ASCO 2020 Data Drive New Discussions in NSCLC

Joshua M. Bauml, MD

In a special OncLive video program, The Board, Joshua M. Bauml, MD, assistant professor of medicine, Perelman School of Medicine, University of Pennsylvania, led a discussion regarding key abstracts that were presented during the 2020 ASCO Virtual Scientific Program in non–small cell lung cancer (NSCLC).

Bauml was joined by:

• Paul Bunn, MD: Distinguished Professor of Medicine-Medical Oncology, James Dudley Chair in Cancer Research, University of Colorado School of Medicine
• Stephen Liu, MD: associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center
• Gilberto De Lima Lopes, MD: associate professor of clinical oncology and associate director of global oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System
• Sandip P. Patel, MD: associate professor of medicine, Moores Cancer Center, University of California San Diego Health
• Jonathan W. Riess, MD, MS: associate professor of medicine, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center
• Mark A. Socinski, MD: executive medical director, AdventHealth Cancer Center
• Viola W. Zhu, MD, PhD: medical oncologist/hematologist, Chao Family Comprehensive Cancer Center, University of California, Irvine
• David R. Spigel, MD: chief scientific officer, director, Lung Cancer Research Program, principal investigator, Sarah Cancer Research Institute

During the discussion, these experts considered the results of the controversial phase 3 ADAURA trial, data supporting emerging targets in NSCLC, and their predictions for what the future of NSCLC treatment may look like.

ADAURA Provides Controversial, Yet Compelling Data

Bauml kicked off the discussion with what was “probably the most controversial topic presented at ASCO this year.”

Results from the ADAURA trial revealed that disease-free survival (DFS) had not yet been reached with adjuvant osimertinib (Tagrisso; 95% CI, 38.8–not calculated) compared with 20.4 months (95% CI, 16.6-24.5) with placebo (HR, 0.17; 95% CI, 0.12-0.23; P <.0001) among patients with EGFR-mutated, stage II to IIIA NSCLC.¹

Additionally, though overall survival (OS) remain immature, the 2-year DFS rates in patients with stage IB, II, IIIA disease was 87%, 91%, and 88% with osimertinib, respectively, versus 73%, 56%, and 32% with placebo, respectively (overall HR, 0.50, 0.17, and 0.12, respectively).

“Osimertinib is a third-line central nervous system (CNS)–penetrating EGFR-directed TKI,” said Patel. “The vast majority of us in the United States utilize osimertinib in the frontline [metastatic] space based on the FLAURA [trial] data. The question is whether we can move this therapy into earlier-stage disease...are we suppressing disease? Are we curing these patients?”

The utility of the drug, which is likely to be approved in this indication, said Bauml, was met with mixed reactions from the panelists on The Board.

“You have to go back to basic biology and the neoadjuvant studies,” said Bunn, who raised his hand, stating he would not use adjuvant osimertinib for a stage II EGFR-mutant patient. “First of all, 60% of patients in all recent trials with adjuvant chemotherapy are cured. [Using osimertinib] means that 60% of patients are going to pay [for a drug] for 3 years and have the [adverse effects (AEs)] with no benefit whatsoever. In basic biology, patients present with 1012 cells. If you get a partial response, you’re killing 1 or 2 logs. You don’t get complete responses and resistance is inevitable. TKIs don’t give you enough kill to get a cure.”

Although the majority of the panel agreed with Bunn’s position, Riess raised the concept of tumor heterogeneity and whether acting earlier with osimertinib may be beneficial. Additionally, Lopes and Patel spoke to the experience observed in gastrointestinal stromal tumors and achieving complete responses (CRs) with osimertinib.

However, other controversies included challenges with EGFR testing, issues with the control arm, the fixed-duration of osimertinib, the 40% of patients in ADAURA who did not receive chemotherapy, what to give following treatment, and the lack of mature OS data, which most of the experts agreed will determine whether the trial is practicing-changing.

Safety with the agent was as expected; however, Socinski said, “Grade 1 or 2 toxicities may be easier to tolerate when you have stage 4 disease than when you have recovered from your surgery. Try to go to work every day with grade 2 diarrhea, paronychia, or rash. I don’t think it is as easy as people think it is going to be.”

Spigel added, “We are awaiting more data, but assuming we have what we have [now in terms of available treatments], I think it is a therapy that is going to get approved and be used globally,” to which the group agreed.

Additionally, final OS data of another trial, the randomized phase 3 CTONG 1104 study, showed intriguing findings when stacked up against ADAURA as the DFS advantage observed with adjuvant gefitinib (Iressa) did not translate into an OS benefit for patients with resected N1-N2, EGFR-mutant NSCLC.²

Combos, Radiation, and Novel Drugs Expand Options in Metastatic EGFR+ NSCLC

Moving to the metastatic setting, findings from an ongoing phase 1/2 trial (NCT03122717)³ demonstrated an overall response rate (ORR) of 88.9% with concurrent gefitinib and osimertinib as first-line treatment for patients with EGFR-mutant NSCLC.

Moreover, the regimen elicited rapid and near-complete plasma EGFR mutation clearance for patients.

Evaluable patients (n = 27), who received 250 mg of gefitinib and 40 mg of daily osimertinib, had to have stage IV disease, an EGFR L858R mutation or exon 19 deletion, no prior therapy for metastatic disease, and an ECOG performance status of 0 or 1.

Regarding safety, no dose-limiting toxicities were observed in the dose-escalation phase of the study. Moreover, the toxicities were consistent with the expected safety profile of EGFR TKIs. Most notably, rash, diarrhea, and dry skin. Grade 3 treatment-related AEs (TRAEs) included diarrhea, increased alanine aminotransferase (ALT), rash, increased aspartate transaminase (AST), nausea, decreased left ventricular ejection fraction, and vomiting. No grade 4 or 5 TRAEs were observed.

In the absence of a complete understanding of the mechanisms of resistance to osimertinib, the panel agreed that pending progression-free survival (PFS) and OS outcomes will likely shed light on the overall utility of dual EGFR-directed TKI therapy.

The interim results of the randomized phase 3 SINDAS trial revealed that up-front stereotactic body radiotherapy to metastatic lesions at diagnosis combined with first-line TKI therapy led to a significant improvement in PFS and OS compared with a TKI alone for patients with EGFR-mutant oligometastatic NSCLC.⁴

“[While there are potential flaws of this study, this is a little different from some of the other strategies that we are already implementing where we are maybe ablating or resecting oligoprogressive disease or oligoresidual disease,” said Liu. “This is right up front we are going to radiate these lesions and give everyone a TKI.”

Patients with NSCLC who harbor an EGFR exon20 insertion generally have a poor prognosis. As such, an ongoing phase 1 study evaluating the anti-EGFR/MET bispecific antibody amivantamab (JNJ-61186372) demonstrated significant antitumor activity in this patient population and a manageable safety profile.⁵

The ORR was 36% with the agent and 41% for patients post-platinum chemotherapy. Of 39 evaluable patients, 14 achieved a partial response. The median PFS was 8.3 months in the overall population and 8.6 months for post-platinum patients.

Despite some increased infusion-related reactions, the regimen was well-tolerated, and safety was as expected.

According to the panelists, amivantamab may join a list of other potential agents that are designed to target this genetic subtype of NSCLC; however, it is a historically challenging mutation to target.

Antibody-Drug Conjugate (ADC) Shows Promise in HER2-Mutant NSCLC

Interim results of the ongoing phase 2 DESTINY-Lung01 trial demonstrated intriguing clinical activity with the ADC fam-trastuzumab deruxtecan-nxki (Enhertu) among patients with HER2-mutant metastatic NSCLC.⁶

The agent induced a confirmed ORR of 61.9% (95% CI, 45.6%-76.4%) with an estimated median PFS of 14 months within this patient population.

Additionally, a 90.5% disease-control rate (95% CI, 77.4%-97.3%) was observed, and the median duration of response has not yet been reached (95% CI, 5.3 months-not estimable).

Baseline patient characteristics showed that 45.2% of patients had CNS metastases. Additionally, the majority of patients (90.5%) received prior platinum-based therapy, while 54.8% and 19% received prior anti–PD-1/PD-L1 inhibitors and docetaxel, respectively.

Regarding safety, treatment-emergent AEs (TEAEs) associated with dose reduction were mainly fatigue and nausea while those associated with dose interruption were decreased neutrophil count and lung infection.

Five patients died as a result of TEAEs; however, they were not related to the treatment.

As with the breast cancer experience, interstitial lung disease (ILD) is a concern with trastuzumab deruxtecan. In the DESTINY-Lung01 study, 11.9% of patients developed grade 2 ILD with a median time-to-onset of 86 days. No grade 3, 4, or 5, ILD cases were reported.

“I thought this was one of the most impressive, if not the most impressive, lung abstract presented in the field,” said Patel. “The data that is shown is seen in real life which adds a flavor to it as well. It is a really good drug…and hits [multiple] targets simultaneously; it is like a cluster bomb approach. Amongst a half dozen agents being developed in this space, [trastuzumab deruxtecan] is probably what I would go for.”

New Targets Emerge in NSCLC

Registrational findings from the phase 1/2 ARROW trial showed that the potent, selective RET inhibitor pralsetinib (BLU-667) induced a 65% ORR, including a 6% CR rate among 116 response-evaluable patients with RET fusion–positive NSCLC. Moreover, responses were observed irrespective of RET fusion genotype or prior therapies.⁷

Additionally, the agent appears to have CNS penetrance as intracranial ORR in 9 patients with measurable baseline CNS metastases was 56%. Three patients achieved an intracranial CR with the agent.

Regarding safety, 4% of patients discontinued treatment due to TRAEs. Common grade 3 or higher AEs included increased AST, anemia, increased ALT, constipation, hypertension, neutropenia, diarrhea, white blood cell count decrease, fatigue, neutrophil count decrease, and asthenia.

The Board Predicts a Bright Future Ahead

In rounding out the discussion, Bauml asked the discussants to “take out their crystal balls” and provide a snapshot of what the future of NSCLC treatment may look like 5 years down the line.

Predictions included refining biomarkers to inform which patients should receive immunotherapy, developing additional combination strategies, improving comprehensive genetic testing, bringing immunotherapy earlier in the treatment paradigm, implementing blood-based testing more frequently, expanding the armamentarium in the oligometastatic setting, and targeting KRAS G12C mutations.

“If I had to put my nickel down on the thing most likely to be paradigm shifting in the next 5 years, neoadjuvant chemoimmunotherapy in earlier-stage NSCLC has the most likely chances of success,” said Riess. “In terms of more speculative things that may happen, looking at more plasma-based diagnostics, minimal residual disease, and timing and frequency of resistance mutations development [will be important].”

References:

1. Herbst RS, Tsuboi M, John T, et al. Osimertinib as adjuvant therapy in patients (pts) with stage IB-IIIA EGFR mutation positive (EGFRm) NSCLC after complete tumor resection: ADAURA. J Clin Oncol. 2020;38(suppl 18):LBA5. doi:10.1200/JCO.2020.38.18_suppl.LBA5
2. Wu Y, Zhong W, Wang Q, et al. CTONG1104: Adjuvant gefitinib versus chemotherapy for resected N1-N2 NSCLC with EGFR mutation—final overall survival analysis of the randomized phase III trial 1 analysis of the randomized phase III trial. J Clin Oncol. 2020;38(suppl 15):9005. doi: 10.1200/JCO.2020.38.15_suppl.9503
3. Rotow JK, Costa DB, Paweletz CP, et al. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9507. doi:10.1200/JCO.2020.38.15_suppl.9507
4. Wang X, Zeng M. First-line tyrosine kinase inhibitor with or without aggressive upfront local radiation therapy in patients with EGFRm oligometastatic non-small cell lung cancer: interim results of a randomized phase III, open-label clinical trial (SINDAS) (NCT02893332). J Clin Oncol. 2020;38(suppl 15):9508. doi:10.1200/JCO.2020.38.15_suppl.9508
5. Park K, John T, Kim SW, et al. Amivantamab (JNJ-61186372), an anti-EGFR-MET bispecific antibody, in patients with EGFR exon 20 insertion (exon20ins)-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9512. doi:10.1200/JCO.2020.38.15_suppl.9512
6. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer: interim results of DESTINY-Lung01. J Clin Oncol. 2020;38(suppl 15):9504. doi:10.1200/JCO.2020.38.15_suppl.9504
7. Gainor JF, Curigliano G, Kim DW, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi:10.1200/JCO.2020.38.15_suppl.9515