Hall Addresses Selection for Chemoimmunotherapy in NSCLC

Richard D. Hall, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Richard D. Hall, MD

Immunotherapy has continued to expand its role in the non—small cell lung cancer (NSCLC) treatment landscape over the last few years. Now, recent data with combinations and a growing understanding of molecular abnormalities have raised questions over who is best eligible for immunotherapy and where it will optimally work, said Richard D. Hall, MD.

In a presentation at the OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Hall, assistant professor, Hematology/Oncology, University of Virginia Health System, recapped updates from the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting. Hall discussed the potential impact of recent combination trials in NSCLC prior to addressing the question of whether immunotherapy is for all-comers with this disease.

KEYNOTE-189 was presented at the 2018 AACR Annual Meeting and was published simultaneously in the New England Journal of Medicine (NEJM).¹ In this trial, patients with stage IV nonsquamous NSCLC were given either pembrolizumab (Keytruda) plus pemetrexed (Alimta) with either cisplatin or carboplatin, or placebo plus pemetrexed (Alimta) with either cisplatin or carboplatin.

The median overall survival (OS) was not reached (NR) in the pembrolizumab arm versus 11.3 months in the placebo arm. Moreover, the addition of pembrolizumab reduced the risk of death by 51% in patients with NSCLC without EGFR or ALK mutations.

"One of the components of KEYNOTE-189 that is important to point to out is that all of the patients had to have their PD-L1 status evaluable," explained Hall. "Negative patients were enrolled, and in all of the groups, whether they were negative, intermediate, or had high levels of PD-L1 expression, the pembrolizumab combination showed a superior OS that was statistically significant."

Findings from KEYNOTE-189 have provided clinicians with a new standard of care for patients with nonsquamous NSCLC, said Hall. In August 2018, the FDA granted a full approval to the frontline combination for patients with metastatic nonsquamous NSCLC based on these data followed an accelerated approval in May 2017.

A second trial, CheckMate-227, evaluated nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with treatment-naïve stage IV NSCLC. Patients were separated into 2 groups. Those with PD-L1 ≥1% were randomized to 1 of 3 arms: nivolumab plus ipilimumab, platinum-doublet chemotherapy, or nivolumab monotherapy. Patients with PD-L1 <1% were randomized to 1 of 3 arms: nivolumab plus ipilimumab, platinum-doublet chemotherapy, or nivolumab plus platinum-doublet chemotherapy.

In results presented at the 2018 AACR Annual Meeting and published simultaneously in NEJM,² the 2 nivolumab plus ipilimumab arms from each group were combined and compared with the platinum-doublet chemotherapy arms. Patients who were evaluable for tumor mutational burden (TMB) were specifically looked at. Progression-free survival (PFS) was measured by TMB.

"TMB is defined as the number of mutations per megabase pair of DNA," explained Hall. "Lung squamous and lung adenocarcinoma are the 2 and 3 most mutated of cancers in this cohort. There has been this thought that TMB might help us understand and explain why lung cancer responds to immunotherapy."

In patients with high TMB ( ≥10 mutations/megabase [mut/mB]), the 12-month PFS was 42.6% in patients treated with nivolumab plus ipilimumab versus 13.2% with chemotherapy (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001). In patients with low TMB (<10/ mut/mB), the 1-year PFS was 25% for nivolumab plus ipilimumab versus 17% for platinum-doublet chemotherapy (HR, 1.07; 95% CI, 0.84-1.35).

Hall said that one of the takeaways from this trial was that TMB was able to predict patients who would respond to combination immunotherapy, whereas PD-L1 expression did not.

"There is no difference, statistically, between these 2 curves,” said Hall. “In both groups, nivolumab plus ipilimumab showed a significant improvement in PFS, but PD-L1 did not seem to be particularly important.”

Following the presentation of these results at the 2018 AACR Annual Meeting, overall PFS by TMB for the PD-L1—low group (<1%) was presented at the 2018 ASCO Annual Meeting. The 1-year PFS for the full unselected population with nivolumab plus chemotherapy versus chemotherapy was 5.6 and 4.7 months, respectively (HR, 0.74; 95% CI, 0.58-0.94).³

For patients who were TMB high (≥10 mut/mB) and PD-L1 negative, regardless of histology, median PFS with nivolumab plus ipilimumab was 7.7 months compared with 5.3 months for chemotherapy and 6.2 months for nivolumab and chemotherapy. PFS at 1 year was 45% for patients treated with nivolumab and ipilimumab, 27% for those treated with nivolumab and chemotherapy, and 8% for chemotherapy alone. In the overall group of patients with metastatic PD-L1—negative, TMB-high NSCLC, the combination of nivolumab and ipilimumab reduced the risk of progression or death by 52% compared with platinum-doublet chemotherapy.

"Here, we see that TMB did predict the patients who were more likely to benefit from combination nivolumab plus chemotherapy if [the patient] was TMB high," said Hall.

In June 2018, the FDA accepted a supplemental biologics license application (sBLA) for the combination of nivolumab and ipilimumab as a frontline treatment for patients with advanced NSCLC with TMB ≥10 mut/Mb, based on the CheckMate-227 findings.

Phase III data from IMpower150 presented at the 2018 ASCO Annual Meeting and published in NEJM showed that in patients with wild-type nonsquamous NSCLC, the combination of atezolizumab (Tecentriq), bevacizumab (Avastin), carboplatin, and paclitaxel (ABCP) reduced the risk of death by 22% compared with bevacizumab and chemotherapy (BCP).^4,5

Median OS for patients who received ABCP was 19.2 months (95% CI, 17.0-23.8) compared with 14.7 months (95% CI, 13.3-16.9) in the BCP arm (HR, 0.78; 95% CI, 0.64-0.96; P = .0164). The 24-month OS rate was 43% versus 34% for ABCP and BCP, respectively. Median PFS was improved with the addition of atezolizumab by 1.5 months compared with BCP (8.3 vs 6.8 months; HR, 0.59; 95% CI, 0.50-0.70; P <.0001).

In May 2018, the FDA granted a priority review to an sBLA for atezolizumab for use in combination with bevacizumab, carboplatin, and paclitaxel for the first-line treatment of patients with metastatic nonsquamous NSCLC based on these data.

In squamous disease, the KEYNOTE-407 trial, which was also presented at the 2018 ASCO Annual Meeting, evaluated pembrolizumab plus frontline carboplatin with either paclitaxel or nab-paclitaxel (Abraxane) versus chemotherapy alone in patients with metastatic squamous NSCLC. Findings from this phase III trial showed a reduction in the risk of death by 36% with the addition of pembrolizumab, with a median OS of 15.9 months (95% CI, 13.2-NR) with pembrolizumab versus 11.3 months (95% CI, 9.5-14.8) with chemotherapy alone (HR, 0.64; 95% CI, 0.49-0.85; P = .0008).⁶

Patients in KEYNOTE-407 trial treated with frontline pembrolizumab plus chemotherapy experienced an OS benefit regardless of PD-L1 expression level, taxane used, age, sex, and ECOG performance status, said Hall. Further, the median PFS with the addition of pembrolizumab was 6.4 months (95% CI, 6.2-8.3) compared with 4.8 months (95% CI, 4.3-5.7) with chemotherapy alone (HR, 0.56; 95% CI, 0.45-0.70; P <.0001). Although there was a correlation between an increase in PD-L1 level and benefit, all patients across PD-L1 levels experienced a PFS benefit.

Based on these data, the FDA granted a priority review designation in July 2018 to an sBLA for frontline pembrolizumab for use in combination with carboplatin and paclitaxel or nab-paclitaxel for the treatment of patients with metastatic squamous NSCLC, regardless of PD-L1 expression.

"I do think that combination immuno-oncology agents and chemotherapy is a new standard option for treatment-naïve squamous and nonsquamous patients with NSCLC, but there are a couple caveats that are important," said Hall.

The first caveat, Hall explains, is patients with oncogene-driven NSCLC were excluded in these trials, except in IMpower150 after their oral therapy options were exhausted. The next is that pembrolizumab as monotherapy remains an option for patients with PD-L1 ≥50%. The last is that with multiple soon-to-be FDA-approved chemoimmunotherapy regimens, there are not established biomarkers to aid in selection.

"While the nivolumab/ipilimumab data are interesting—that TMB predicted who would benefit from the combination of nivolumab and ipilimumab&mdash;we have some opportunities here to improve TMB testing," Hall said. "Standardizing how TMB testing is done is an issue, and we will just have to see as more data come out with CheckMate-227 and other studies."

Hall said that the question of whether immunotherapy is right for all patients with NSCLC has been under discussion in the lung cancer sphere. Findings from some recent studies, such as KEYNOTE-042 and ImmunoTarget, have contributed to the debate.

Findings from KEYNOTE-042, presented at the 2018 ASCO Annual Meeting, evaluated pembrolizumab versus chemotherapy.⁷ Patients eligible for this trial had untreated locally advanced or metastatic NSCLC of any histology, a PD-L1 tumor proportion score (TPS) ≥1%, no sensitizing EGFR or ALK alterations, an ECOG performance score of 0 or 1, no untreated or resectable CNS metastases, and no history of pneumonitis that require systemic corticosteroids.

Patients on this trial randomized to frontline pembrolizumab lived 4 to 8 months longer than those who received standard chemotherapy, depending on their level of PD-L1 expression. Specifically, high PD-L1 expression was associated with a greater OS. OS for patients with TPS ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; P = .0003), TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92; P = .002), and TPS ≥1% (16.7 vs 12.1 months; HR, 0.81; 95% CI, 0.71-0.93; P = .0018) compared with chemotherapy.

"If you look at the endpoint from 1%, this was a positive study," said Hall. "But at the other cutoffs, both 20% and 50%, you see that it remained significant—the pembrolizumab was better than just platinum chemotherapy. But in an exploratory analysis, the intermediate group of 1% to 49%, there was no statistical difference in OS."

One of the big takeaways from KEYNOTE-042 is that if a patient has an intermediate expression of PD-L1, pembrolizumab monotherapy might not be the better option, Hall concluded.

The ImmunoTarget study evaluated 551 patient outcomes to immunotherapy according to their genetic mutations. The majority of patients were KRAS-positive (n = 271), followed by EGFR-positive (n = 125), and BRAF-positive (n = 43).⁸

Investigators of this study concluded that patients with NSCLC who had a KRAS mutation showed a clear PFS benefit from checkpoint inhibitors across all subgroups. For those with EGFR mutations, checkpoint inhibitors could be considered in PD-L1—positive patients after all TKIs were exhausted. Checkpoint inhibitors could be considered in patients with BRAF mutations who are smokers; for those with either MET or HER2 mutations, this treatment could be considered after conventional therapy. Additionally, those with ALK, RET, and ROS1 alterations, were noted to have poor outcomes and need new biomarkers to determine if they will derive benefit from checkpoint inhibitors.

"Should we be giving everyone with lung cancer immuno-oncology agents? The answer is, ‘No.’ KEYNOTE-042 was a positive study, but it looked like the results were driven by patients with high PD-L1. Except for KRAS and maybe BRAF, oncogene-addicted tumors have low responses to anti—PD-1/PD-L1 therapies," Hall said.

Understanding the interplay between biomarkers, such as PD-L1 and TMB, and clinical factors, like smoking status, will be imperative in selecting the optimal therapies for patients, Hall added.

References

1. Gandhi L, Rodgríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non—small-cell lung cancer. N Engl J Med. 2018;378:2078-2092. doi: 10.1056/NEJMoa1801005.
2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104. doi: 10.1056/NEJMoa1801946.
3. Borghaei H, Hellmann MD, Paz-Ares LG, et al. Nivolumab (nivo) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (Tx) for advanced non-small cell lung cancer (NSCLC) with <1% tumor PD-L1 expression: results from CheckMate 227. J Clin Oncol. 2018;36(suppl; abstr 9001).
4. Socinski MA, Jotte R, Cappuzzo F, et al. Overall survival (OS) analysis of IMpower150, a randomized Ph 3 study of atezolizumab (atezo) chemotherapy (chemo) ± bevacizumab (bev) vs chemo + bev in 1L nonsquamous (NSQ) NSCLC. J Clin Oncol. 2018;36(suppl; abstr 9002).
5. Socinski MA, Jotte R, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288-2301. doi: 10.1056/NEJMoa1716948.
6. Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (chemo) with or without pembrolizumab (pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(suppl; abstr 105).
7. Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36 (suppl; abstr LBA4).
8. Mazieres J, Drilon AE, Mhanna L, et al. Efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) patients harboring activating molecular alterations (ImmunoTarget). J Clin Oncol. 2018;36(suppl; abstr 9010).