Biomarker Testing to Optimize NSCLC Care: Multidisciplinary Perspectives

Biomarker Testing in Advanced NSCLC

Matthew Gubens, MD, MS:
In the 13 years since the first targeted therapy was found to improve OS compared with standard chemotherapy in advanced NSCLC in the first-line setting, many targeted therapies have received FDA approval.¹⁴ Therefore, biomarker testing is very important for optimal treatment selection and for patient survival.

EGFR Mutations in Advanced NSCLC: Overview

Matthew Gubens, MD, MS:
EGFR mutations are found in approximately 10% of patients with NSCLC in the United States but are most common in patients who have never smoked tobacco, patients with a minimal tobacco smoking history, patients of East Asian ethnicity, and patients who are women.¹⁵

The majority of patients have “classical” mutations that are EGFR exon 19 deletions and exon 21 L858R substitution mutations. A smaller subset of patients has “atypical” EGFR mutations, namely, exon 18 G719X point mutations, exon 21 L861Q point mutations, and exon 20 S768I point mutations. Lastly, there are EGFR exon 20 insertion mutations.

EGFR‑directed tyrosine kinase inhibitors (TKIs), particularly the third-generation drug osimertinib, have shown remarkable benefit for patients with classical mutations and arguably for patients with atypical mutations, too. The current standard of care is to use first-line osimertinib, which has demonstrated an overall response rate (ORR) of 80%, median PFS of 17.7 months, and a median OS of 38.6 months among patients with EGFR mutation-positive NSCLC.

The third-generation TKI osimertinib is less toxic than the first-generation and second-generation TKIs, which are less specific for the mutated EGFR and inhibit the wild‑type form of EGFR in the skin and gut more than osimertinib does. Although mild to moderate rash and diarrhea remain key toxicities associated with EGFR TKIs, these adverse events are less common with osimertinib, and proactive management may reduce their severity.

ALK Rearrangements in Advanced NSCLC: Overview

Matthew Gubens, MD, MS:
Another breakthrough in NSCLC was the realization that approximately 4% to 6% of patients have ALK rearrangements.¹⁶ Patients with this alteration are typically younger with minimal or no tobacco history, and there do not appear to be the same gender and racial differences that have been seen with EGFR mutations.

There are currently 5 FDA-approved TKIs targeting ALK, 3 of which are preferred in the first‑line setting.⁶ Out of the 3 preferred first-line options, alectinib and brigatinib are second-generation TKIs, whereas lorlatinib is a third-generation TKI. All 3 of these agents are superior to the first-generation ALK inhibitor crizotinib. In clinical trials for patients with previously untreated, advanced ALK-positive NSCLC, alectinib had an ORR of 83% and a median PFS of 34.8 months.^17,18 First-line brigatinib demonstrated an ORR of 74% and median PFS of 29.4 months in patients with advanced ALK-positive NSCLC.¹⁹ The third-generation ALK-directed TKI, lorlatinib demonstrated an ORR of 77%. Although lorlatinib was initially approved after disease progression on first-line therapy in the resistance setting, lorlatinib is also a first‑line option.^20,21

Shared decision-making is very important because of the distinct toxicity profiles of these agents. Alectinib causes myalgias, brigatinib causes early pulmonary events, and lorlatinib has unique neurocognitive toxicities and affects lipid profiles.

ROS1 Rearrangements in Advanced NSCLC: Overview

Matthew Gubens, MD, MS:
ROS1 rearrangements occur in 1% to 2% of patients with NSCLC, and it typically occurs in younger patients and in patients with minimal or no tobacco history.²² Crizotinib and the next-generation ROS1 inhibitor entrectinib are approved first‑line therapies for patients with advanced NSCLC harboring ROS1 rearrangements, and entrectinib has activity in patients with central nervous system metastases. In patients with ROS1-rearranged advanced NSCLC, crizotinib had an ORR of 72% and a median PFS of 19.3 months.²³ The ORR was 67%, and the median PFS was 15.7 months with entrectinib in patients with advanced ROS1-fusion–positive NSCLC.²⁴

At progression, healthcare professionals can consider lorlatinib (off label) or pemetrexed‑based chemotherapy.⁶ Key safety findings with these drugs include visual disturbances with crizotinib and weight gain with entrectinib.

BRAF V600E Mutations in Advanced NSCLC: Overview

Matthew Gubens, MD, MS:
BRAF V600E mutations are better known in the melanoma setting, but they also are present in 1% to 2% of NSCLC, most commonly in patients with a history of tobacco use.²⁵ The only approved drug regimen in patients with BRAF V600E–mutant metastatic NSCLC is dabrafenib plus trametinib, which in the first-line setting had an ORR of 63.9%, median PFS of 10.8 months, and median OS of 17.3 months. In second and later lines, the ORR was 68.4%, median PFS was 10.2 months, and a median OS was 18.2 months.²⁶ The efficacy in both first-line and later lines of therapy is unique and different from other targeted therapies where the best response occurs in the first-line setting. I tend to use dabrafenib plus trametinib as first-line therapy, but the combination is also a reasonable option in subsequent lines of therapy.

The incidence of pyrexia is high and can be complicated by hypotension, rigors, chills, dehydration, or renal failure. Antipyretics are recommended for secondary prophylaxis, and corticosteroids can be used for second or subsequent pyrexia. But largely, it is possible to make this oral combination work for patients.

New and Emerging Therapeutic Targets Beyond EGFR, ALK, ROS1, BRAF Alterations

Matthew Gubens, MD, MS:
In NSCLC, EGFR, ALK, ROS1, and BRAF alterations have been established for some time. Newer therapeutic targets include NTRK fusions, MET exon 14 skipping mutations, and RET fusions, where there are first‑line indications. There are 2 new second‑line options for KRAS G12C mutations and EGFR exon 20 insertion mutations. HER2 targeted therapies are also on the horizon in NSCLC.

NTRK Rearrangements and TRK Fusions in Cancer

Matthew Gubens, MD, MS:
NTRK has a normal role in neuronal development, but in cancer, rearrangement of NTRK causes overexpression or constitutive activation of the tyrosine kinase domain.²⁷NTRK fusions are rare events, affecting fewer than 1% of patients with lung cancer.

Efficacy of Pan-TRK Inhibitors Regardless of Tumor Type

Matthew Gubens, MD, MS:
Larotrectinib was the first molecularly targeted drug to gain tumor-agnostic FDA approval; entrectinib also has received tumor-agnostic approval. Both larotrectinib and entrectinib elicit activity across multiple tumor types. In a pan-tumor clinical trial, the ORR with larotrectinib in 12 patients with NSCLC was 75%, and duration of response for all-comers was 35.2 months.²⁸ The ORR with entrectinib in 10 patients with NSCLC was 70%, with a duration of response of 10.4 months across multiple tumor types.²⁹

cMET Receptor Tyrosine Kinase and MET Exon 14 Skipping Mutations in NSCLC

Matthew Gubens, MD, MS:
MET has a normal role in embryogenesis and wound healing, and the MET exon 14 skipping mutation occurs in 3% to 4% of nonsquamous NSCLC and 20% to 30% of sarcomatoid cancers.^30-32MET exon 14 skipping mutations result in constitutive activity of the receptor tyrosine kinase and oncogenic transformation. Patients with this alteration are more likely to have a tobacco history, but it is important to perform NGS testing for all patients regardless of their age and tobacco history. Whereas DNA-based NGS is able to detect MET exon 14 skipping mutations, RNA-based NGS has increased sensitivity for its detection.

Capmatinib and Tepotinib: Approved Selective MET Inhibitors for METex14-Positive Advanced NSCLC

Matthew Gubens, MD, MS:
Capmatinib and tepotinib are both effective and approved by the FDA for patients with MET exon 14 mutation–positive metastatic NSCLC. The ORR in patients who previously received platinum-based chemotherapy was 44% for capmatinib and 44.6% for tepotinib; however, the ORR with capmatinib in treatment-naive patients was 66.7% compared with 44.9% with tepotinib in this patient population.^33-36 The median PFS in previously untreated patients was reasonable for both drugs, and the median duration of response rivals what one would expect with unselected chemotherapy or immunotherapy in the first-line setting. The tumor response with respect to change in tumor size from baseline with capmatinib follows a similar trend to that was obtained with tepotinib in treatment-naive patients. So, either drug is reasonable to use as first-line therapy for patients with MET exon 14 mutation-positive advanced NSCLC.

RET Receptor Tyrosine Kinase and RET Fusions in NSCLC

Matthew Gubens, MD, MS:
RET plays an important role in neural and genitourinary development. RET fusions give rise to proteins with a constitutively active RET kinase domain, making them an important target in NSCLC.^37-39 ET fusions are present in 1% to 2% of nonsquamous NSCLC and 10% to 20% of papillary thyroid carcinoma. Like other fusions, RET fusions can be detected by DNA-based NGS, but sensitivity is increased with RNA-based NGS testing.

Selpercatinib and Pralsetinib: Approved RET Inhibitors for RET Fusion–Positive Advanced NSCLC

Matthew Gubens, MD, MS:
Selpercatinib and pralsetinib are both approved by the FDA for patients with metastatic RET fusion–positive NSCLC. The ORR in patients with advanced NSCLC who previously have received platinum-based chemotherapy was 61% with either selpercatinib or pralsetinib.^40-42 In treatment-naive patients, however, the ORR was 84.1% with selpercatinib and 70% with pralsetinib. With selpercatinib, the duration of response was 20.2 months, and it was 9.0 months with pralsetinib in treatment-naive patients. Overall, the response rate is higher in the first-line setting when either of these drugs is used.

KRAS Mutations in Advanced NSCLC

Matthew Gubens, MD, MS:
Mutant KRAS is the most common oncogenic driver in NSCLC. It is present in 37% of nonsquamous NSCLC and 4% of squamous cell NSCLC.⁴³KRAS mutations are heterogenous, which makes drug design against these mutations challenging. The KRAS G12C mutation is the most common variant and comprises 40% of KRAS mutations overall, with an incidence of approximately 15% in lung adenocarcinoma. Although the KRAS G12C mutation is the only actionable KRAS mutation to date, it represents an important step in the right direction.

Phase II CodeBreaK100 Trial: Sotorasib in Pretreated Advanced KRAS G12C Mutation–Positive NSCLC

Matthew Gubens, MD, MS:
Sotorasib was evaluated in the phase II CodeBreak100 trial that enrolled patients with advanced solid tumors harboring KRAS G12C mutations.⁴⁴ In the cohort of patients with previously treated advanced NSCLC, the confirmed ORR was 40.7%, and the disease control rate was 83.7%. The median duration of response was 12.3 months, and the median PFS was 6.3 months. Based on the results of this trial, sotorasib received accelerated FDA approval for patients with KRAS G12C mutation–positive locally advanced or metastatic NSCLC who have received ≥1 prior systemic therapy.

The treatment-related adverse events (TRAEs) associated with sotorasib therapy include diarrhea (31%), elevated liver enzymes (18%), nausea (16%), and fatigue (12%). Sotorasib was well tolerated with no fatal TRAEs or TRAEs leading to discontinuations after 1 year. Grade 3 or 4 adverse events were observed in 21% of patients, of which only 1 patient experienced an onset of grade 3 or 4 hemolytic anemia after 1 year. It is exciting that KRAS G12C mutations finally can be targeted; however, further work is still needed in identifying innate and acquired resistance mechanisms to sotorasib.

KRYSTAL-1: Adagrasib in Pretreated Advanced KRAS G12C Mutation–Positive NSCLC

Matthew Gubens, MD, MS:
Adagrasib is an investigational, orally bioavailable, highly selective and potent small-molecule inhibitor of KRAS G12C. Adagrasib achieved an ORR of 42.9% and a disease control rate of 79.5% in patients with KRAS G12C mutation–positive NSCLC who previously have received platinum-based chemotherapy and an immune checkpoint inhibitor.⁴⁵ The median PFS was 6.5 months, and the median OS was 12.6 months. Grade ≥3 TRAEs included diarrhea (0.9%), nausea (4.3%), fatigue (6.9%), dyspnea (10.3%), hyponatremia (8.6%), and pneumonia (12.1%). Of note, there were 2 grade 5 TRAEs from pulmonary hemorrhage and cardiac failure, and TRAEs led to discontinuation in 6.9% of patients and dose reduction in 51.7%. Adagrasib is currently under FDA review for use in the treatment of patients with KRAS G12C mutation–positive NSCLC who have received ≥1 prior line of systemic therapy.

EGFR Exon 20 Insertions in Advanced NSCLC

Matthew Gubens, MD, MS:
EGFR exon 20 insertion mutations account for approximately 10% of EGFR mutations among patients with advanced NSCLC and 1% of actionable biomarkers in this space overall.⁴⁶ Unfortunately, EGFR TKI therapy is markedly less effective in patients with EGFR exon 20 insertion mutations compared with patients who have common EGFR mutations. A retrospective study assessed real-world clinical outcomes in patients with advanced NSCLC harboring EGFR exon 20 insertion mutations vs common EGFR mutations. The median real-world PFS among patients with EGFR exon 20 insertion mutations was 2.9 months vs 10.5 months among patients with common EGFR mutations (adjusted HR: 2.69; 95% CI: 2.1-3.6; P <.0001).⁴⁷ This is partly a drug delivery problem due to many exon 20 insertion mutations resulting in configurations that limit the binding of EGFR TKIs to their binding sites.

Recently Approved Second-line Therapies for Pretreated EGFR Ex20ins+ Advanced NSCLC

Matthew Gubens, MD, MS:
Two agents, amivantamab and mobocertinib, recently received accelerated FDA approval for patients with locally advanced and metastatic NSCLC harboring EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy. Amivantamab is a fully humanized bispecific antibody targeting EGFR and MET, and mobocertinib is a first-in-class, irreversible EGFR exon 20 insertion mutation–specific TKI.^47-49

In the phase I CHRYSALIS trial for previously treated patients with NSCLC harboring EGFR exon 20 insertion mutations, amivantamab demonstrated an ORR of 40%, with a median duration of response of 11.1 months. The median PFS was 8.3 months, and the median OS was 22.8 months.⁴⁸ In the phase I/II Study 101 trial for patients with NSCLC, mobocertinib demonstrated an ORR of 28%, with a median duration of response of 17.5 months. The median PFS was 7.3 months, and the median OS was 24 months among patients with exon 20 insertion mutation–positive disease who previously had received platinum-based therapy.⁴⁹

What Is HER2-Positive NSCLC?

Matthew Gubens, MD, MS:
HER2 mutations are present in 2.6% of patients with NSCLC.⁵⁰ Among 920 patients with HER2 mutations, approximately 71% had no history of tobacco use. The majority of patients with HER2 mutation–positive NSCLC were diagnosed with stage IV disease. Of 115 NSCLC specimens, HER2 overexpression was found in 23%, with a high expression in 4% of the patients.⁵¹HER2 gene amplification was identified in 9/41 (22%) of samples, of which approximately 7% had high amplification. Of note, HER2 is an emerging and actionable target in NSCLC.

Targeting HER2 Exon 20 Insertions in NSCLC: Several Agents Under Active Investigation

Matthew Gubens, MD, MS:
We have seen efficacy with drugs that have received FDA approval for the treatment of breast cancer, such as T-DM1 and trastuzumab deruxtecan (T‑DXd). In particular, T‑DXd is a HER2-directed antibody–drug conjugate that demonstrated a confirmed ORR of 55% with a median duration of response of 9.3 months and a median PFS of 8.2 months in a phase II study of 91 patients with metastatic HER2-mutant NSCLC that is refractory to standard therapy.⁵² Of note, HER2 mutation now appears in the NCCN guidelines as an emerging biomarker in NSCLC. Given these data, I would strongly consider off‑label treatment with T-DXd if the patient’s disease harbors a HER2 exon 20 insertion mutation, at least in the second line. Other HER2-targeting agents that are currently under investigation in NSCLC include poziotinib and tarloxotinib.

2022 Treatment Paradigm for Molecular Biomarker–Positive Advanced NSCLC

Matthew Gubens, MD, MS:
The current treatment paradigm for molecular biomarker‑positive advanced NSCLC includes an algorithm to follow for several biomarkers.⁶ There are now first‑line targeted agents for 7 genetic alterations, and second-line and beyond targeted treatment options for patients with disease harboring KRAS G12C mutations and EGFR exon 20 insertion mutations. Although these targeted agents are very effective in patients harboring these alterations, it is critical to remember that the appropriate targeted treatment cannot be offered to a patient if an alteration has not been identified.

Several other alterations—such as NRG1 gene fusions, FGFR gene alterations, and TROP2 overexpression—are emerging. If these alterations are identified, ongoing trials of drugs targeting these alterations are being investigated in clinical trials for patients with advanced NSCLC, and some of these agents already have shown promising activity in other cancer types. One cannot overemphasize the importance of broad biomarker testing at diagnosis of advanced NSCLC to identify patients with these alterations to guide the treatment approach.

Molecular and PD-L1 Testing Should Be Done at Initial Diagnosis of Advanced NSCLC to Guide 1L Tx Decisions

Matthew Gubens, MD, MS:
A substantial number of patients do not have targetable alterations. Even for these patients, results from molecular testing and determination of PD-L1 expression level are still important for the medical oncologist and pathologist to have in hand. This is particularly important because the PD‑L1 status plays a key role in the choice of first‑line therapy for patients with advanced NSCLC without any actionable alteration.

2022 Paradigm for Immunotherapy in Advanced NSCLC Without an Actionable Mutation

Matthew Gubens, MD, MS:
Patients with advanced NSCLC and a PD‑L1 expression level of ≥50% can receive single‑agent anti–PD‑1/PD-L1 antibody therapy due to the high ORR and duration of benefit in this patient population.⁶ Immune checkpoint inhibitors that have received FDA approval for use as single agents for patients with newly diagnosed advanced NSCLC that does not harbor any actionable alterations are pembrolizumab, atezolizumab, and cemiplimab.

However, patients with PD-L1 expression level of <1% to 49% should generally receive chemotherapy in combination with either an immune checkpoint inhibitor or dual immune checkpoint inhibitor therapy. Of note, there is a role for PD‑1 inhibition in combination with CTLA-4 inhibition with or without chemotherapy in this setting. The optimal choice of first-line treatment combination has not yet been settled in comparative trials. Again, it is important to have the PD-L1 status in hand to be able to make the best upfront treatment decision, especially if the disease does not harbor any actionable alteration.

Clinical Implications of Biomarker Testing in NSCLC

Matthew Gubens, MD, MS:
Due to the availability of highly effective targeted therapies, testing for biomarkers or genetic alterations such as EGFR mutations, ALK fusions/rearrangements, ROS1 rearrangements, BRAF mutations, NTRK fusions, MET exon 14 skipping mutations, or RET fusions at diagnosis is mandatory for all patients with nonsquamous NSCLC. It is also important to note that there are newly available targeted therapies for patients with advanced NSCLC harboring KRAS G12C mutations and EGFR exon 20 insertion mutations. In essence, broad molecular testing with NGS for both required and emerging biomarkers is highly recommended and is the standard of care at this point in time.

PD‑L1 testing remains important in the initial treatment decision-making phase; however, it is very important to avoid the temptation to initiate treatment solely based on the PD-L1 status before receiving the molecular testing results from the pathology laboratory. This is particularly important because the PD-L1 status is irrelevant in the first-line setting in tumors with actionable alterations. For instance, it is important not to start upfront chemoimmunotherapy in a patient with an EGFR mutation for whom ideally first-line osimertinib is the optimal treatment choice. Doing so induces unnecessary toxicity and causes a missed opportunity to give the best and least toxic initial systemic therapy. Although testing rates are not yet ideal and the turnaround times can sometimes delay treatment initiation, appropriate communication and collaboration between the medical oncologist and the pathologist are strongly encouraged to circumvent these challenges.