Naidoo Analyzes the PACIFIC Regimen for NSCLC

Jarushka Naidoo, MBBCh

During a Targeted Oncology Case Based Peer Perspective event, Jarushka Naidoo, MBBCh, an assistant professor of Oncology for Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, MD, discussed a case of a 63-year-old patients with non–small cell lung cancer (NSCLC).

Targeted Oncology™: Which treatment options are available for this patient?

NAIDOO: I’m a big fan of platinum [therapy with] pemetrexed [Alimta]. I’ve found this to be a tolerable regimen, and certainly something that I go with.

The different chemotherapy regimens [include] the classic SWOG [Cancer Research Network] regimens, so it’s etoposide, carboplatin/pemetrexed, cisplatin/pemetrexed—the newer regimens for adenocarcinoma or nonsquamous disease—and then weekly carboplatin/paclitaxel, or even carboplatin/paclitaxel every 3 weeks. All options are included in the NCCN [National Comprehensive Cancer Network] guidelines.¹

Can you discuss some of the important trials in this setting?

The PACIFIC study [NCT02125461] was a phase 3 randomized study where patients who had stage III unresectable disease and a life expectancy of greater than 12 weeks were randomized within 42 days of chemoradiation to durvalumab [Imfinzi] monotherapy every 2 weeks for a year versus placebo. The study had coprimary end points of progression-free survival [PFS] and overall survival [OS].²

The paper published by Scott Antonia, MD, [and colleagues] in September 2018…demonstrated a median PFS benefit with a hazard ratio of 0.51 that was statistically significant [17.2 months with durvalumab vs 5.6 with placebo].

The subgroup analysis demonstrated that the benefit was across the board for most of the parameters. Some of the areas that are of interest [are] PD-L1 status and EGFR status. The patients who had high PD-L1 using the AstraZeneca monoclonal antibody and a cutoff of 25% appeared to do better, whereas those who were lower with PD-L1 crossed the threshold of 1.00, and it was [similar] for the patients with EGFR mutational status.

What do you think of the answers to this poll? How do these answers align with the PACIFIC study?

Most said 21 to 40 days—64% of respondents. And 0 to 20 days is also an option; 29% of respondents. That fits within the inclusion criteria for the PACIFIC trial and is the goal or the hope of when we would start these treatments. But sometimes patients may be delayed for various reasons. Chemotherapy and radiation is a tough treatment. Seven percent of folks said that beyond 41 days can sometimes occur.

[From time of] last radiation to randomization of less than 14 days [for patients in the trial, there was] an unstratified hazard ratio of 0.39 [95% CI, 0.26-0.58].³ Starting earlier appeared to be associated with doing better, although this is with the PFS end point. [For patients with] last radiation greater than 14 days, the hazard ratio was still good, at 0.63 [95% CI, 0.49-0.80].

How have the updated results for this trial shown benefit for patients?

The updated results that were presented in 2019 [showed] the 36-month OS rate for durvalumab at 57% versus 43% with placebo.⁴ So [there was] a clear benefit for the durvalumab arm in this study in terms of OS.

The overall survival data by subgroup [showed] patients had PD-L1–negative disease and had an unstratified hazard ratio of 1.36 [95% CI, 0.79-2.34].2 This is something that is being looked into in detail and has been a reason for potentially not giving it in this population in some jurisdictions.

There was a post hoc analysis, [which said] fewer than 60% of patients had adequate tissue for PD-L1.4 This is a caveat to some of these interpretations. At 3 years of follow-up, the hazard ratio has dropped to 1.14, and therefore, the role in this particular subset of patients is really unknown.

The PD-L1 was not a stratification factor in the PACIFIC trial, so there [was] not an even amount of patients in each PD-L1 subgroup. That was the reason for the post hoc analysis; this wasn’t a representative group.

What were the adverse events (AEs) seen in PACIFIC?

Durvalumab was well tolerated compared [with] placebo; 29.9% of patients had grade 3 or higher AEs versus 26.1% with placebo.³ Serious AEs [were seen in] 28.6% versus 22.6%, respectively. Grade 3/4 immune-related AEs [were seen in] 3.4% with durvalumab as opposed to 2.6% with placebo. Unsurprisingly, there was more pneumonitis in those patients treated with durvalumab, but there was not much of a difference when you look at the high-grade events—3.4% versus 2.6%. Importantly, the attribution to pneumonitis was not specifically separated. It was grouped together as either immune related or radiation related.

Grade 5 events were 1.1% versus 1.7%, and the rate of discontinuation of durvalumab based on AEs was low, at 6.3% versus 4.3%.

How do the guidelines recommend treating with durvalumab?

The NCCN guidelines show concurrent chemoradiation options, and [the guidelines] now include durvalumab as a new standard of care—as maintenance therapy after definitive chemoradiation. This is a category 1 recommendation.¹

Another important caveat is prior to the initiation of this new standard of care, it was also an option to receive 2 additional cycles of consolidation chemotherapy after definitive chemoradiation. However, this has subsequently been removed from the NCCN guidelines because of a potential increase in risk of pneumonitis. So consolidation chemotherapy is an option after concurrent chemoradiation for patients who are not receiving durvalumab because of medical contraindications or other reasons.

What is your approach toward the diagnosis of pneumonitis and its management in patients who receive a single-agent checkpoint inhibitor? Also, how are you tapering your corticosteroids for patients with pneumonitis?

A collaboration between ASCO [American Society of Clinical Oncology] and NCCN [went over] some of the basic principles.⁵ Grade 1 pneumonitis is radiographic only, and patients are asymptomatic. In these patients, one may hold immunotherapy and offer repeat CT in 3 to 4 weeks. Pulmonary function tests can be considered in patients in whom there is radiographic and/or clinical improvement. It will usually be radiographic, because these patients are asymptomatic. You may resume the checkpoint inhibitor. If there is no improvement, or the patient develops symptoms, then one would treat as grade 2.

Grade 2 patients are symptomatic. For those patients, you hold immunotherapy until complete resolution or reduction in severity to grade 1. The dose of prednisone is…based on weight, prednisone 1 to 2 mg/kg per day, usually tapered by 5 to 10 mg per week over 4 to 6 weeks.

In some patients, we may offer bronchoscopy. This is to discern between infection or progression and pneumonitis. We may consider empiric antibiotics. If patients do not improve after 48 to 72 hours of corticosteroids, then we would escalate and treat as grade 3.

Grade 3 or greater is defined as severe pneumonitis requiring hospitalization, and grade 4 requiring the intensive care unit. These patients need to discontinue the checkpoint inhibitor. They may get a higher dose of steroids at methylprednisolone 1 to 2 mg/kg intravenously. If they do not improve after 48 hours, options for immunosuppressive therapy include infliximab [Remicade], mycophenolate [Myfortic], or intravenous immunoglobulin. We have had good experience with intravenous immunoglobulin. These patients can taper their corticosteroids over 4 to 6 weeks. Bronchoscopy, pulmonary, and intravenous input are all valued.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Non–small cell lung cancer, version 6.2020. Accessed September 8, 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}