Husain Evaluates Real-World Evidence for Immunotherapy in Stage III NSCLC

Hatim Husain, MD

Associate Professor

Department of Medicine

UC San Diego School of Medicine

San Diego, CA

CASE SUMMARY

• A 63-year-old man presented to his primary care physician with intermittent cough and dyspnea on exertion.
• Medical history: hypothyroidism, managed on levothyroxine; chronic obstructive pulmonary disease managed with inhalers
• Recently quit smoking; 40-pack-year history
• Physical examination: intermittent wheezing; otherwise negative
• ECOG performance status: 1
• Laboratory profile: complete blood count positive differential, serum chemistries, and creatinine: within normal limits
• Chest CT: 3.1-cm spiculated, left upper lobe mass; 2 enlarged left mediastinal lymph nodes (stations 4L and 7) measuring 2.5 cm and 1.7 cm; moderate emphysema
• PET scan: confirmed lung lesion and mediastinal lymphadenopathy without evidence of distant metastases
• Brain MRI: negative
• Pulmonary function tests: FEV1 1.2; DLCO 35%
• Bronchoscopy with transbronchial lung biopsy of left upper lobe mass and lymph node sampling via endobronchial ultrasound revealed adenocarcinoma at primary site with positive nodes in stations 4L and 7.
• Staging: T2aN2M0, stage IIIA
• Molecular testing: negative for actionable driver mutations
• PD-L1 expression level less than 1%

Targeted Oncology: How was the PACIFIC trial (NCT02125461) designed to evaluate the use of durvalumab (Imfinzi) in patients with unresectable stage III non– small cell lung cancer?

HUSAIN: This was a phase 3 randomized, double-blind, placebo-controlled international study. The staging was based on the American Joint Committee on Cancer [staging system], seventh edition. Patients were included if they had not progressed after definitive platinum-based concurrent chemoradiation, and they had to have received 2 or more cycles of chemotherapy.

During that concurrent radiation, most importantly, archival tissue was collected and that’s how some of the analyses for EGFR and PD-L1 were assessed. Between 1 and 42 days post concurrent chemoradiation, patients were randomly assigned between durvalumab and placebo on a 2:1 basis. There was stratification by age, gender, and smoking history. Durvalumab was given every 2 weeks for up to 12 months, and the same with placebo. The coprimary end points were progression-free survival [PFS] by blinded independent review and overall survival [OS].

Some key secondary end points were overall response rate, duration of response, safety and tolerability, and patient-reported quality-of-life metrics. A key point is that the randomization happened within 42 days of the completion of chemoradiation. Circulating [soluble] factors and circulating DNA and plasma were also collected for further assessments. Brain MRIs were included with tumor assessments, if indicated.

What were the key efficacy outcomes of the trial?

Looking at updated overall survival in the intent-to-treat patient population, the median OS was 47.5 months [95% CI, 38.1-52.9] compared with placebo at 29.1 months [95% CI, 22.1-35.1].¹ One of the most dramatic figures is the tail of the [Kaplan-Meier] curve for patients at 5 years, where 43% of patients at 5 years were alive, compared with 33% on placebo, a 10% [numerical difference] in survival rate with the consolidation durvalumab.

In terms of PFS by blinded independent review at 5 years, 33% of patients were without progression compared with 19% with placebo, and the median PFS was [16.9] months [95% CI, 13.0-23.9] compared with 5.6 months [95% CI, 4.8-7.7] with placebo. There have been studies that have shown that the patients who completed [12 months of durvalumab] are doing better than those who don’t complete it. It seems almost intuitive, but there are data around that point as well.

There were some subgroup analyses, and…specifically, how did the patients who had stable disease at the finish of the concurrent chemoradiation do? Their [unstratified] HR was 0.7 favoring the durvalumab treatment compared with placebo [95% CI, 0.53-0.92]. Patients with stable disease were doing as well as patients with partial response [HR, 0.71; 95% CI, 0.52-0.96]. If we look at the EGFR-[mutated] category, this is a cohort where the confidence interval crosses 1.

It is an area where there’s been a lot of scrutiny, and thinking about the EGFR-mutant patients, they appear to be doing less well than the EGFR-negative patients [HR of 0.85 favoring durvalumab in the EGFR-positive group vs HR of 0.66 in the EGFR-negative group]. There were some analyses, both from the initial analysis as well as post hoc analyses, where if one looks at PD-L1 expression less than 25% vs greater than or equal to 25%, patients are getting benefit with durvalumab, and more benefit in patients with greater than 25% PD-L1 expression. If we look at the PD-L1 expression less than 1%, those patients seem to be doing less well with durvalumab, and in fact better with placebo in this post hoc analysis.

What adverse events (AEs) are of most concern when treating these patients with durvalumab based on this trial?

The rate of grade 3 and 4 pneumonitis was pretty comparable in the placebo and the durvalumab groups [2.6% vs 3.4%, respectively].² I thought that was interesting and reassuring in a way. The rate of any-grade pneumonitis was higher with the durvalumab [33.9% with durvalumab vs 24.8% with placebo]. But the rate of any-grade 3 and 4 AEs leading to discontinuation was comparable across [the arms]; it comes out to approximately 15% with durvalumab vs 10% with placebo. Grade 3 or 4 immune-mediated AEs occurred in approximately 3% with durvalumab and 2.6% with the placebo.

What real-world evidence informs the use of durvalumab in this disease setting?

On the heels of the phase 3 PACIFIC study, there has also been a study that many people have not seen. This is known as the PACIFIC-R study [NCT03798535], which is a real-world evidence observational study of durvalumab after chemotherapy and radiation. It had a similar design, but this was looking at real-world observational data to see how patients in real practice in the US and across the world function with durvalumab. There were approximately 1400 patients included in the final analysis. Most of the patients were from the US, but there were some non-US participating countries as well.

The primary end point was investigator-assessed PFS and OS, similar to the end points in the PACIFIC trial, but these were investigator assessed. The real-world median PFS was 21.7 months, actually higher than in PACIFIC, and the 2-year real-world PFS was 48%.³ The median OS rate at 2 years was 70%. We’re seeing data that at least supports in real-world practice that the survival benefit appears to be consistent. There was an effort to look at sequential [chemotherapy and radiation, since] some patients can’t get concurrent chemotherapy and radiation. Those patients had a real-world median PFS of 19.3 months, compared with 23.7 months with concurrent [chemoradiation], so it was a bit better with concurrent than sequential.

Another key point was that one-third of patients started the durvalumab within 1 to 42 days after the completion of radiation. Most patients are getting it but may fall out of that [time span]. How do we prioritize earlier intervention of durvalumab under these circumstances?

What other findings stood out in PACIFIC-R compared with PACIFIC?

There were fewer patients with stage IIIA, meaning more with stage IIIB or IIIC [disease], in the PACIFIC-R real-world data. The Kaplan-Meier curve for the PFS in the full data analysis showed [a median of] 21.7 months. If we look at PD-L1 negative vs positive, we see a difference where median PFS for PD-L1 positive was 22.4 months, compared with 15.6 months for PD-L1 negative. That distinction across PD-L1 [level] was maintained in this real-world analysis. There were patients [93 of 1399 total] who had inconsistent or indeterminant PD-L1 [with a median PFS of 25.2 months].

[Looking at efficacy] by histology, patients with squamous histology are underperforming, with [median PFS of] 14.6 months compared with 25.3 months [with nonsquamous histology]. Then if we look at the concurrent vs sequential, sequential was 19.3 months vs 23.7 months. In terms of EGFR mutations, EGFR-positive patients are underperforming compared with the KRAS-positive patients, or those with any other alteration [Table³]. They looked at rates of toxicity as well, and looked specifically at pneumonitis. The rate of pneumonitis requiring treatment interruption was 5%, and permanent discontinuation [was needed] in approximately 9%. Diarrhea or colitis led to temporary interruption in 1.1% and permanent discontinuation in 1.1%. Endocrinopathies were in that range, as well.

What guidance is there for managing immune-related adverse events in patients treated with immune checkpoint inhibitors?

There are efforts to consolidate this information into the American Society of Clinical Oncology guidelines.⁴ For grade 1, one would hold the checkpoint inhibitor, proceed with close monitoring, and may resume the checkpoint inhibitor if there’s improvement. For grade 2, [one would hold until there is] improvement to grade 1, and then a long course of steroids with a taper, and consider bronchoscopy if needed. For grade 3 and 4, [one would] permanently discontinue the medicine and may consider some other immunosuppressive depending on how severe it is, and taper the steroids over a long course as well.

_REFERENCES

_{1. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308}

_{2. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/ NEJMoa1709937}

_{3. Girard N, Bar J, Garrido P, et al. Treatment characteristics and real-world progression-free survival in patients with unresectable stage III NSCLC who received durvalumab after chemoradiotherapy: findings from the PACIFIC-R study. J Thorac Oncol. 2023;18(2):181-193. doi:10.1016/j.jtho.2022.10.003}

_{4. Schneider BJ, Naidoo J, Santomasso BD, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021;39(36):4073-4126. doi:10.1200/JCO.21.01440}