KRAS Inhibitors, Immunotherapy, and ADCs Carve Out Newfound Applications in NSCLC

Melissa Johnson, MD

The 2021 ASCO Annual Meeting was chock full of practice-changing, practice-affirming, and exciting preliminary research in non–small cell lung cancer (NSCLC), said Melissa Johnson, MD, evidenced by the movement of atezolizumab (Tecentriq) into the adjuvant setting, confirmation of benefit of single-agent immunotherapy in patients with high PD-L1 expression, and pan-mutational activity of antibody-drug conjugates (ADCs) in the advanced setting.

Practice-Changing Trials

Starting with the adjuvant setting, Johnson highlighted the phase 3 IMpower010 trial (NCT02486718), which enrolled patients with completely resected stage IB to IIIA NSCLC. Following 4 cycles of cisplatin-based chemotherapy, patients were randomized to 1200 mg of atezolizumab (Tecentriq) or best supportive care (BSC) for 1 year.¹

The primary end point of disease-free survival (DFS) in the PD-L1–positive (tumor cells ≥1%), stage II to IIIA population was not reached in the atezolizumab arm (95% CI, 36.1-not evaluable [NE]) vs 35.3 months in the BSC arm (95% CI, 29.0-NE) at a median follow-up of 32.8 months. This translated to a 34% reduction in the risk of disease progression or death (HR, 0.66; 95% CI, 0.50-0.88; P = .004). The 3-year DFS rates were 60.0% vs 48.2%, respectively.

Per the statistical hierarchical design of the trial, investigators, having demonstrated significance in the PD-L1–positive population, subsequently evaluated DFS in all-randomized patients with stage II to IIIA disease. In this population, the median DFS was 42.3 months (95% CI, 36.0-NE) in the atezolizumab arm vs 35.3 months (95% CI, 30.4-46.4) in the BSC arm (HR, 0.79; 95% CI, 0.64-0.96; P = .02). The 3-year DFS rates were 55.7% vs 49.4%, respectively.

Finally, in the intention-to-treat population of patients with stage IB to IIIA disease, the median DFS was NE in the atezolizumab arm (95% CI, 36.1-NE) vs 37.2 months in the BSC arm (95% CI, 31.6-NE), translating to a 19% reduction in the risk of disease progression or death (HR, 0.81; 95% CI, 0.67-0.99; P = .04). The 3-year DFS rates were 57.9% vs 52.6%, respectively.

“Atezolizumab improved survival for all patients, but the most clinically significant end point to me is the [DFS in the PD-L1–positive population], so I foresee that we will be treating patients with PD-L1 expressing cancers with a year of atezolizumab,” said Johnson, program director of Lung Cancer Research at Sarah Cannon Research Institute, in a virtual presentation during the 2021 ASCO Direct Highlights^TM webcast in Nashville, a program developed by Physicians’ Education Resource^® LLC.

Overall survival (OS) data were immature at the interim DFS analysis, explained Johnson. However, a trend toward OS improvement with atezolizumab was seen in the PD-L1–positive population with stage II to IIIA disease.

“I doubt that the FDA will wait for OS results to grant the approval, just like they didn’t [wait] for [OS data for the approval of] adjuvant osimertinib [Tagrisso],” said Johnson. “I predict that we’ll be making the decision whether to add a year of atezolizumab to chemotherapy in the months to come.”

Turning to the neoadjuvant setting, Johnson highlighted the phase 3 CheckMate-816 trial (NCT02998528), which randomized patients with newly diagnosed, resectable, stage IB to IIIA NSCLC to 360 mg of nivolumab (Opdivo) plus 3, 3-week cycles of chemotherapy or chemotherapy alone followed by surgery and optional adjuvant chemotherapy with or without radiation.²

Prior findings from the study had shown a significant improvement in pathologic complete response with the addition of nivolumab, meeting the primary end point of the study. The surgical outcomes data, which were presented at the 2021 ASCO Annual Meeting, demonstrated that patients who had received nivolumab had a higher likelihood of undergoing minimally invasive surgery compared with patients who received chemotherapy alone, at 30% vs 22%.

“Patients had a better surgical outcome when they were treated with nivolumab and chemotherapy,” said Johnson.

The rates of thoracotomy were similar between arms, at 59% with nivolumab/chemotherapy vs 63% with chemotherapy alone. Additionally, the rates of intended minimally invasive surgery that required open surgery were 11% vs 16%, respectively, “suggesting that nivolumab/chemotherapy is not resulting in adverse surgical outcomes,” said Johnson.

Additionally, the rate of patients who underwent lobectomy was higher in the nivolumab/chemotherapy arm at 77% vs 61% with chemotherapy alone, and the rate of pneumonectomy was lower in the nivolumab/chemotherapy arm at 17% vs 25% with chemotherapy alone.

“These data reinforce that this is a safe way to make the surgery easier, so it’s ok to wait the 9 weeks preoperatively while this therapy is being administered,” said Johnson.

Shifting focus to the evaluation of targeted therapy in the advanced setting, Johnson discussed the pivotal phase 2 CodeBreaK100 trial (NCT03600883), which enrolled patients with pretreated locally advanced or metastatic KRAS G12C–mutant NSCLC. Patients received 960 mg of sotorasib (Lumakras) once daily until disease progression.³

At a median follow-up of 15.3 months, the overall response rate (ORR) was 37.1% (95% CI, 28.6%-46.2%), the median progression-free survival (PFS) was 6.8 months (95% CI, 5.1-8.2), and the median OS was 12.5 months (95% CI, 10.0-NE). Moreover, the duration of response (DOR) was 11.1 months (95% CI, 6.9-NE).

On May 28, 2021, the FDA approved sotorasib as the first treatment for adult patients with NSCLC whose tumors harbor KRAS G12C mutations and who have received at least 1 prior systemic therapy.

Of note, patients with STK11-mutant, KEAP wild-type disease, a population with historically poor responses to frontline chemoimmunotherapy, derived an ORR of 50%, a median PFS of 11.0 months (95% CI, 2.8-NE), and a median OS of 15.3 months (95% CI, 4.8-NE).

“[Sotorasib] may [represent] an opportunity [for frontline treatment] for these patients, but I wouldn’t make any decisions based on an STK11 mutation right now,” said Johnson. “I would, however, prescribe sotorasib for patients with a KRAS G12C mutation in the second-line setting.”

If prescribed, Johnson advised monitoring for nausea, gastrointestinal adverse effects such as diarrhea, and transaminase elevations, all of which were reported in the pivotal trial.

Practice-Affirming Trials

Looking at the locally advanced setting, Johnson highlighted the 5-year findings from the phase 3 PACIFIC trial (NCT02125461), which enrolled patients with unresectable, stage III NSCLC without progression after definitive platinum-based concurrent chemotherapy and radiation. Patients were randomized to 10 mg/kg of durvalumab (Imfinzi) every 2 weeks for up to 1 year or placebo. Earlier findings had shown a significant improvement in PFS (HR, 0.52; 95% CI, 0.42-0.65; P < .0001) and OS (HR, 0.68; 95% CI, 0.53-0.87; P = .00251) with durvalumab.⁴

Primary findings from the study served as the basis for the February 2018 FDA approval of durvalumab in this patient population.

The updated results reflected a median OS of 47.5 months (95% CI, 38.1-52.9) with durvalumab vs 29.1 months (95% CI, 22.1-35.1) with placebo (HR, 0.72; 95% CI, 0.59-0.89). The 5-year OS rates were 42.9% vs 33.4%, respectively.

The median PFS was 16.9 months (95% CI, 13.0-23.9) with durvalumab vs 5.6 months (95% CI, 4.8-7.7) with placebo (HR, 0.55; 95% CI, 0.45-0.68). The 5-year PFS rates were 33.1% vs 19.0%, respectively.

“Five years later, the curves are still separated, which is pretty remarkable,” said Johnson.

However, she added that additional research is needed to fill the unmet need of patients who are still progressing on the regimen. To that end, Johnson called attention to the phase 3 SKYSCRAPER-03 trial (NCT04513925), which is evaluating atezolizumab plus tiragolumab vs durvalumab in the same population as PACIFIC.

Another phase 3 and practice-affirming trial, EMPOWER-Lung1 trial (NCT03088540), enrolled patients with treatment-naïve advanced NSCLC with high PD-L1 expression (≥ 50%) and treated, clinically stable central nervous system metastases. Patients were randomized to 350 mg of cemiplimab-rwlc (Libtayo) monotherapy every 3 weeks for up to 108 weeks in the absence of progressive disease or 4 to 6 cycles of investigator’s choice chemotherapy.⁵

“This is a group of patients that we often say we feel nervous about treating with single-agent checkpoint inhibitors because patients with brain metastasis will have received steroids prior to going onto their PD-1/PD-L1 therapy,” said Johnson.

However, the results showed that this group of patients did well with cemiplimab.

Specifically, the ORR was 41.2% (95% CI, 24.6%-59.3%), which was “in line with what we know of the pembrolizumab [Keytruda] data,” said Johnson, vs 8.8% (95% CI, 1.9%-23.7%) with chemotherapy.

Additionally, the median PFS was 10.4 months (95% CI, 4.2-NE) with cemiplimab vs 5.3 months (95% CI, 2.2-6.5) with chemotherapy. The median OS was 18.7 months (95% CI, 17.3-NE) vs 11.7 months (95% CI, 7.0-NE), respectively.

“The steroids didn’t seem to impair the ability of cemiplimab to do its job,” said Johnson. “EMPOWER-Lung1 brings the third PD-1 inhibitor to the frontline PD-L1 high–expressing space. We see reassuringly that those patients, even when they have brain metastasis, get excellent clinical benefit from PD-1 monotherapy, so based on this data, I would think more seriously about PD-1 monotherapy than I have in the past for a PD-L1 high–patient with brain metastasis.”

Drugs to Watch

On May 21, 2021, the FDA approved amivantamab-vmjw (Rybrevant) as the first treatment for adult patients with NSCLC who harbor EGFR exon 20 insertion mutations.

The approval was based on findings from a cohort of the phase 1 CHRYSALIS trial (NCT02609776). In another cohort, findings from which were presented at the 2021 ASCO Annual Meeting, investigators evaluated the EGFR/MET bispecific antibody, amivantamab plus the third-generation EGFR TKI, lazertinib in patients with osimertinib (Tagrisso)-relapsed, chemotherapy-naïve NSCLC with EGFR exon 19 deletions or exon 21 (L858R) mutations.⁶

The results showed an ORR of 36% (95% CI, 22%-51%), with a median DOR of 9.6 months (95% CI, 5.3-not reached). The median PFS was 4.9 months (95% CI, 3.7-9.5).

Among patients with EGFR/MET-based resistance, the ORR was 47%, the median DOR was 10.4 months, and the median PFS was 6.7 months.

“More patients with EGFR/MET-based resistance had response, but even patients without an EGFR or MET mechanism of resistance [derived] benefit from this drug, so I believe this is coming as a potential option for your patients post-osimertinib,” said Johnson.

The pivotal MARIPOSA trial (NCT04487080), now ongoing, is evaluating the combination, osimertinib alone, and lazertinib monotherapy in previously untreated patients with EGFR sensitizing mutations.

With regard to novel ADCs in development, Johnson first spoke to patritumab deruxtecan, a HER3-specific ADC designed to overcome EGFR TKI resistance mechanisms. The drug is currently under study in a phase 1 trial (NCT03260491) in patients with locally advanced or metastatic EGFR-mutant NSCLC with disease progression on prior EGFR TKI treatment.

Results from the phase 1 study demonstrated that the subgroup of patients treated with prior osimertinib with or without platinum-based chemotherapy derived an ORR of 39% (95% CI, 26%-52%).⁷

“You might think that unless you have a patient with a HER3 alteration, this [drug] won’t work, but to the contrary, there were patients with T790M [mutations], EGFR C797S [mutations], MET amplification, ALK rearrangements, and KRAS mutations, and all were responding [to patritumab deruxtecan],” said Johnson.

“This is an interesting drug to keep your eye on. This [agent] is not FDA approved yet, but is moving there quickly in my estimation,” added Johnson.

Another ADC, datopotamab deruxtecan is being evaluated in the phase 1 TROPION-PanTumor01 trial (NCT03401385). The agent, directed toward Trop-2, demonstrated ORRs of 24%, 26%, and 24% across doses of 4 mg/kg, 6 mg/kg, and 8 mg/kg, respectively, in patients with relapsed/refractory advanced or metastatic NSCLC.⁸

“The response rates are a little lower than with patritumab deruxtecan, but this drug is also moving forward in the phase 3 TROPION-Lung01 [NCT04656652] and phase 2 TROPION-Lung05 [NCT04484142] trials,” concluded Johnson.

References

1. Wakelee HA, Altorki NK, Zhou C, et al. IMpower010: primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8500. doi:10.1200/JCO.2021.39.15_suppl.8500
2. Spicer J, Wang C, Tanaka F, et al. Surgical outcomes from the phase 3 CheckMate 816 trial: Nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo alone as neoadjuvant treatment for patients with resectable non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):8503. doi:10.1200/JCO.2021.39.15_suppl.8503
3. Skoulidis F, Li BT, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003. doi:10.1200/JCO.2021.39.15_suppl.9003
4. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes with durvalumab after chemoradiotherapy in unresectable stage III NSCLC: an update from the PACIFIC trial. J Clin Oncol. 2021;39(suppl 15):8511. doi:10.1200/JCO.2021.39.15_suppl.8511
5. Ozguroglu M, Sezar A, Kilickap S, et al. Cemiplimab monotherapy as first-line (1L) treatment of patients with brain metastases from advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) ≥ 50%: EMPOWER-Lung 1 subgroup analysis. J Clin Oncol. 2021;39(suppl 15):9085. doi:10.1200/JCO.2021.39.15_suppl.9085
6. Bauml J, Cho BC, Park K, et al. Amivantamab in combination with lazertinib for the treatment of osimertinib-relapsed, chemotherapy-naïve EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC) and potential biomarkers for response. J Clin Oncol. 2021;39(suppl 15):9006. doi:10.1200/JCO.2021.39.15_suppl.9006
7. Janne PA, Baik CS, Su WC, et al. Efficacy and safety of patritumab deruxtecan (HER3-DXd) in EGFR inhibitor-resistant, EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9007. doi:10.1200/JCO.2021.39.15_suppl.9007
8. Meric-Bernstam F, Spira AI, Lisberg AE, et al. TROPION-PanTumor01: Dose analysis of the TROP2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd, DS-1062) for the treatment (Tx) of advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9058. doi:10.1200/JCO.2021.39.15_suppl.9058