Checkpoint Blockade Stumbles in Advanced EGFR-Mutant NSCLC

CHICAGO — In patients with metastatic EGFR-positive lung cancer who progressed on targeted agents, adding pembrolizumab (Keytruda) to a standard chemotherapy regimen demonstrated no survival benefit, a randomized trial found.

When given alongside platinum plus pemetrexed (Alimta), small differences in progression-free and overall survival (PFS, OS) favored the checkpoint inhibitor over placebo, but neither outcome reached statistical significance:

• Median PFS: 5.6 vs 5.5 months, respectively
• Median OS: 15.9 vs 14.7 months

Results of the trial, KEYNOTE-789, are consistent with prior reports showing that patients with EGFR-mutant non-small cell lung cancer (NSCLC) derive less benefit from PD-1/L1 inhibitors, said James Chih-Hsin Yang, MD, PhD, of the National Taiwan University Cancer Center in Taipei, who presented the study at the American Society of Clinical Oncology (ASCO) annual meeting here.

Study participants had nonsquamous disease that had progressed on EGFR-directed tyrosine kinase inhibitors (TKIs), the standard frontline approach for tumors with sensitizing EGFR mutations, and nearly half of the patients had received osimertinib (Tagrisso) as first-line (12%) or second-line (36%) treatment.

“Would I add pembrolizumab to platinum-pemetrexed in advanced EGFR-mutant lung cancer? No,” said ASCO-invited discussant Jonathan Riess, MD, of the University of California Davis Comprehensive Cancer Center.

He explained that by and large, EGFR-mutant tumors have a suppressed immune microenvironment — low PD-L1 expression, tumor mutational burden, tumor-infiltrating lymphocytes, and T-cell clonality — making these cancers less-than-ideal candidates for immunotherapy.

This and other factors, said Riess, resulted in the exclusion of these patients from the pivotal first-line studies of pembrolizumab, including the KEYNOTE-189 trial. That study demonstrated a substantial (and significant) survival benefit when the anti-PD-1 drug was added to platinum-pemetrexed chemotherapy, and helped usher in a new standard of care for NSCLC.

In a statement to the media, an ASCO-designated expert said the new findings “have significant implications for clinical practice.”

“Many community oncologists had generalized the results of the KEYNOTE-189 trial to all patient populations, but this study clearly demonstrates that chemoimmunotherapy is not suitable for EGFR-positive NSCLC patients after progression on osimertinib,” said Jyoti Patel, MD, a medical oncologist at the Feinberg School of Medicine at Northwestern University in Chicago. “Immediate changes in patient care are necessary to avoid unnecessary toxicity and focus on more effective treatment strategies.”

To that end, Riess noted that the inclusion of anti-VEGF with checkpoint blockade and chemotherapy deserves more investigation, and several trials are ongoing, “but will an overall survival benefit be shown?” So far, he pointed out, the strategy has yielded PFS improvements that failed to translate into OS.

But among the litany of immunotherapy trials in EGFR-mutant NSCLC, some patients have shown true benefit with anti-PD-1/L1, said Riess. “They’re few and far between but they’re there, and I would put a call out that we need to study exceptional responders, and the few patients that do benefit, to find out what’s unique in their immune system, in their immune microenvironment.”

Study Details

Yang presented data on KEYNOTE-789, a phase III study that included 492 adults with confirmed stage IV nonsquamous NSCLC and EGFR-positive disease. They were randomized 1:1 to treatment with four cycles of carboplatin or cisplatin and pemetrexed, plus either pembrolizumab (200 mg) or placebo every 3 weeks (with pembrolizumab or placebo continued for up to 2 years).

To be included in the trial, all patients had to have progressed on a TKI therapy: either frontline osimertinib, any TKI for T790M-negative tumors, or first- or second-line osimertinib for patients with a T790M mutation. Stratification factors included PD-L1 expression, prior receipt of osimertinib, and geographic region.

Patients had a median age of about 63 years, over 60% were women, and most were enrolled in East Asia. In terms of patients’ tumor characteristics, 21% had high PD-L1 expression, 57% had EGFR exon 19 deletion mutations, and 42% had L858R mutations in exon 21. More than half were negative for T790M mutations.

PFS and OS were the dual endpoints of the study, with the prespecified statistical plan calling for a P-value of 0.0117 to reach significance for PFS and 0.0118 for OS. Secondary endpoints included overall response rate (ORR) and duration of response (DOR). Median time from randomization to data cutoff for the final analysis was 42 months.

Pembrolizumab was associated with a non-significant 20% reduction in the risk for disease progression or death (HR 0.80, 95% CI 0.65-0.97, P=0.0122) and a non-significant 16% reduction in the risk for death (HR 0.84, 95% CI 0.69-1.02, P=0.0362).

Landmark OS analyses of the pembrolizumab and placebo arms were as follows:

• 1 year: 61.6% vs 59.4%, respectively
• 2 years: 30.6% vs 26.4%
• 3 years: 14.6% vs 11.4%

HRs for OS were similar regardless of whether patients had received osimertinib in first-line (HR 0.91, 95% CI 0.53-1.57) or second-line (HR 0.91, 95% CI 0.67-1.23). PD-L1 expressors (≥1%) had a median OS of 18.6 months with pembrolizumab versus 14.1 months with placebo (HR 0.77, 95% CI 0.58-1.02), a group worthy of further study with this approach, said Yang.

ORRs were similar between the two arms (29% in the investigational arm and 27.1% in the control arm), with median DORs of 6.3 and 5.6 months.

Following progression in the pembrolizumab arm, 29% of patients went on to TKIs and 7% received more PD-1/L1 inhibition. In the control arm, 36% crossed over to receive pembrolizumab and 41% received another TKI.

No new safety signals were seen, and adverse events (AEs) were manageable, said Yang. Grade ≥3 treatment-related AEs were more frequent with pembrolizumab (43.7% vs 38.6%), as were grade ≥3 immune-mediated AEs and infusion reactions (4.5% vs 2.0%). Death due to toxicity was recorded in five patients in the pembrolizumab group and 12 in the placebo group.