Locally Advanced NSCLC: Looking Ahead

Howard (Jack) West, MD:The huge benefit seen with durvalumab on the PACIFIC trial in a curative setting has raised the obvious question of whether we can deliver similar benefits and potentially achieve more cures in earlier-stage patients or those with operable disease, whether that is prior to surgery as a potential neoadjuvant therapy with chemotherapy, as a few treatments of immunotherapy alone before surgery, or as therapy in the adjuvant setting. There are several trials looking into this. I think this is extremely exciting. It’s an obvious extension of the benefits we’ve seen in stage 4 and now in stage 3 locally advanced but unresectable disease. We will need to see much more of this.

We do have a publication in theNew England Journal of Medicineby Patrick Forde and colleagues that looked at neoadjuvant nivolumab, but that was in fewer than 2 dozen patients. It showed at least a proof of principle with a good response seen. Major pathologic responses were seen in 45% of their patients after just 2 treatments with nivolumab before starting surgery, and then they could go on to whatever treatment after, including chemotherapy if appropriate. This is going to be very well studied. In fact, it’s being studied right now in many trials that we will see the results of in the coming months and years. I think it’s actually quite likely that in the next 3 to 5 years, we will integrate immunotherapies into preoperative or postoperative therapy. But right now, I would say that it remains an investigational option and still the subject of clinical trials and careful discussion with patients. Where it’s best studied is in unresectable stage 3 along with stage 4 disease.

It’s been very gratifying to finally, for the first time in my career that goes back a couple of decades now as a thoracic oncology specialist, be able to offer a meaningful benefit beyond what we’ve been doing since I started, which was concurrent chemotherapy and radiation. We’ve tried adding more chemotherapy on the back end as consolidation, escalating the radiation, or adding targeted therapies in stage 3 unresectable disease. All of these have led to no benefit, or harm, to the patients. I think some of us were becoming resigned that this is just such a hard nut to crack.

Seeing immunotherapy lead to meaningful benefits in an incurable population with stage 4 disease has been gratifying, but it’s especially gratifying to see it move into these very difficult areas to treat. Stage 3 unresectable disease is an extremely common scenario. It’s about a third of our patients, and we’ve just had such trouble breaking that impasse. Having immunotherapy in general and durvalumab specifically to deliver not just a statistically significant benefit but also a striking clinically significant benefit that we are eager to adopt, and is now FDA approved, is extremely welcome, both for what we can offer to our patients now and for the promise of what we think is likely to be available in the future. This is just the beginning. I think it’s an immensely great start after banging our heads against the wall for so long, but it’s especially great as an omen for the future of integrating immunotherapies into earlier lines and potentially translating the benefits we’ve seen into more patients being cured of non—small cell lung cancer.

Transcript edited for clarity.

A 60-year-old Asian Woman With Unresectable, Locally Advanced NSCLC

• A 60-year-old Asian woman presents with complaints of chest pain and shortness of breath. She reports developing a persistent cough about 1 year ago, which she attributed to allergies. In the past month, she has “spit up” blood several times, which caused her to make the appointment.
• Her history includes:
  • Former smoker, quit smoking at age 35 when she became pregnant
  • Normal BMI, postmenopausal, no history of cardiovascular disease
  • No previous cancer history
• Evaluation and follow up testing reveal
  • Stage IIIA NSCLC in right bronchi: 3.5-cm tumor with pleural involvement and spread to mediastinal lymph nodes
  • WHO performance status 1
  • Histology: Squamous cell
  • Biomarkers:
    • EGFR,BRAF,ALK/ROS1negative
    • PD-L1 status: 10%
• After multidisciplinary evaluation, the patient was determined not to be a candidate for surgery, and completed chemoradiotherapy:
  • Carboplatin/paclitaxel doublet plus 55 Gy radiotherapy
  • Achieved stable disease without progression 14 days after completing treatment
  • Began treatment with durvalumab