

2. Senan S, Brade A, Wang L-H, et al. PROCLAIM: randomized phase III trial of pemetrexed- cisplatin or etoposide-cisplatin plus thoracic radiation therapy followed by consolidation chemotherapy in locally advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2016;34(9):953-962. doi:10.1200/JCO.2015.64.8824

3. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: a double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. Ann Oncol. 2017;28(suppl 5):v634. doi:10.1093/annonc/mdx440.049

4. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi:10.1056/NEJMoa1809697

5. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

6. Grey JE, Villegas AE, Daniel DB, et al. Three-year overall survival update from the PACIFIC trial. J Clin Oncol. 2019;37(suppl 15):8526. doi:10.1200/JCO.2019.37.15_suppl.8526

7. Summary of product characteristics. European Medicines Agency. Accessed October 5, 2020. https://bit.ly/2SxKahO

8. Imfinzi. Prescribing information. AstraZeneca; 2017. Accessed October 5, 2020. https://bit.ly/3jANBAa

9. Brahmer JR, Lacchetti C, Schneider BJ, et al; National Comprehensive Cancer Network. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018;36(17):1714-1768. doi:10.1200/JCO.2017.77.6385