Immunotherapy and Targeted Therapies Continue to Improve Patient Outcomes in Lung Cancer

Devika Das, MD, MSHQS

Updated data from key trials in non–small cell lung cancer continue to demonstrate the superiority of immunotherapy and targeted therapy regimens for NSCLC treatment, but the optimal use of these agents in the adjuvant vs neoadjuvant settings is still contested. Meanwhile, the need for effective alternatives to lurbinectedin (Zepzelca) persists in the second-line setting for small cell lung cancer (SCLC), according to faculty from an OncLive^® Institutional Perspectives in Cancer (IPC) webinar on lung cancer.

The event was chaired by Devika Das, MD, MSHQS, clinical assistant professor of hematology and oncology at University of Alabama at Birmingham (UAB) Medicine. Presentations highlighted treatment updates across lung cancer subtypes, including key trials supporting the use of immunotherapies such as cemiplimab-rwlc (Libtayo) in NSCLC, the role of EGFR-targeted approaches like osimertinib (Tagrisso) in this space, and the debate over neoadjuvant vs adjuvant therapies in early-stage lung cancer. The management of SCLC in the first and second line was also discussed.

Das was joined by her colleagues:

• Maya Khalil, MD, assistant professor, O’Neal Comprehensive Cancer Center, UAB Medicine;
• Jason Porter, MD, director, Lung Cancer Disease Research, West Cancer Center & Research Institute in Germantown, Tennessee;
• Brian Mitzman, MD, assistant professor, Thoracic Surgery, Huntsman Cancer Institute, University of Utah Health in Salt Lake City; and
• Rami Manochakian, MD, associate professor of medicine, Mayo Clinic in Jacksonville, Florida.

Below, Khalil, Porter, Mitzman, Manochakian and Das summarize the main messages from their presentations.

Clinical Trial Updates Demonstrate the Efficacy of Cemiplimab With or Without Chemotherapy in NSCLC

Khalil: Immunotherapy has revolutionized the treatment of [patients with] advanced NSCLC. We now see longer durations of response and survival in patients, [sometimes by] years. Several trials [in this space] have reported significant updates in the past year, [including] the phase 3 EMPOWER-Lung 1 [NCT03088540] and EMPOWER-Lung 3 [NCT03409614] trials.

EMPOWER-Lung 1 looked at patients with treatment-naïve, advanced NSCLC with 50% or higher PD-L1 expression. Patients were randomized to 4 to 6 cycles of the investigator’s choice of chemotherapy vs cemiplimab monotherapy every 3 weeks until disease progression. The primary end points of the study were overall survival [OS] and progression-free survival [PFS]. At 3-year follow-up, cemiplimab did produce significantly longer PFS compared with chemotherapy alone in patients with high PD-L1 expression, with a hazard ratio of 0.5. The median PFS was about 8.1 vs 5.3 months in cemiplimab and chemotherapy arms, [respectively]. OS was significantly improved with cemiplimab vs chemotherapy alone in the high PD-L1 expression cohort, with a hazard ratio of 0.57. [This indicates that] cemiplimab is another option for our patients with high PD-L1 expression.

EMPOWER-Lung 3 [evaluated] patients with advanced NSCLC that were treatment-naive, including both nonsquamous and squamous histologies. Patients were randomized 2:1 to cemiplimab vs placebo every 3 weeks in addition to 4 cycles of platinum doublet chemotherapy. The primary end point of OS was significantly improved in patients who received chemotherapy and cemiplimab vs chemotherapy and placebo, with a hazard ratio of 0.7. The median OS was 22 months in patients receiving chemotherapy and cemiplimab, as opposed to 13 months [with] chemotherapy and placebo. PFS was also significantly longer in the treatment vs placebo arm.

[One] thing to highlight here is that the improvement in OS decreased as PD-L1 expression decreased. However, patients who had squamous histology benefited meaningfully and significantly [from cemiplimab]. There were no major safety [signals with the combination].

[This trial shows that] cemiplimab is another [viable] treatment option [in this space], particularly for patients who have squamous histology. Although it was a subgroup analysis, this is a signal that we ought to investigate further.

Updated Data Support Osimertinib as the Standard of Care for EGFR-mutated NSCLC

Porter: In summary, osimertinib remains a standard of care in metastatic, EGFR-mutant NSCLC. Biopsy and sequencing are essential to elucidate the mechanism of resistance for our patients [in this space.]

[Additionally], adjuvant osimertinib has [shown both] improved progression-free survival [PFS] and intracranial PFS. Maturation of this data is ongoing, and [we hope it will] confirm the overall survival benefit.* [Given] the strong hazard ratios that we see [with this therapy], I believe that [this outcome] is almost certain.

[Lastly], exon 20 insertion mutation–positive NSCLC portends a poorer prognosis. [However], we now have FDA approval for amivantamab-vmjw [Rybrevant] and mobocertinib [Exkivity]. Newer generation exon 20 insertion–specific drugs [are also] coming along, and will hopefully minimize off-target effects [which will] allow us to keep patients on therapy.

The Advantages and Disadvantages of Neoadjuvant Immunotherapy in NSCLC From a Surgical Perspective

Mitzman: On the pro side, [neoadjuvant therapy was] well tolerated [and showed] higher compliance and completion rates [in the phase 3 CheckMate 816 trial (NCT02998528)]. Neoadjuvant treatment [also] allows us to assess the responsiveness of systemic therapy prior to surgery. If someone progresses through systemic therapy, we know that surgery is probably not the right answer for them.

We could [also] potentially improve resectability [with this approach], [leading to less invasive] resections. Before we started the webinar, the panel was [discussing whether] we should be looking to [operate on] patients [who were previously deemed] inoperable, but this has not been studied yet. As a multidisciplinary team, there are some cases where we offer surgery to patients who have an amazing response [to neoadjuvant therapy], but this should [not be standard practice].

The cons to neoadjuvant [therapy include the fact that] you don’t know the true risk factors [associated with] earlier stage tumors until they’re [removed]. Will [patients] really need adjuvant therapy, and are you just [administering] it based on size? Or do they truly have lymphovascular invasion, visceral pleural invasion, satellite lesions, or metastatic disease? [Moreover], if a patient has an adverse reaction to neoadjuvant therapy, that may preclude resection. Though, that was low [in CheckMate-816]. [You could also] miss the window to operate if they progress.

Finally, there’s been [concern] about the development of pulmonary hilar fibrosis from neoadjuvant immunotherapy or targeted therapies, which make surgery harder. A handful of studies [have investigated this issue, including] a [phase 2] trial [NCT02259621] by Matthew J. Bott, MD, of Memorial Sloan Kettering Cancer Center in New York, New York. [In this study], they looked at 20 patients who got resection after neoadjuvant nivolumab [Opdivo] and found that their operative results were similar to historical lobectomy results.

In CheckMate-816, they found [that] the median duration of surgery was shorter, the use of minimally invasive approaches was more common, and pneumonectomy was less common in the experimental arm.

The Optimal Use of Neoadjuvant vs Adjuvant Therapy in NSCLC Continues to Spark Debate

Manochakian: [Although] I presented data on adjuvant [therapy], and Dr Mitzman presented data on neoadjuvant [therapy], we do not [necessarily ascribe to either camp].

[There is a lot of debate regarding whether] we should use neoadjuvant vs adjuvant immunotherapy [in NSCLC]. My take [on this issue] is that we need to review all the data and discuss it with patients. Some patients may fit [the appropriate] criteria [for these therapies], and [others] may not. As it stands, the data on neoadjuvant [therapy] is impressive. It clearly [shows] that pathological response can be [achieved] by exposing the patient only to certain neoadjuvant treatments after surgery.

There is [also some] debate [regarding whether] the patient [should be] exposed to adjuvant therapy for a whole year.

When I think of patient care, [the goal is to achieve] good outcomes and expose my patient to less treatment. Having said that, many patients cannot [receive] neoadjuvant therapy for different reasons. [Yet] certain patients with higher PD-L1 status now have contraindications for adjuvant treatment.

We’re waiting on more updated analysis. There are [also] trials looking into a comparison of [neoadjuvant vs adjuvant therapies], and we will hopefully know more in a couple of years.

Further Research Is Needed to Expand Second-line Therapeutic Options for SCLC

Das: Unfortunately, a lot of patients have disease recurrence or relapse after we treat them for extensive-stage SCLC. The options at that point, unfortunately, are very limited, and the answer [to this problem] is clinical trials. For several years, our [best] second-line option in relapsed, extensive-stage SCLC was topotecan. The best response rate seen [with topotecan] in several clinical trials was very [low], at 24%. The median duration of response [DOR] is about 18 weeks, which is [comparable to lurbinectedin] and OS is about 8.5 months. [However], very high levels of grade 3 and higher treatment-related toxicities were seen [with] a 5-day regimen [of topotecan] in these trials. Patients are just not able to tolerate it.

The biggest advance [for second-line SCLC] in recent years [was] the approval of lurbinectedin. This approval was really based on the phase 2 [PM1183-B-005-14] trial [NCT02454972]. The overall response rate [with lurbinectedin in this trial] was 35%, median PFS was 3.5 months, and median OS is 9.3 months. It is better tolerated than topotecan. About 10% of patients have grade 3 and higher toxicities, and several patients have grade 1 and 2 toxicities. [Toxicity is] a big factor in terms of quality of life, and [influences] how we pick treatments for these patients in the second-line setting.

In terms of toxicity and tolerability, lurbinectedin is the best available option in the second line if your patient cannot tolerate topotecan. This is [partially] because no other regimens [in this space have] been studied [enough]. We need enrollment into clinical trials in small cell lung cancer [to achieve the same] advances we’ve made in the NSCLC space.

Editor’s Note:

Dr. Khalil reports serving as a principal investigator on trials in collaboration with/sponsored by: National Cancer Institute, Bristol Myers Squibb, Amgen, Top Alliance, Janssen, Cantargia, Guardant Health, Numab, Nitto BioPharma, Spectrum Pharmaceuticals, Eastern Cooperative Oncology Group (ECOG), Southwest Oncology Group (SWOG), Alliance cooperative group.

Disclosure information was not found/submitted for Drs. Porter, Mitzman, Manochakian and Das.

*This meeting took place prior to the announcement that osimertinib produced a statistically significant and clinically meaningful improvement in OS compared with placebo as adjuvant treatment for patients with stage IB, II, or IIIA, EGFR-mutated NSCLC after complete tumor resection with curative intent, according to updated results from the phase 3 ADAURA trial (NCT02511106).