Rybrevant-Leclaza Combo Outperforms Tagrisso in EGFR-Mutant Advanced NSCLC

Frontline tehrapy with Rybrevant (amivantamab-vmjw) plus Leclaza (lazertinib) reduced the risk of disease progression or death by 30% versus Tagrisso (osimertinib) alone in patients with advanced non–small cell lung cancer (NSCLC) harboring EGFRmutations, according to findings from the MARIPOSA trial.

Results from this phase 3 trial were presented at the 2023 ESMO Congress.

At a median follow-up of 22 months, the median progression-free survival (PFS; the time during and after treatment when a patient with cancer is alive without disease worsening) was 23.7 months with the combination versus 16.6 months with Tagrisso alone. The 12- and 24-month PFS rates with the combination were 73% and 48%, respectively, versus 65% and 34% with Tagrisso alone. Leclaza monotherapy led to a median PFS of 18.5 months.

Moreover, the combination reduced the risk of extracranial (outside of the bones that surround the brain) progression or death by 32% versus Tagrisso alone. Median extracranial PFS was 27.5 months with the combination versus 18.5 months with Tagrisso alone. The 12- and 24-month extracranial PFS rates were 77% and 53% with the combination, respectively, versus 67% and 38% with Tagrisso alone.

Interim overall survival (OS; the time from the start of treatment when a patient with cancer is still alive), though not yet mature, showed a trend favoring the combination. The estimated 24-month PFS rates were 74% and 69% with the combination and Tagrisso alone, respectively.

“(Rybrevant) plus (Leclaza) represents a new standard of care in patients with first-line, EGFR-mutant advanced NSCLC,” lead study author Dr. Byoung Chul Cho, professor at Yonsei Cancer Center in Seoul, Korea, said in a presentation of the data.

Tagrisso is the standard frontline therapy for the approximately 15% to 50% of patients with EGFR-mutant advanced NSCLC. However, resistance to therapy remains an unmet need.

Rybrevant is an EGFR-MET bispecific antibody with immune cell–directing activity against a variety of EGFRand MET alterations. Leclaza is a highly selective, central nervous system penetrant and well-tolerated, third-generation EGFR TKI, rendering it an ideal combination partner.

By combining the two agents, investigators expect to see improved activity against resistance mechanisms, resulting in improved outcomes without the need for chemotherapy.

For the phase 3 MARIPOSA trial, eligibility criteria required patients to have treatment-naïve (haven’t been treated before), locally advanced or metastatic NSCLC; a documented EGFR exon 19 deletion or L858R mutation; and an ECOG performance status of 0 or 1 (fully active or unable to do strenuous activities).

A total of 1,074 patients were randomly assigned to Rybrevant plus Leclaza (429 patients), Tagrisso alone (429 patients) or Leclaza alone (216 patients).

The primary end point was PFS for the combination versus Tagrisso. Secondary end points included OS, objective response rate (ORR; the percentage of patients with a partial or complete response to treatment), duration of response (DOR; the time from when a patient responds to treatment until progression or death), PFS after first subsequent therapy, symptomatic PFS, intracranial PFS and safety.

Consistent PFS benefit was seen in patients regardless of the presence or absence of brain metastases. Among patients with a history of brain metastases, the median PFS was 18.3 months with the combination versus 13 months with Tagrisso alone. Among patients without a history of brain metastases, the median PFS was 27.5 months with the combination versus 19.9 months with Tagrisso alone.

Notably, more patients in the combination arm remained in response at data cutoff (62%) versus those in the Tagrisso monotherapy arm (48%). The median DOR was 25.8 months with the combination versus 16.8 months with Tagrisso alone, “suggesting longer time to resistance and progression,” Cho stated.

The ORR among all responders was 86% with the combination versus 85% with Tagrisso alone. Confirmed responders experienced an ORR of 80% with the combination versus 76% with Tagrisso alone. In the combination arm, best responses included complete response (CR; disappearance of all signs of cancer from treatment; 7%), partial response (PR; decrease in tumor size or extent in the body from treatment; 79%), stable disease (SD; cancer that is neither increasing or decreasing in severity; 7%) and progressive disease (PD; cancer that is spreading, growing or getting worse; 2%); 5% of patients were not evaluable. In the Tagrisso arm, best responses included CR (4%), PR (81%), SD (10%) and PD (3%); 3% of patients were not evaluable.

The combination also reduced the risk of second disease progression or death by 25%. At 24 months, 72% of patients in the combination arm remained free from second progression versus 64% in the Tagrisso monotherapy arm. Cho stated that the most common first subsequent therapy among the 98 patients who received additional treatment in the combination arm was an EGFR TKI (49%) and chemotherapy (33%). In the 137 patients who received subsequent therapy in the Tagrisso monotherapy arm, the most common next-line treatment was chemotherapy (39%) and an EGFR TKI (27%).

The median duration of treatment was 18.5 months with the combination versus 18 months with Tagrisso.

Regarding safety, severe or worse side effects occurred in 75% of patients in the combination arm versus 43% of patients in the Tagrisso arm. Serious side effects occurred in 49% and 33% of patients in the combination and monotherapy arms, respectively. Side effects leading to death occurred in 8% and 7% of patients, respectively. Notably, at least half as many patients in the combination arm versus the Tagrisso arm experienced a side effect leading to treatment interruption, reduction or discontinuation.

The most common treatment-related side effects in the combination arm included paronychia (infection of the folds around the nails), rash, diarrhea, dermatitis acneiform (a rash that resembles acne), stomatitis (inflammation inside the mouth), pruritus (itching), hypoalbuminemia (when the body doesn’t produce enough albumin protein to keep fluid in the blood vessels), peripheral edema (leg swelling), infusion-related reaction, alanine aminotransferase increase (indicating liver disease), constipation, aspartate aminotransferase increase (indicating liver damage), COVID-19, decreased appetite, anemia, nausea, hypocalcemia (low calcium levels in the blood) and cough. 

Cho added that the rates of interstitial lung disease (scarring of the lung tissue) and pneumonitis (lung inflammation) remained low at approximately 3% in both arms.

Venous thromboembolism (a blood clot in the vein) was a side effect of special interest, occurring at a frequency of 37% overall in patients in the combination arm (mild, 1%; moderate, 25%; severe, 10%; life-threatening, 0.5%; fatal, 0.5%). The median time to onset of first venous thromboembolism event was 84 days, with most patients (62%) experiencing an event within the first four months of treatment. Cho stated that prophylactic dose anticoagulation is now recommended for the first four months of treatment in ongoing trials evaluating the combination.

“(Rybrevant) plus (Leclaza) had higher rates of EGFR- and MET-related (side effects) and venous thrombotic events, (but) the majority were grade 1 and 2 (mild or moderate). (We also saw) infrequent discontinuations due to (treatment-related side effects) at 10%,” Cho concluded.

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