Arnaoutakis Makes a Case for Immunotherapy Following Concurrent Chemoradiotherapy in Stage III NSCLC

Konstantinos Arnaoutakis, MD

During a Targeted Oncology Case Based Peer Perspectives event, Konstantinos Arnaoutakis, MD, hematologist/oncologist, Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences (UAMS) and associate professor, Department of Internal Medicine, Division of Hematology and Oncology, UAMS Health, discussed the case of a 63-year-old patient with non–small cell lung cancer (NSCLC).

Targeted Oncology™: Which concurrent chemotherapy regimens could be considered for use in this patient with stage III disease?

ARNAOUTAKIS: These are the NCCN [National Comprehensive Cancer Network] guidelines, the most recent version [TABLE].1 There are regimens with cisplatin etoposide—that’s the SWOG protocol—then the weekly carboplatin/paclitaxel with the additional 2 cycles of consolidation. For [patients with] nonsquamous cell carcinoma, there is carboplatin/pemetrexed [Alimta] or cisplatin/pemetrexed, since these regimens have been used in some of the studies that evaluated the efficacy of chemoradiation.

Are there clinical trial data supporting the use of therapy after this phase of treatment?

The PACIFIC study [NCT02125461] was a phase 3 trial. Patients had a performance status of 0 or 1. They had unresectable [disease], and they have not progressed after 2 cycles of a platinum-based chemotherapy. The randomization happened up to 42 days after completion of chemoradiation. The first arm was the durvalumab [Imfinzi] arm, with 10 mg/kg of the agent administered every 2 weeks for up to 12 months. The other group was the placebo group. The primary end point was progression-free survival [PFS] per blinded independent central review and overall survival [OS]. Response rates, duration of response, safety, and patient-reported outcomes were secondary end points.

Was there a benefit to therapy for patients with less than 1% PD-L1 expression?

There was this post hoc analysis; it wasn’t planned. They looked into the PD-L1 less than 1% and more than 1% subgroups. They also looked at patients with between 1% and 24% expression. Those were done after the study was completed. The less than 1% group did not seem to benefit, which was not totally unexpected [HR, 1.36; 95% CI, 0.79-2.34], and that was not statistically significant.

Are you using durvalumab regardless of PD-L1 expression, or are you checking PD-L1 and deciding what to do after that?

Retesting PD-L1 after chemoradiation can be tricky. Regardless of PD-L1, there is a need to treat people who are candidates with durvalumab. But this is hypothesis generating.

What is the effect of durvalumab on new metastatic lesions?

If you look at the different groups, there were no major surprises in terms of the incidence of new lesions. In the group that got durvalumab, there were fewer brain [6.3% vs 11.8%] and liver [1.9% vs 3.4%] metastases.²

What do the safety data say about the use of immunotherapy in this setting?

In terms of the safety in the PACIFIC trial, the grade 3/4 toxicity rate was similar in both groups [29.9% with durvalumab vs 26.1% with placebo]. There was a higher incidence of immune-mediated adverse effects [imAEs] in the durvalumab arm [24.2% vs 8.1%], but the grade 3/4 imAE rate was similar.

The [all-grade] pneumonitis rate was 33.9% versus 24.8% [for durvalumab and placebo, respectively], but the grade 3/4 rate was similar at 3.4% versus 2.6%. One of the things that I think a lot of people were concerned with before they started using durvalumab is how much they’re going to contribute to a new incidence of pneumonitis in some of these patients who had completed chemoradiation. There was a higher incidence of pneumonias, 13.1% versus 7.7%. But the grade 3/4 toxicity rate was similar between the 2 groups [4.4% vs 3.8%].³

Have the NCCN guidelines been updated to reflect the PACIFIC data?

They have incorporated durvalumab as the standard of care in those patients [with unresectable stage III non–small cell lung cancer with a performance score of 0 or 1 and no progressive disease after 2 or more cycles of definitive chemotherapy/RT] every 2 weeks for up to 12 months.¹

There is a footnote that was added that said if you’re using durvalumab, an additional 2 cycles of chemotherapy are not recommended if patients have not received full-dose chemotherapy concurrently with radiation. There were some concerns that consolidation chemotherapy could increase the risk of pneumonitis if patients are also receiving durvalumab.

So personally, after completing weekly carboplatin/paclitaxel, I do not do the 2 additional cycles of chemotherapy like I used to.

What are your impressions of the patient's case at this point?

This was done before COVID-19 [coronavirus disease 2019]. But the CT scan was ordered. It was about 16 weeks after chemoradiation to assess the patient’s symptoms. There were some patchy infiltrates in the left lung.

What is your approach toward pneumonitis diagnosis and management for patients receiving single-agent checkpoint inhibitors?

There are some guidelines, and there’s some clinical judgment in regard to the management of patients who develop pneumonitis after a checkpoint inhibitor. In particular, addressing how do you treat and how do you taper steroids.

Guidelines that were published in the Journal of Clinical Oncology a few years ago [indicate that steroids be administered at] 1 to 2 mg/kg per day, tapering over 4 to 6 weeks, considering bronchoscopy and bronchoalveolar lavage.⁵

The guidelines [also] recommend permanently discontinuing therapy for grade 3 [pneumonitis]. For grade 2, some people will rechallenge.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 6.2020. Accessed August 24, 2020. https://bit.ly/30NKRrb}

_{2. 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}

_{3. 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}

_{4. Gray 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}

_{5. Brahmer JR, Lacchetti C, Schneider BJ, et al; in collaboration with the 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}