Frontline Therapy Advances Are Current Focus in SCLC and NSCLC

Matthew Gubens, MD, MS

Lung cancer management methods are rapidly evolving to encompass immunotherapy in the frontline setting and approved second-line options with tyrosine kinase inhibitors (TKIs) and monoclonal antibodies in non–small cell lung cancer (NSCLC), as well as treatment advances in first- and second-line small cell lung cancer (SCLC), according to faculty from an OncLive^® Institutional Perspectives in Cancer webinar on lung cancer.

The event, chaired by Matthew Gubens, MD, MS, thoracic oncologist, University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, associate clinical professor of medicine, Division of Hematology/Oncology, Department of Medicine, UCSF, focused on the benefits of neoadjuvant and frontline immunotherapy in NSCLC, promising treatments for patients with EGFR exon 20 insertion–positive disease, active second-line drugs with first-line potential, and therapeutic updates within SCLC.

Gubens was joined by his colleagues:

• Johannes Kratz, MD, thoracic surgeon, assistant professor in residence, cardiothoracic surgery, UCSF Helen Diller Family Comprehensive Cancer Center
• Collin Blakely, MD, PhD, assistant clinical professor, Division of Hematology/Oncology, Department of Medicine, UCSF Helen Diller Family Comprehensive Cancer Center
• Claire Mulvey, MD, thoracic medical oncologist, assistant professor of medicine, UCSF Helen Diller Family Comprehensive Cancer Center

Below, Gubens, Kratz, Blakely, and Mulvey summarize the main points from their presentations.

Neoadjuvant and Frontline Immunotherapy in NSCLC

Kratz: [In my presentation, I] talked a little bit about surgically resectable disease and also later-stage disease. Surgically resectable disease is staged now in the 8th edition staging system II to IIIA.

[I also] talked about the CheckMate 816 trial [NCT02998528]. That trial suggests that neoadjuvant [nivolumab (Opdivo)] plus [chemotherapy] prior to surgery may be beneficial vs [chemotherapy] alone as induction therapy.

The IMpower010 trial [(NCT02486718) suggests that] if you give patients adjuvant chemotherapy, consider adding atezolizumab [Tecentriq] in this setting.

For late-stage and recurrent disease, we looked at the CheckMate 227 trial [NCT02477826], which presented evidence that [nivolumab] plus [ipilimumab (Yervoy)] was an acceptable first-line therapy—and a a better first-line therapy than chemotherapy.

We also looked at the CheckMate 9LA trial [NCT03215706], which suggests that [nivolumab plus ipilimumab] and [chemotherapy] is an acceptable first-line therapy for stage IV and recurrent [NSCLC].

Finally, we looked at the KEYNOTE[-407] trial [NCT02775435]. This study looked at patients with advanced squamous cell carcinoma and suggested that adding immunotherapy in this setting to [chemotherapy] was an acceptable first-line treatment for these patients.

EGFR and Exon 20 Therapies

Blakely: In the FLAURA study [NCT02296125], first-line osimertinib [Tagrisso] demonstrated superior progression-free survival, [central nervous system (CNS)] control, and overall survival [OS] compared with first-generation EGFR TKIs. In the CHRYSALIS study [NCT02609776], amivantamab-vmjw [Rybrevant] plus lazertinib demonstrated activity at osimertinib resistance for patients with EGFR exon 19 deletions and L858R mutations. Additionally, adjuvant osimertinib improved [disease-free survival (DFS)] in patients with stage II and stage IIIA disease whose tumors harbor EGFR L858R mutations or exon 19 deletions.

Furthermore, amivantamab and mobocertinib [Exkivity] are active in EGFR exon 20 insertion–positive [NSCLC and are] now both FDA approved as second-line treatment options.

Targeted Therapy for NSCLC

Gubens: [In my presentation, I gave] a quick tour through the treatment landscape for patients with KRASG12C mutations, where we see sotorasib [Lumakras] active in the second line and beyond. Adagrasib is en route, but [there are] many [combinations we can use] to try to see if we can bump up that response rate, bump up that duration of response, and start moving some of these therapies to the first line.

For RET mutations, we see 2 approved drugs, [selpercatinib (Retevmo) and pralsetinib (Gavreto)], that are very good, selective TKIs, very similar in their toxicity and benefit. Next-generation TKIs are also coming.

In [ALK–positive NSCLC], we have lorlatinib [Lorbrena], a third-generation drug, which we’ve been using for resistance in the second line, [and which] really is now a viable first-line option as well. Differential toxicity [is something] we have to counsel our patients about and look out for with [lorlatinib, but it] might be more effective, particularly for variant 3. [It’s] something to have on the menu, to think about using [in the] first line, but certainly otherwise to pull out in [the] second line and beyond.

In this day and age, I always want to think about considering biopsy on progression, [because] unique resistance mechanisms do emerge that we can treat with off-label combinations or certainly consider for trials. Any of us on this panel, and certainly our colleagues at other institutions, are always welcome to entertain calls to think about what trials may be available for your patients in this setting.

Current Management of SCLC

Mulvey: I [shared] a couple of updates in the [SCLC] space, starting with the CASPIAN [trial (NCT03043872)] update that was presented at the 2021 ESMO Congress. I [went over] the IMpower133 [trial (NCT02763579)] update from 2021 as well, and [I ended] with a couple words about second-line [SCLC] treatment.

Treatment for [SCLC] has historically lagged quite a bit behind [treatment for NSCLC]. Most patients with [SCLC] still have extensive-stage disease at diagnosis, and their prognosis remains quite poor. For nearly 30 years, there were no changes to the standard frontline treatment for extensive-stage [(ES)-SCLC]; it was etoposide and platinum chemotherapy [EP]. It’s really just been over the past 3 to 4 years that we have a new standard of care, which has become the combination of [EP] with PD-L1 therapy, either atezolizumab or durvalumab [Imfinzi].

The conclusions from the 3-year update of the CASPIAN trial were that there’s a sustained [OS] benefit from the combination of durvalumab plus EP compared with EP alone. Now, after a median follow-up of over 3 years, and 3 years out, 17.6% of patients treated with durvalumab plus EP were alive compared with 5.8% treated with [chemotherapy] alone. Many of those 17.6% were still receiving durvalumab 3 years out. Overall, this combination has a tolerable safety profile that is consistent with previous reports.

The conclusions from [the updated analysis of the IMpower 133 trial] are [that] there is a sustained OS benefit from the combination of atezolizumab plus EP after, now, a median follow-up of almost 2 years. This benefit was observed in most patient subgroups, with the potential exception of an imbalance in patients with baseline brain [metastases] compared with those without. The benefit was observed across PD-L1 and [tumor mutational burden (TMB)] subgroups, neither of which appear to be a predictive biomarker of response.

Today, [in] 2022, [in terms of] frontline treatment options for [ES-SCLC], we have 2 largely equivalent approaches: that from the CASPIAN trial with durvalumab and that from the IMpower133 trial with atezolizumab. There are a few nuances between the 2 studies, in terms of the platinum agents that were allowed, the number of cycles of chemotherapy in the control arm, and whether prophylactic cranial irradiation was allowed in both arms vs the control arm. At a very high level, the OS benefit seems comparable, so both options are standard-of-care options for the frontline setting.

The advance [for second-line therapy options in ES-SCLC] in the past 2 years has been lurbinectedin [Zepzelca]. Lurbinectedin is a selective inhibitor of oncogenic transcription. It received accelerated approval based on a single-arm, open-label, phase 2 study that enrolled 105 patients with [SCLC] whose cancer had progressed after platinum-based chemotherapy. In this study, the objective response rate [ORR] was [35.2%], which was far and away above what was seen standard in the second line. Based on these data, this drug got accelerated approval.