Disease Analysis: Non-Small Cell Lung Cancer (NSCLC)
Author: Ellie Davenport
Publisher: Datamonitor Healthcare
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Disease Overview
Lung cancer is generally categorized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Of these, NSCLC is the most common type of lung cancer, accounting for roughly 85% of all cases. NSCLC can be further divided into non-squamous and squamous NSCLC histologies. Squamous NSCLC refers to patients with squamous cell carcinoma, whereas non-squamous NSCLC includes patients with adenocarcinoma, large cell carcinoma, and other less common subtypes. Incidence of adenocarcinoma and squamous cell carcinoma varies greatly by both geographic region and gender. In general, adenocarcinoma comprises approximately 30–50% of all lung cancer cases, while squamous cell carcinoma accounts for roughly 25–35%.
Latest key takeaways
- Datamonitor Healthcare estimates that in 2018, there were 1.8 million incident cases of non-small cell lung cancer (NSCLC) worldwide, and expects that number to increase to 1.9 million incident cases by 2027. The majority of NSCLC diagnoses (65.4%) worldwide are in males, ranging from 52.9% to 72.1% across regions.
- In recent years, the number of therapies targeting specific sensitizing mutations in metastatic NSCLC has drastically increased, permanently altering the treatment landscape. Many of the new drugs have shown dramatically increased response rates over the previous standard-of-care therapies. However, given the relatively small percentage of metastatic NSCLC patients presenting with each oncogenic driver, competition is fierce and first-to-market advantage is critical.
- Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1)-targeted monoclonal antibodies for NSCLC are forecast to remain the best-selling class of drugs for this indication. Keytruda was the first PD-1/PD-L1 inhibitor to gain regulatory approval for first-line NSCLC patients without an oncogenic driver and has risen to dominance in this market as label expansions have broadened its target patient population and as late-phase trials have revealed consistently positive data. Furthermore, the commercial potential of this class of drugs will increase over the forecast period as the use of checkpoint inhibitors will likely soon extend beyond the metastatic patient population. Label expansions into earlier treatment settings may provide an opportunity for the other checkpoint inhibitors to differentiate themselves from Keytruda and carve out a niche in this lucrative market.
- PD-L1 inhibitor Imfinzi’s approval for sequential therapy of locally advanced patients following chemoradiation minimizes direct competition with established immunotherapies and has allowed the drug to secure a modest market share.
- Third-generation EGFR inhibitor Tagrisso is now the first-line standard-of-care treatment for NSCLC patients whose tumors harbor activating EGFR mutations (exon 19 deletion or L858R point mutation). Despite competition from Tarceva, Iressa, Gilotrif, Vizimpro, and Alunbrig, Tagrisso will continue to dominate the EGFR inhibitor market due to continued uptake and a recent label expansion into the adjuvant setting. However, Janssen’s ongoing Phase III MARIPOSA study of amivantamab in combination with lazertinib is the first head-to-head trial against Tagrisso, and the combination could eventually threaten Tagrisso’s position in the first-line setting.
- Both Rybrevant and Exkivity have recently been approved for metastatic NSCLC patients whose tumors harbor an exon 20 insertion mutation in EGFR, a patient population where there were previously no approved targeted therapies. Although Exkivity has demonstrated more favorable overall survival data, Rybrevant won the first-to-market advantage and will likely dominate this setting. However, the relative rarity of this mutation limits the commercial potential of an approval in this patient population, and both therapies are also in development for the treatment of other actionable mutations.
- Alecensa has become the new first-line standard of care for ALK rearrangement-positive NSCLC. The Phase III ALEX study demonstrated superior progression-free survival when treated with Alecensa compared with previous standard of care Xalkori. Alecensa will likely remain the class leader even though it will face competition in the first-line setting from other ALK inhibitors such as Zykadia, Alunbrig, and Lorbrena. Dual ALK/ROS1 inhibitor Lorbrena is also approved in both the first- and second-line settings, but has experienced only modest uptake thus far.
- The ALK inhibitors Rozlytrek and Xalkori are both approved for the treatment of metastatic NSCLC patients whose tumors have a ROS1 rearrangement or fusion. Rozlytrek is also approved as a monotherapy for patients with NTRK+ gene fusions. The combined data from Rozlytrek’s development program compare favorably to the data for Xalkori, particularly in patients with CNS metastases at baseline. ROS1 gene rearrangements are present in 1–2% of NSCLC patients, while NTRK fusions are present in approximately 0.2% of cases.
- The combination of BRAF inhibitor Tafinlar and MEK inhibitor Mekinist has become the standard of care for advanced or metastatic NSCLC with BRAF V600E mutations. However, only 1–2% of NSCLC patients have a BRAF V600E mutation, which limits the combination’s commercial potential.
- Two MET inhibitors, Tabrecta and Tepmetko, have been approved for NSCLC patients with a MET exon 14 skipping mutation in the US and Japan. Both drugs are also in development for MET-amplified NSCLC and for patients with EGFR-mutated, c-MET-amplified NSCLC who have progressed after EGFR inhibitor treatment. Potential label expansions into these treatment settings represent a noteworthy market opportunity. Approximately 1–4% of NSCLC patients have a MET exon 14 skipping mutation.
- Retevmo was the first drug approved for the treatment of patients with RET fusion-positive NSCLC, and the confirmatory Phase III LIBRETTO-431 trial is ongoing. In its pivotal Phase I/II trial, Retevmo demonstrated efficacy in RET fusion-positive patients and in a subgroup of patients with brain metastases. However, Retevmo will face competition from Gavreto, which has also been approved in the US and Europe.
- The approval of the first KRAS inhibitor, Lumakras, for previously treated patients with KRAS G12C-mutant NSCLC is an encouraging step forward for a patient population that was previously thought to be undruggable. This is a significant market opportunity for Lumakras, given that approximately 13% of NSCLC patients have KRAS p.G12C mutations. Adagrasib, another KRAS inhibitor, is in development for the second-line or later treatment of patients with KRAS G12C-mutant NSCLC.
- As checkpoint inhibitor regimens dominate in the first-line setting for patients without sensitizing mutations, effective treatments for the post-immunotherapy setting remain the largest unmet need within the indication. Treatment for these patients is largely palliative, and patients currently have very limited treatment options. A number of therapies, including Cabometyx, Lenvima, sitravatinib, and tusamitamab ravtansine, are in development for this treatment setting.
- The overall likelihood of approval of a Phase I NSCLC asset is 8.6%, and the average probability a drug advances from Phase III is 38.8%. NSCLC drugs, on average, take 9.2 years from Phase I to approval, compared to 9.7 years in the overall oncology space.
- Key upcoming catalysts include topline Phase III results for Libtayo in combination with Opdivo, a supplemental NDA filing for Imfinzi based on the Phase III POSEIDON trial, and a supplemental EU filing for Rozlytrek for the first-line treatment of ROS1 mutation-positive NSCLC patients.
CONTENTS
11 OVERVIEW
11 Latest key takeaways
13 DISEASE BACKGROUND
13 Definition
13 Risk factors
14 Symptoms
15 Screening
15 Diagnosis
15 Prognosis
16 Patient segmentation
18 TREATMENT
18 Early-stage NSCLC (Stage I–II; all subtypes)
18 Advanced NSCLC (Stage IIIa–IIIc; all subtypes)
18 Metastatic NSCLC: molecular profiling
19 Metastatic NSCLC: EGFR+
20 Metastatic NSCLC: EGFR+, second line
21 Metastatic NSCLC: KRAS G12C mutation
21 Metastatic NSCLC: ALK+
22 Metastatic NSCLC: ROS1+
23 Metastatic NSCLC: BRAF V600E mutation
24 Metastatic NSCLC: MET exon 14 skipping
25 Metastatic NSCLC: RET+
26 Metastatic NSCLC: NTRK+
27 Metastatic NSCLC: PD-L1+ (≥50%)
28 Metastatic NSCLC: PD-L1+ (≥1–49%)
29 Metastatic NSCLC: all other
30 Metastatic NSCLC: maintenance therapy
31 Metastatic NSCLC: all other second line or later
33 EPIDEMIOLOGY
33 Incidence methodology
36 Prevalence of common non-small cell lung cancer biomarkers
38 MARKETED DRUGS
48 PIPELINE DRUGS
73 KEY REGULATORY EVENTS
73 US Poziotinib Approval Expected
73 US FDA Puts Mirati’s KRAS Challenger To Amgen In The Slow Lane
73 Foreign Data: Sintilimab’s Development Shows What Not To Do When Pursuing US Approval
74 Casualty Of Change? Innovent/Lilly’s Chinese PD-1 Inhibitor Sintilimab Falls Hard At US FDA Panel
74 New Submissions Under FDA Review
74 Tremelimumab Filed In EU For NSCLC
74 Keeping Track: Breakthrough Designations Fuel Expansion Of Genomically-Defined NSCLC Therapy
75 Pfizer, CStone Score China’s Seventh Immuno-Oncology Approval
75 13 New Drugs On Track For EU Approval
75 Rx For Immuno-Oncology Excess? Top US FDA Cancer Officials Take On Development ‘Wild West’
76 Spectrum Eyes Niche NSCLC Market With Poziotinib NDA
76 Evrysdi & Tagrisso Among Myriad Products To Win English Funding
77 Sotorasib Gets Green Light From EMA For KRAS G12C Mutated NSCLC
77 Scotland’s HTA Body OKs New Indications For Tagrisso And Tecentriq
77 EMA Schedules Oral Explanation Meetings For Four Sponsors
77 Tyvyt Regulatory Setback
78 Tecentriq Becomes First PD-1/L1 For Adjuvant NSCLC
78 EMA Recommends Granting Conditional Marketing Authorization To Rybrevant
78 EGFR Exon20-Mutated NSCLC Gets A New Option With Exkivity
79 Roche/Blueprint’s Gavreto Among Nine Drugs To Win EU Marketing Thumbs Up
79 Amgen Strikes Early Access Deal In England For Lung Cancer Drug Lumakras
80 Mobocertinib, Asciminib & Surufatinib Among Latest New Filings In EU
80 More PD-1/L1 Inhibitor Adjuvant Submissions
80 Foundation Medicine Obtains FDA Approval For Non-Small Cell Lung Cancer Companion Diagnostic
80 Mirati Marks Another Milestone With Adagrasib
81 Approvals Boost AstraZeneca’s China Cancer Presence
81 NICE Says Yes To Tecentriq For NSCLC
81 Guardant Health Receives FDA Companion Diagnostic Nod
82 Amgen Wins World-First Lumakras Approval, Faces Challenge Of COVID-Era Launch
82 New Approval Strengthens Top Spot For AstraZeneca’s Tagrisso
82 China Biotechs Race To Get First Global IO Green Light Within Months
82 J&J’s Rybrevant May Find Limited Uptake Outside Academic Centers
83 Takeda Touts Mobocertinib Mechanism
83 UK Pips EU To The Post With ‘Project Orbis’ Approval For Tagrisso
83 China Inc. Shines In Latest Batch Of Approvals
84 Positive CHMP Opinion For Tecentriq
84 US FDA Grants Full Approval For Pfizer’s Lorbrena
85 PROBABILITY OF SUCCESS
86 LICENSING AND ASSET ACQUISITION DEALS
86 Tianjin Tasly Inks $40m Licensing Deal With Sutro For ADC Cancer Treatment
86 Novartis Expands BeiGene Tie-Up To TIGIT Inhibitor In $1bn-Plus Option Deal
86 Taiho Takes Up Japan/Asia Option For Arcus Oncology Antibodies
87 Blueprint May Corner EGFR Exon Mutated Lung Cancer Market With Lengo Buyout
87 Deal Watch: Sanofi To Tap Owkin’s AI, Machine Learning In Oncology
87 Zai Lab Licenses Two Blueprint Medicines EGFR Inhibitors
87 Takeda Licenses Two Drugs To Calithera
88 Turning Point And EQRx Announce Clinical Collaboration
88 Fosun Licenses Cancer Supportive Care Drug Rights From Helsinn
88 GSK Exits $4.2bn Cancer Drug Deal With Merck KGaA After Multiple Failures
89 Innovent In-Licenses KRAS G12C Inhibitor From GenFleet
89 Hunger Game: Hengrui Hunts New Cancer Drug With $200m BeyondSpring Tie-Up
89 Processa Licenses Global Rights For Ocuphire’s RX-3117
89 GSK Spends Heavily On iTeos’ TIGIT To Build A New IO Cornerstone
90 Innovent Acquires Chinese Rights To AnHeart’s Taletrectinib
90 Bristol Pays Out $200m For Agenus’ Preclinical Bispecific TIGIT
90 Sorrento Acquires Abivertinib Partner ACEA
91 MD Anderson Inks New Cancer Collaboration With Mirati
92 CLINICAL TRIAL LANDSCAPE
93 Sponsors by status
94 Sponsors by phase
95 Recent events
104 DRUG ASSESSMENT MODEL
104 EGFR inhibitors
106 ROS1 and NTRK gene fusions
106 ALK inhibitors
108 KRAS inhibitors
108 RET inhibitors
108 BRAF inhibitors
109 PARP inhibitors
109 MET inhibitors
110 PD-1/PD-L1 inhibitors
112 TIGIT inhibitor
112 Microtubule inhibitors
112 Folate analog metabolic inhibitor
113 VEGF inhibitors
113 Interleukin 1b antagonist
113 Post-immunotherapy
116 MARKET DYNAMICS
117 FUTURE TRENDS
117 Keytruda is forecast to remain the leading immunotherapy approved for NSCLC
117 Checkpoint inhibitors are expected to move into earlier stages of NSCLC
118 Approvals and subsequent uptake of new therapies in the post-immunotherapy setting will contribute significantly to growth in the NSCLC market
118 Alecensa is expected to continue leading the ALK inhibitor class due to strong results in the first-line setting, despite potential competition
119 Tagrisso will remain the best-selling EGFR inhibitor due to continued uptake in the first-line setting and a label expansion into the adjuvant setting
119 New EGFR inhibitors will address the EGFR exon 20 insertion mutation, which is associated with poor response to current treatments
120 The approval and uptake of MET inhibitors is expected to address unmet needs in patients with exon 14 skipping mutations
120 Recent approvals and subsequent uptake of therapies targeting new mutational drivers will support growth in the NSCLC market over the forecast period
120 Generic or biosimilar erosion of key brands will have minimal impact on growth
122 CONSENSUS FORECASTS
129 RECENT EVENTS AND ANALYST OPINION
129 Sintilimab for NSCLC (February 10, 2022)
130 Bavencio for NSCLC (February 8, 2022)
131 Ilaris for NSCLC (October 25, 2021)
133 Libtayo for NSCLC (September 19, 2021)
134 Rybrevant for NSCLC (September 19, 2021 and September 17, 2021)
136 Enhertu for NSCLC (September 18, 2021)
137 Ilaris for NSCLC (September 17, 2021)
138 Imfinzi for NSCLC (September 17, 2021)
140 Imfinzi for NSCLC (September 9, 2021)
141 Libtayo for NSCLC (August 5, 2021)
143 Plinabulin for NSCLC (August 4, 2021)
144 LN-145 for NSCLC (June 29, 2021)
146 Iressa for NSCLC (June 6, 2021)
148 Tecentriq for NSCLC (June 6, 2021)
150 CLN-081 for NSCLC (June 4, 2021)
152 DZD9008 for NSCLC (June 4, 2021)
153 Imfinzi for NSCLC (June 4, 2021)
155 Keytruda for NSCLC (June 4, 2021)
156 Lumakras for NSCLC (June 4, 2021)
157 Patritumab Deruxtecan for NSCLC (June 4, 2021)
158 Ameile for NSCLC (May 19, 2021)
160 Multiple Drugs for NSCLC (May 19, 2021)
161 TAK-788 for NSCLC (May 19, 2021)
162 Opdivo for NSCLC (April 10, 2021)
164 Poziotinib for NSCLC (April 10, 2021)
165 Telisotuzumab Vedotin for NSCLC (April 10, 2021)
167 Tecentriq for NSCLC (March 21, 2021)
168 Ilaris for NSCLC (March 9, 2021)
171 KEY UPCOMING EVENTS
174 KEY OPINION LEADER INSIGHTS
175 UNMET NEEDS
176 BIBLIOGRAPHY
179 APPENDIX
LIST OF FIGURES
35 Figure 1: Trends in incident cases of NSCLC, 2018–27
48 Figure 2: Overview of pipeline drugs for NSCLC in the US
48 Figure 3: Pipeline drugs for NSCLC, by company
49 Figure 4: Pipeline drugs for NSCLC, by drug type
49 Figure 5: Pipeline drugs for NSCLC, by classification
85 Figure 6: Probability of success in the NSCLC pipeline
92 Figure 7: Clinical trials in NSCLC
92 Figure 8: Top 10 drugs for clinical trials in NSCLC
93 Figure 9: Top 10 companies for clinical trials in NSCLC
93 Figure 10: Trial locations in NSCLC
94 Figure 11: NSCLC trials status
95 Figure 12: NSCLC trials sponsors, by phase
104 Figure 13: Datamonitor Healthcare’s drug assessment summary for NSCLC
116 Figure 14: Market dynamics in NSCLC
117 Figure 15: Future trends in NSCLC
131 Figure 16: Bavencio for NSCLC (February 8, 2022): Phase III – JAVELIN Lung 100
133 Figure 17: Ilaris for NSCLC (October 25, 2021): Phase III – CANOPY-1 (w/Pembrolizumab and Chemo)
134 Figure 18: Libtayo for NSCLC (September 19, 2021): Phase III – EMPOWER-Lung 3
137 Figure 19: Enhertu for NSCLC (September 18, 2021): Phase II – DESTINY-Lung01
140 Figure 20: Imfinzi for NSCLC (September 17, 2021): Phase II – COAST
141 Figure 21: Imfinzi for NSCLC (September 9, 2021): Phase III – POSEIDON (w/Tremelimumab)
143 Figure 22: Libtayo for NSCLC (August 5, 2021): Phase III – EMPOWER-Lung 3
144 Figure 23: Plinabulin for NSCLC (August 4, 2021): Phase III – DUBLIN-3
146 Figure 24: LN-145 for NSCLC (June 29, 2021): Phase II – IOV-COM-202
148 Figure 25: Iressa for NSCLC (June 6, 2021): Phase III – IMPACT, WJOG6410L (Japan)
150 Figure 26: Tecentriq for NSCLC (June 6, 2021): Phase III – IMpower 010 (PD-L1 Selected, Post-Adjuvant)
152 Figure 27: CLN-081 for NSCLC (June 4, 2021): Phase I/IIa – EGFR Exon 20 Mut.
155 Figure 28: Imfinzi for NSCLC (June 4, 2021): Phase III – PACIFIC
160 Figure 29: Ameile for NSCLC (May 19, 2021): Phase III – AENEAS (China)
162 Figure 30: TAK-788 for NSCLC (May 19, 2021): Phase I/II – EXCLAIM
164 Figure 31: Opdivo for NSCLC (April 10, 2021): Phase III – CheckMate-816
167 Figure 32: Telisotuzumab Vedotin for NSCLC (April 10, 2021): Phase II – c-Met+
170 Figure 33: Ilaris for NSCLC (March 9, 2021): Phase III – CANOPY-2
171 Figure 34: Key upcoming events in NSCLC (one of five)
172 Figure 35: Key upcoming events in NSCLC (two of five)
172 Figure 36: Key upcoming events in NSCLC (three of five)
173 Figure 37: Key upcoming events in NSCLC (four of five)
173 Figure 38: Key upcoming events in NSCLC (five of five)
LIST OF TABLES
16 Table 1: Five-year survival rates of lung cancer, by stage at diagnosis
17 Table 2: Non-small cell lung cancer staging and corresponding TNM classifications
20 Table 3: Preferred branded first-line treatment regimens for patients with Stage IV EGFR+ NSCLC
21 Table 4: Preferred branded treatment regimens for patients who progress on first- and second-generation EGFR TKIs
22 Table 5: Preferred branded first- and second-line treatment regimens for patients with Stage IV ALK+ NSCLC
23 Table 6: Preferred treatment regimens for patients with Stage IV ROS1+ NSCLC
24 Table 7: Preferred treatment regimens for patients with Stage IV BRAF V600E mutated NSCLC
25 Table 8: Preferred treatment regimens for patients with Stage IV NSCLC and a MET exon 14 skipping mutation
26 Table 9: Preferred treatment regimens for patients with Stage IV RET+ NSCLC
27 Table 10: Preferred treatment regimens for patients with Stage IV NTRK+ NSCLC
28 Table 11: Preferred branded first-line treatment regimens for patients with advanced NSCLC and PD-L1+ TPS ≥50%
29 Table 12: Preferred branded first-line treatment regimens for patients with advanced NSCLC and PD-L1+ TPS ≥1–49%
30 Table 13: Preferred branded first-line treatment regimens for patients with advanced NSCLC
32 Table 14: Preferred branded second-line or later treatment regimens for patients with metastatic NSCLC
34 Table 15: Incident cases of NSCLC, 2018–27
36 Table 16: Incident cases of NSCLC, by gender, 2018
39 Table 17: Marketed drugs for NSCLC
50 Table 18: Pipeline drugs for NSCLC in the US
123 Table 19: Historical global sales, by drug ($m), 2016–20
126 Table 20: Forecasted global sales, by drug ($m), 2022–26
129 Table 21: Sintilimab for NSCLC (February 10, 2022)
130 Table 22: Bavencio for NSCLC (February 8, 2022)
132 Table 23: Ilaris for NSCLC (October 25, 2021)
133 Table 24: Libtayo for NSCLC (September 19, 2021)
135 Table 25: Rybrevant for NSCLC (September 19, 2021 and September 17, 2021)
136 Table 26: Enhertu for NSCLC (September 18, 2021)
138 Table 27: Ilaris for NSCLC (September 17, 2021)
139 Table 28: Imfinzi for NSCLC (September 17, 2021)
140 Table 29: Imfinzi for NSCLC (September 9, 2021)
142 Table 30: Libtayo for NSCLC (August 5, 2021)
143 Table 31: Plinabulin for NSCLC (August 4, 2021)
145 Table 32: LN-145 for NSCLC (June 29, 2021)
147 Table 33: Iressa for NSCLC (June 6, 2021)
148 Table 34: Tecentriq for NSCLC (June 6, 2021)
151 Table 35: CLN-081 for NSCLC (June 4, 2021)
153 Table 36: DZD9008 for NSCLC (June 4, 2021)
154 Table 37: Imfinzi for NSCLC (June 4, 2021)
156 Table 38: Keytruda for NSCLC (June 4, 2021)
157 Table 39: Lumakras for NSCLC (June 4, 2021)
158 Table 40: Patritumab Deruxtecan for NSCLC (June 4, 2021)
159 Table 41: Ameile for NSCLC (May 19, 2021)
160 Table 42: Multiple Drugs for NSCLC (May 19, 2021)
161 Table 43: TAK-788 for NSCLC (May 19, 2021)
163 Table 44: Opdivo for NSCLC (April 10, 2021)
164 Table 45: Poziotinib for NSCLC (April 10, 2021)
165 Table 46: Telisotuzumab Vedotin for NSCLC (April 10, 2021)
168 Table 47: Tecentriq for NSCLC (March 21, 2021)
169 Table 48: Ilaris for NSCLC (March 9, 2021)
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