Efforts to Effectively Target Rare Oncogenes Propel Progress in Lung Cancer


With 9 approved markers in non–small cell lung cancer and a plethora of established and emerging therapies that have been designed to target them, the need for molecular testing is more important than ever.

Joel W. Neal, MD, PhD

Joel W. Neal, MD, PhD

With 9 approved markers in non–small cell lung cancer (NSCLC) and a plethora of established and emerging therapies that have been designed to target them, the need for molecular testing is more important than ever, according to Joel W. Neal, MD, PhD, who added that this group is projected to expand even further, with the emergence of targets such as HER2 exon 20 insertions and amplification, MET amplification, and NRG1 fusions.

“It is really [imperative] to do the testing; [we need] to find all these targetable molecular alterations. Tumor testing is the gold standard. However, I believe RNA tissue testing is going to be [an emerging] gold standard—especially for patients in whom we didn’t find [a driver alteration] by liquid biopsy or tumor tissue biopsy,” Neal said in a presentation delivered during the 19th Annual Winter Lung Cancer Conference®, an event hosted by Physicians’ Education Resource®, LLC.1 “The problem is, with next-generation sequencing and DNA testing of tissue, [the process] can be really slow. Liquid biopsies are fast and convenient. But [we’ll] keep looking until we find it. The rest of my talk is irrelevant if you miss the target in the patient.”

In his presentation, Neal, an associate professor of medicine/oncology at Stanford University, detailed the many advancements made in the treatment of patients with NSCLC whose tumors harbor ALK mutations, ROS1 rearrangements, MET exon 14 alterations, RET fusions, and NTRK fusions, as well as emerging information on newer targets that have come to light.

ALK Mutations

The preferred options for utilization in the first-line setting in ALK-positive lung cancer are brigatinib (Alunbrig) and alectinib (Alecensa), according to Neal. “That is because these drugs, along with lorlatinib [Lorbrena], have all cleanly been shown to be superior to crizotinib [Xalkori], the first drug that was FDA approved for [this disease],” Neal said.

In December 2015, the FDA granted an accelerated approval to alectinib for the treatment of patients with ALK-positive disease following progression on or were intolerant of crizotinib, based on data from 2 single-arm phase 2 clinical trials (NCT01871805; NCT01801111), which showed objective response rates (ORRs) ranging from 38% to 48%.2-3 Approximately 2 years later, in November 2017, they agent received a regular approval based on findings from the phase 3 ALEX trial (NCT02075840), after it was found to result in improved progression-free survival (PFS) vs crizotinib.4

Among 303 patients with ALK-positive disease who did not previously receive systemic therapy for metastatic disease, the median PFS with alectinib (n = 152) was 25.7 months (95% CI, 19.9–not estimable) per independent review committee (BIRC) assessment vs 10.4 months (95% CI, 7.7-14.6) with crizotinib (n = 151; HR, 0.53; 95% CI, 0.38-0.73; P < .0001).

In April 2017, the FDA granted an accelerated approval to brigatinib for use in patients with ALK-positive NSCLC whose disease was resistant to prior crizotinib.5 This decision was based on data from the phase 2 ALTA trial (NCT02737501). Final data from the trial, presented during the 2021 ESMO Congress, showed that at a median follow-up of 40.4 months (range, 0-52.4) with brigatinib (n = 137) and 15.2 months (range, 0.1-5.7) with crizotinib (n = 138), the median BIRC-assessed PFS was 24.0 months (95% CI, 18.5-43.2) and 11.1 months (95% CI, 9.1-13.0), respectively (HR, 0.48; 95% CI, 0.35-0.66; P < .0001).6

In November 2018, lorlatinib garnered an accelerated approval for the treatment of patients with metastatic ALK-positive NSCLC who progressed on 1 or more ALK TKIs.7 The indication was expanded in March 2021, for use in the frontline setting based on data from the phase 3 CROWN trial (NCT03052608), in which lorlatinib resulted in a 72% reduction in the risk of disease progression or death vs crizotinib in 296 treatment-naïve patients (HR, 0.28; 95% CI, 0.19-0.41; P < .0001) per BICR assessment.8

“Why are [these options] superior [to crizotinib]? Well, alectinib, brigatinib, and lorlatinib all [have shown the ability to] overcome many of the acquired resistance mutations, which are much more complicated than the relatively simple T790M that we used to see in EGFR-mutant lung cancer,” Neal explained. “In addition, most of the newer second- and third-generation ALK inhibitors have much better central nervous system [CNS] penetration, and [this population] has a high risk of brain metastases. As such, it’s clear that crizotinib is no longer the standard of care.”

Tumors that have become resistant to any of these drugs can be re-biopsied to identify secondary mutations. Only approximately 30% of those who have these tumors have secondary mutations that are targetable, according to Neal. “If we try second- or third-generation ALK inhibitors and they become ineffective, chemotherapy is the standard,” Neal said. “I do not recommend immunotherapy with that. I favor bevacizumab [Avastin]-based [treatment] or just platinum chemotherapy.”

ROS1 Gene Rearrangements

In March 2016, crizotinib was approved by the FDA for use in patients with advanced NSCLC whose tumors harbor a ROS1 gene alteration, based on findings from the phase 1 PROFILE 1001 trial (NCT00585195).9 Data from an expansion cohort of the phase 1 trial showed that among 50 patients who received the agent at the standard twice-daily dose of 250 mg, crizotinib elicited an ORR of 72% (95% CI, 58%-84%) with a median duration of response (DOR) of 17.6 months (95% CI, 14.5–not reached [NR]) and a median PFS of 19.2 months (95% CI, 14.4-NR).10

Additional findings from the EUROS1 cohort of a retrospective study showed that among 32 patients, 29 of whom evaluable for best response, the ORR achieved with crizotinib was 80%, the disease control rate was 86.7%, and the median PFS was 9.1 months.11

“It was just a stroke of luck that crizotinib happened to inhibit ROS1 gene rearrangements. It was originally designed was a MET inhibitor, and that’s what the phase 1 trial was,” Neal noted. “There’s a lot of evidence for crizotinib, which is an FDA-approved therapy based on data from phase 1 extensions of clinical trials and phase 2 expansion cohorts.”

Entrectinib (Rozlytrek) joined the US treatment arsenal for this population in August 2019 after the agent was shown to elicit an ORR of 78% in 51 adult patients examined across several clinical studies.12 Of the 40 patients who were noted to have experienced tumor shrinkage, 55% had shrinkage that persisted for at least 1 year.

Additional data from 32 patients with ROS1 inhibitor–naïve NSCLC who were enrolled across phase 1 and 2 trials examining the agent at a once-daily dose of 600 mg given in 4-week cycles showed that the BICR-assessed ORR was 69%, the median DOR was 28.6 months (95% CI, 6.8-34.8), and the median PFS was 29.6 months (95% CI, 7.7-36.6).13

“Entrectinib has a slightly different toxicity profile than crizotinib, which tends to be pretty well tolerated with some mild gastrointestinal [GI] effects and lower extremity edema. Entrectinib is also fairly well tolerated, with a bit more dysgeusia, fatigue, some dizziness, weight increases, and paresthesia,” Neal noted. “However, the biggest distinguishing factor between the 2 options is the CNS penetration. It’s clear that entrectinib can get into the CNS, whereas crizotinib does not have effective CNS penetration.”

Integrated data from three phase 1/2 trials—ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810), and STARTRK-2 (NCT02568267)—showed that at a median follow-up of 15.5 months, within the cohort of patients with ROS1-positive NSCLC who had measurable CNS disease (n = 12/53), the intracranial ORR achieved with entrectinib was 75.0% (95% CI, 42.8%-94.5%).14 The median intracranial DOR was 12.9 months (95% CI, 4.6–not evaluable [NE]), and the median intracranial PFS was 19.3 months (95% CI, 3.8-19.3).

“With crizotinib, usually we would see CNS response rates ranging from 20% to 30% and they are not durable,” Neal said. “Entrectinib is clearly the preferred agent for patients with newly diagnosed ROS1-positive NSCLC and brain metastases. Otherwise, it’s a toss-up right now.”

After disease progression on crizotinib or entrectinib, agents like lorlatinib and repotrectinib may represent potentially effective options. Data from a phase 2 trial (NCT01970865) showed that among 34 patients who had received prior crizotinib, lorlatinib elicited an ORR of 27%, a median DOR that had not yet been reached, and a median PFS of 8.5 months.15 Additionally, preliminary findings from the phase 1/2 TRIDENT-1 trial (NCT03093116) showed that among 18 patients with ROS1-positive NSCLC who were TKI pretreated, repotrectinib elicited a confirmed ORR of 39% (95% CI, 17%-64%).16

“After crizotinib or entrectinib, lorlatinib is not on label, but it is an agent to consider and see if it works,” Neal said. “Then there’s repotrectinib, not yet FDA approved, but has promising data both for systemic response rates after crizotinib and some CNS intracranial penetration. Repotrectinib is an exciting new therapy that we can keep our eyes on.”

MET Exon 14 Skipping Mutation

Crizotinib has known activity in patients with MET exon 14 (METex14) skipping mutations, according to Neal. Data from an expansion cohort of the phase 1 PROFILE 1001 (NCT00585195) showed that among 52 evaluable patients who harbored this mutation and received a twice-daily dose of 250 mg, the ORR was 32%, the median DOR was 9.1 months, and the median PFS was 7.3 months.17

However, 2 new agents have since garnered regulatory approval from the FDA for use in this patient population: tepotinib (Tepmetko) and capmatinib (Tabrecta).18,19 Findings from the phase 2 VISION trial (NCT02864992) indicated that 157 patients with METex14-altered disease, the ORR with tepotinib was 44.7% (95% CI, 36.7%-53.0%), the median DOR was 11.1 months (95% CI, 8.4-18.5), and the median PFS was 8.9 months (95% CI, 8.2-11.2).20 

Data from the phase 2 GEOMETRY mono-1 trial (NCT02414139) showed that capmatinib induced an ORR of 68% (95% CI, 48%-84%) by independent review in 28 treatment-naïve patients with METex14-altered disease.21 Among those who received 1 or 2 prior lines of therapy (n = 69), the ORR with capmatinib was 41% (95% CI, 29%-53%).

“They look similarly effective overall, with similar safety profiles. Both have better CNS penetration than crizotinib, and they look like they have a longer DOR overall,” Neal said. “I would go with tepotinib or capmatinib before I would consider crizotinib [in these patients].”

Other MET inhibitors, like glesatinib (MGCD265), savolitinib, and elzovantinib (TPX-0022) are currently under development, along with MET bispecific antibodies and antibody-drug conjugates.

RET Fusions

“Off label, we used to use a lot of drugs to treat those with RET gene rearrangements that were identified, but most of these drugs had a lot of VEGF activity, a lot of toxicity,” Neal explained. “Vandetanib [Caprelsa], cabozantinib [Cabometyx], even alectinib, were fairly toxic and not particularly well tolerated. As such, it was super exciting when a couple of new agents came out.”

In May 2020, the FDA granted an accelerated approval to selpercatinib (LOXO-292; Retevmo) for use in patients with RET-positive NSCLC based on findings from the NSCLC cohort of the phase 1/2 LIBRETTO-001 trial (NCT03157128).22 Among 105 patients who were previously treated with platinum chemotherapy, the ORR with the agent was 64% (95% CI, 54%-73%). Earlier data revealed that selpercatinib also elicited a CNS ORR of 91% (95% CI, 59%-100%); at a median follow-up of 9.6 months, the median PFS with the agent was 18.4 months (95% CI, 12.9-24.9).23 “We’re looking at an 18-month PFS, which is like what we see for EGFR and osimertinib [Tagrisso]—this is great,” Neal underscored. “Regarding [adverse] effects, there is peripheral edema, headaches, and some VEGF-associated toxicities, but they are generally manageable.”

Later that year, in September 2020, the FDA gave the green light to pralsetinib (Gavreto) for use in adult patients with RET fusion–positive NSCLC based on findings from the phase 1/2 ARROW trial (NCT03037385).24 At a data cutoff of May 22, 2020, the ORR was 61% (95% CI, 50%-71%) among 87 patients who previously received platinum-based chemotherapy; the ORR was 70% (95% CI, 50%-86%) among 27 treatment-naïve patients.25 Data from a post-hoc analysis of the trial indicated that the ORR was 51% (95% CI, 34%-68%) in those with a history of CNS involvement and prior platinum-based treatment.

“Pralsetinib…has similarly high efficacy and response rates in virtually all patients who receive it. [We also see] shrinkage of brain metastases. Both agents appear to be effective in the CNS,” Neal said. “As such, I would recommend selpercatinib or pralsetinib for the first-line treatment of these patients, as well as the consideration of chemotherapy and probably immunotherapy in the next-line setting.”

NTRK Fusions

NTRK was identified across many tumor types, including about 0.1% of NSCLCs. I think we have had 2 patients, ever, at Stanford who have been diagnosed with it,” Neal explained. “It is very, very rare in lung cancer, but there are a couple of FDA-approved therapies [for those whose tumors harbor it].”

In November 2018, larotrectinib (Vitrakvi) was granted an accelerated approval from the FDA for use in adult and pediatric patients with select solid tumors that have a NTRK gene fusion.25 Data from an analysis that incorporated findings from 12 patients with NSCLC who were enrolled to 2 clinical trials (NCT02122913; NCT02576431) showed that at a median follow-up of 12.8 months, larotrectinib (Vitrakvi) elicited an ORR of 75%, and the median DOR had not yet been reached (range, 3.9+ to 25.9+).26

“Larotrectinib works in almost all patients with lung cancer, as well as other NTRK-positive tumors,” Neal noted. “It comes with adverse effects, like edema and pyrexia.”

Entrectinib has also been indicated for use in the treatment of adult and pediatric patients aged 12 years or older with solid tumors that harbor an NTRK fusion.12 The indication is specific to those who have a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity and have progressed on therapy or have no alternative treatments.

Integrated data from ALKA-372-001, STARTRK-1, and STARTRK-2 showed that among 10 patients with NTRK-positive NSCLC, the ORR with entrectinib was 70.0% (95% CI, 34.75%-93.33%), the median DOR was not yet evaluable (95% CI, 10.4-NE), and the median PFS was 14.9 months (95% CI, 4.7-NE). Notably, the BICR-assessed intracranial response achieved with the agent was 66.7%.14

Additionally, LOXO-195 (BAY 2731954) is a selective TRK inhibitor that is currently under exploration in a phase 1 study (NCT03215511), where it has already demonstrated preliminary efficacy in those with resistance to prior TRK inhibitors mediated by TRK kinase mutations.27 Among 20 patients with a TRK kinase mutation, the ORR with the agent was 45%.

“If you have a patient with a NTRK-positive tumor, I recommend a clinical trial after progression through standard therapy and regular chemotherapy. Do not miss [this target], but I do think you will find it doing RNA or DNA sequencing, when you are looking for everything else.”

NRG1 and Other Emerging Targets

NRG1 rearrangements contain EGF-like binding domain of NRG1, or the ERBB3 ligand. The rearrangement is relatively uncommon, according to Neal, who added that the frequency is uncertain but likely occurs in less than 1% of those with NSCLC, and in never smokers.

“They can probably best be detected by RNA-based testing,” Neal added. “Afatinib has a little bit of response, 25%, but I’m not sure that I would recommend it off label yet.”

The fully human anti-HER3 monoclonal antibody seribantumab is under exploration in patients with solid tumors harboring an NRG1 fusion as part of the phase 2 CRESTONE trial (NCT04383210). Tarloxotinib bromide, an irreversible EGFR/HER2 inhibitor is under investigation in patients with NSCLC harboring EGFR exon 20 insertion and HER2-activating mutations, as well as other solid tumors with NRG1/ERBB gene fusions, as part of the phase 2 RAIN-701 trial (NCT03805841). Lastly, the HER2/HER3 bispecific antibody zanocutuzumab (MCLA-128) is being evaluated in patients with solid tumors harboring an NRG1 fusion as part of a phase 1/2 trial (NCT02912949).

“I am excited that some other agents [are under exploration, as well],” Neal concluded. “Let’s just say anti-HER3 inhibition looks like a possible way to target these [fusions].”


  1. Neal, JW. Targeting rare oncogenes in lung cancer. Presented at: 19th Annual Winter Lung Cancer Conference; February 4-6, 2022; Miami, FL. Accessed February 9, 2022.
  2. Gandhi L, Shaw A, Gadgeel SM, et al. A phase II, open-label, multicenter study of the ALK inhibitor alectinib in an ALK+ non-small-cell lung cancer (NSCLC) U.S./Canada population who had progressed on crizotinib (NP28761). J Clin Oncol. 2015;33(suppl 15):8019. doi:10.1200/jco.2015.33.15_suppl.8019
  3. Ou S-HI, Ahn JS, Petris LD, et al. Alectinib in crizotinib-refractory ALK-rearranged non-small-cell lung cancer: a phase II global study. J Clin Oncol. 2016;34(7):661-668. doi:10.1200/jco.2015.63.9443
  4. FDA approves Genentech’s Alecensa (alectinib) as first-line treatment for people with specific type of lung cancer. News release. Genentech; November 6, 2017. Accessed February 9, 2022.
  5. Brigatinib. News release. FDA; April 28, 2017. Accessed February 9, 2022.
  6. Popat S, Kim HR, Ahn MJ, et al. Brigatinib (BRG) vs crizotinib (CRZ) in ALK TKI-naïve ALK+ NSCLC: Final results from ALTA-1L. Ann Oncol. 2021;32(suppl 5):S954-S955. doi:10.1016/j.annonc.2021.08.1800
  7. Lorlatinib prescribing information. FDA. Accessed February 9, 2022.
  8. US FDA expands approval of Pfizer's Lorbrena as first-line treatment for ALK-positive metastatic lung cancer. News release. Pfizer, Inc.; March 3, 2021. Accessed February 9, 2022.
  9. FDA expands use of Xalkori to treat rare form of advanced non-small cell lung cancer. News release. FDA; March 11, 2016. Accessed February 9, 2022.
  10. Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971. doi:10.1056/NEJMoa1406766
  11. Mazières J, Zalcman G, Crinò L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33(9):992-999. doi:10.1200/JCO.2014.58.3302
  12. FDA approves Roche’s Rozlytrek (entrectinib) for people with ROS1-positive, metastatic non-small cell lung cancer and NTRK gene fusion-positive solid tumours. News release. Roche; August 16, 2019. Accessed February 9, 2022.
  13. Ahn M, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). J Thorac Oncol. 2017;12(11):S1783. doi:10.1016/j.jtho.2017.09.411
  14. Paz-Ares L, Dziadziuszko R, Drilon A, et al. Entrectinib in patients with ROS1-positive NSCLC or NTRK fusion-positive solid tumors with CNS metastases. J Thorac Oncol. 2019;14(10):S305. doi:10.1016/j.jtho.2019.08.611
  15. Ou S, Shaw A, Riely G, et al. Clinical activity of lorlatinib in patients with ROS1+ advanced non-small cell lung cancer: phase 2 study cohort EXP-6. J Thorac Oncol. 2018;13(10):S322-S323. doi:10.1016/j.jtho.2018.08.241
  16. Cho BC, Drilon AE, Doebele RC, et al. Safety and preliminary clinical activity of repotrectinib in patients with advanced ROS1 fusion-positive non-small cell lung cancer (TRIDENT-1 study). J Clin Oncol. 2019;37(suppl 15):9011. doi:10.1200/JCO.2019.37.15_suppl.9011
  17. Drilon A, Clark J, Weiss J, et al. Updated antitumor activity of crizotinib in patients with MET exon 14-altered advanced non-small cell lung cancer. J Thorac Oncol. 2018;13(10):S348. doi:10.1016/j.jtho.2018.08.300
  18. FDA grants accelerated approval to tepotinib for metastatic non-small cell lung cancer. News release. FDA; February 3, 2021. Accessed February 9, 2022.
  19. Novartis announces FDA approval of MET inhibitor Tabrecta for metastatic non-small cell lung cancer with METex14. News release. Novartis; May 6, 2020. Accessed February 9, 2022.
  20. Le X, Sakai H, Felip E, et al. Tepotinib efficacy and safety in patients with MET exon 14 skipping NSCLC: outcomes in patient subgroups from the VISION study with relevance for clinical practice. Clin Cancer Res. Published online November 17, 2020. doi:10.1158/1078-0432.CCR-21-2733
  21. Wolf J, Seto T, Han J-Y, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944-957. doi:10.1056/NEJMoa2002787
  22. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. News release. FDA; May 8, 2020. Accessed February 9, 2022.
  23. Lilly announces positive results for selpercatinib (LOXO-292), demonstrating a 68 percent objective response rate and sustained durability in heavily pretreated RET fusion-positive non-small cell lung cancer. News release. Eli Lilly and Company; September 9, 2019. Accessed February 9, 2022.
  24. Gainor JF, Curigliano G, Jim D-W, et al. Pralsetinib for RET fusion-positive non-small-cell lung cancer (ARROW): a multi-cohort, open-label, phase 1/2 study. Lancet Oncol. 2021;22(7):959-969. doi:10.1016/S1470-2045(21)00247-3
  25. FDA approves larotrectinib for solid tumors with NTRK gene fusions. News release. FDA; November 26, 2018. Accessed February 9, 2022.
  26. Farago A, Kummar S, Moreno V, et al. Activity of larotrectinib in TRK fusion lung cancer. J Thorac Oncol. 2019;14(10):S283-S284. doi:10.1016/j.jtho.2019.08.570
  27. Hyman D, Kummar S, Farago A, et al. Abstract CT127: phase I expanded access experience of LOXO-195 (BAY 2731954), a selective next-generation TRK inhibitor (TRKi). Can Res. 2019;79(13). doi:10.1158/1538-7445.AM2019-CT127
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