Disease Analysis: Non-Small Cell Lung Cancer (NSCLC)
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 2021, 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 as sequential therapy for locally advanced patients following chemoradiation minimizes its direct competition with established immunotherapies, allowing the drug to secure a modest market share. Furthermore, its development program in combination with novel therapies monalizumab, oleclumab, and domvanalimab could potentially deter competition expected from other checkpoint inhibitors in development for the Stage III setting.
- 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 8.7%, 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 an NDA filing for plinabulin, as well as PDUFA dates for Libtayo and Enhertu in the first-line setting and previously treated HER2-positive setting, respectively.
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
49 PIPELINE DRUGS
76 KEY REGULATORY EVENTS
76 Merck KGaA’s Tepmetko Secures English Funding For NSCLC
76 Tislelizumab & Tremelimumab Among Latest Filings In EU
76 Tabrecta Among Four Drugs To Receive Thumbs Up From EMA
76 Lilly To Decide Next Steps After Formal FDA ‘Nay’ For First Chinese PD-1
76 Novartis Due For Oral Explanation At EMA For Capmatinib
77 Pricing Deals Spell Good News For Exkivity & Vimizin In England
77 Scotland Okays First ILAP Drugs For Reimbursement
77 BMS Gets First Immunotherapy Approval In Neoadjuvant Lung Cancer, Quickly
78 US Poziotinib Approval Expected
78 US FDA Puts Mirati’s KRAS Challenger To Amgen In The Slow Lane
79 Foreign Data: Sintilimab’s Development Shows What Not To Do When Pursuing US Approval
79 Casualty Of Change? Innovent/Lilly’s Chinese PD-1 Inhibitor Sintilimab Falls Hard At US FDA Panel
79 New Submissions Under FDA Review
80 Tremelimumab Filed In EU For NSCLC
80 Keeping Track: Breakthrough Designations Fuel Expansion Of Genomically-Defined NSCLC Therapy
80 Pfizer, CStone Score China’s Seventh Immuno-Oncology Approval
80 13 New Drugs On Track For EU Approval
81 Rx For Immuno-Oncology Excess? Top US FDA Cancer Officials Take On Development ‘Wild West’
81 Spectrum Eyes Niche NSCLC Market With Poziotinib NDA
81 Evrysdi & Tagrisso Among Myriad Products To Win English Funding
82 Sotorasib Gets Green Light From EMA For KRAS G12C Mutated NSCLC
82 Scotland’s HTA Body OKs New Indications For Tagrisso And Tecentriq
82 EMA Schedules Oral Explanation Meetings For Four Sponsors
83 Tyvyt Regulatory Setback
83 Tecentriq Becomes First PD-1/L1 For Adjuvant NSCLC
83 EMA Recommends Granting Conditional Marketing Authorization To Rybrevant
84 EGFR Exon20-Mutated NSCLC Gets A New Option With Exkivity
84 Roche/Blueprint’s Gavreto Among Nine Drugs To Win EU Marketing Thumbs Up
84 Amgen Strikes Early Access Deal In England For Lung Cancer Drug Lumakras
85 Mobocertinib, Asciminib & Surufatinib Among Latest New Filings In EU
85 More PD-1/L1 Inhibitor Adjuvant Submissions
85 Foundation Medicine Obtains FDA Approval For Non-Small Cell Lung Cancer Companion Diagnostic
86 Mirati Marks Another Milestone With Adagrasib
86 Approvals Boost AstraZeneca’s China Cancer Presence
86 NICE Says Yes To Tecentriq For NSCLC
87 Guardant Health Receives FDA Companion Diagnostic Nod
88 PROBABILITY OF SUCCESS
89 LICENSING AND ASSET ACQUISITION DEALS
89 BMS Hopes Turning Point Buyout Will Fare Better Than Roche’s Ignyta Acquisition
89 Regeneron Takes Full Libtayo Rights As March Into Oncology Progresses
89 Bayer Shuffles Atara’s CAR-Ts Out Of Its Cell Therapy Deck
90 Taiho To Pay $275m Up Front For CLN-081/TAS6417
90 Gilead Gets 5T4-Targeted NK Cell Therapy Candidate From Dragonfly
90 Lilly/Innovent Deal Follows FDA’s Rejection Of Tyvyt In Lung Cancer
91 Tianjin Tasly Inks $40m Licensing Deal With Sutro For ADC Cancer Treatment
91 Novartis Expands BeiGene Tie-Up To TIGIT Inhibitor In $1bn-Plus Option Deal
91 Taiho Takes Up Japan/Asia Option For Arcus Oncology Antibodies
92 Blueprint May Corner EGFR Exon Mutated Lung Cancer Market With Lengo Buyout
92 Deal Watch: Sanofi To Tap Owkin’s AI, Machine Learning In Oncology
92 Zai Lab Licenses Two Blueprint Medicines EGFR Inhibitors
92 Takeda Licenses Two Drugs To Calithera
93 Turning Point And EQRx Announce Clinical Collaboration
93 Fosun Licenses Cancer Supportive Care Drug Rights From Helsinn
93 GSK Exits $4.2bn Cancer Drug Deal With Merck KGaA After Multiple Failures
94 Innovent In-Licenses KRAS G12C Inhibitor From GenFleet
94 Hunger Game: Hengrui Hunts New Cancer Drug With $200m BeyondSpring Tie-Up
94 Processa Licenses Global Rights For Ocuphire’s RX-3117
95 GSK Spends Heavily On iTeos’ TIGIT To Build A New IO Cornerstone
95 Innovent Acquires Chinese Rights To AnHeart’s Taletrectinib
96 CLINICAL TRIAL LANDSCAPE
97 Sponsors by status
98 Sponsors by phase
99 Recent events
109 DRUG ASSESSMENT MODEL
109 EGFR inhibitors
111 ROS1 and NTRK gene fusions
112 ALK inhibitors
113 KRAS inhibitors
113 RET inhibitors
114 BRAF inhibitors
114 PARP inhibitors
114 MET inhibitors
115 PD-1/PD-L1 inhibitors
117 CD73 inhibitor
117 TIGIT inhibitors
118 Natural killer cell therapy
119 Microtubule inhibitors
119 Folate analog metabolic inhibitor
119 VEGF inhibitors
120 Interleukin 1β antagonist
120 Post-immunotherapy
123 MARKET DYNAMICS
124 FUTURE TRENDS
124 Keytruda is forecast to remain the leading immunotherapy approved for NSCLC
125 Checkpoint inhibitors are expected to move into earlier stages of NSCLC
125 Approvals and subsequent uptake of new therapies in the post-immunotherapy setting will contribute significantly to growth in the NSCLC market
125 Alecensa is expected to continue leading the ALK inhibitor class due to strong results in the first-line setting, despite potential competition
126 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
126 New EGFR inhibitors will address the EGFR exon 20 insertion mutation, which is associated with poor response to current treatments
126 The approval and uptake of MET inhibitors is expected to address unmet needs in patients with exon 14 skipping mutations
127 Recent approvals and subsequent uptake of therapies targeting new mutational drivers will support growth in the NSCLC market over the forecast period
127 Generic or biosimilar erosion of key brands will have minimal impact on growth
129 CONSENSUS FORECASTS
136 RECENT EVENTS AND ANALYST OPINION
136 Rybrevant for NSCLC (June 3, 2022)
137 Rybrevant for NSCLC (June 3, 2022)
139 CLN-081 for NSCLC (May 31, 2022)
140 Adagrasib for NSCLC (May 26, 2022)
141 CAN-2409 for NSCLC (May 26, 2022)
142 Multiple Drugs for NSCLC (May 11, 2022)
143 Sintilimab for NSCLC (February 10, 2022)
145 Bavencio for NSCLC (February 8, 2022)
146 Ilaris for NSCLC (October 25, 2021)
147 Libtayo for NSCLC (September 19, 2021)
149 Rybrevant for NSCLC (September 19, 2021 and September 17, 2021)
150 Enhertu for NSCLC (September 18, 2021)
152 Ilaris for NSCLC (September 17, 2021)
153 Imfinzi for NSCLC (September 17, 2021)
155 Imfinzi for NSCLC (September 9, 2021)
156 Libtayo for NSCLC (August 5, 2021)
158 Plinabulin for NSCLC (August 4, 2021)
159 LN-145 for NSCLC (June 29, 2021)
161 Iressa for NSCLC (June 6, 2021)
163 Tecentriq for NSCLC (June 6, 2021)
165 CLN-081 for NSCLC (June 4, 2021)
167 DZD9008 for NSCLC (June 4, 2021)
168 Imfinzi for NSCLC (June 4, 2021)
170 Keytruda for NSCLC (June 4, 2021)
171 Lumakras for NSCLC (June 4, 2021)
172 Patritumab Deruxtecan for NSCLC (June 4, 2021)
174 KEY UPCOMING EVENTS
177 KEY OPINION LEADER INSIGHTS
178 UNMET NEEDS
179 BIBLIOGRAPHY
182 APPENDIX
LIST OF FIGURES
35 Figure 1: Trends in incident cases of NSCLC, 2018–27
49 Figure 2: Overview of pipeline drugs for NSCLC in the US
49 Figure 3: Pipeline drugs for NSCLC, by company
50 Figure 4: Pipeline drugs for NSCLC, by drug type
50 Figure 5: Pipeline drugs for NSCLC, by classification
88 Figure 6: Probability of success in the NSCLC pipeline
96 Figure 7: Clinical trials in NSCLC
96 Figure 8: Top 10 drugs for clinical trials in NSCLC
97 Figure 9: Top 10 companies for clinical trials in NSCLC
97 Figure 10: Trial locations in NSCLC
98 Figure 11: NSCLC trials status
99 Figure 12: NSCLC trials sponsors, by phase
109 Figure 13: Datamonitor Healthcare’s drug assessment summary for NSCLC
123 Figure 14: Market dynamics in NSCLC
124 Figure 15: Future trends in NSCLC
137 Figure 16: Rybrevant for NSCLC (June 3, 2022): Phase I – CHRYSALIS (Advanced NSCLC)
139 Figure 17: Rybrevant for NSCLC (June 3, 2022): Phase I – CHRYSALIS-2 (w/Lazertinib)
143 Figure 18: Tiragolumab and Tecentriq for NSCLC (May 11, 2022): Phase III – SKYSCRAPER-01
146 Figure 19: Bavencio for NSCLC (February 8, 2022): Phase III – JAVELIN Lung 100
147 Figure 20: Ilaris for NSCLC (October 25, 2021): Phase III – CANOPY-1 (w/Pembrolizumab and Chemo)
149 Figure 21: Libtayo for NSCLC (September 19, 2021): Phase III – EMPOWER-Lung 3
152 Figure 22: Enhertu for NSCLC (September 18, 2021): Phase II – DESTINY-Lung01
155 Figure 23: Imfinzi for NSCLC (September 17, 2021): Phase II – COAST
156 Figure 24: Imfinzi for NSCLC (September 9, 2021): Phase III – POSEIDON (w/Tremelimumab)
158 Figure 25: Libtayo for NSCLC (August 5, 2021): Phase III – EMPOWER-Lung 3
159 Figure 26: Plinabulin for NSCLC (August 4, 2021): Phase III – DUBLIN-3
161 Figure 27: LN-145 for NSCLC (June 29, 2021): Phase II – IOV-COM-202
163 Figure 28: Iressa for NSCLC (June 6, 2021): Phase III – IMPACT, WJOG6410L (Japan)
165 Figure 29: Tecentriq for NSCLC (June 6, 2021): Phase III – IMpower 010 (PD-L1 Selected, Post-Adjuvant)
167 Figure 30: CLN-081 for NSCLC (June 4, 2021): Phase I/IIa – EGFR Exon 20 Mut.
170 Figure 31: Imfinzi for NSCLC (June 4, 2021): Phase III – PACIFIC
174 Figure 32: Key upcoming events in NSCLC (one of five)
175 Figure 33: Key upcoming events in NSCLC (two of five)
175 Figure 34: Key upcoming events in NSCLC (three of five)
176 Figure 35: Key upcoming events in NSCLC (four of five)
176 Figure 36: 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
51 Table 18: Pipeline drugs for NSCLC in the US
130 Table 19: Historical global sales, by drug ($m), 2017–21
133 Table 20: Forecasted global sales, by drug ($m), 2022–26
136 Table 21: Rybrevant for NSCLC (June 3, 2022)
138 Table 22: Rybrevant for NSCLC (June 3, 2022)
139 Table 23: CLN-081 for NSCLC (May 31, 2022)
141 Table 24: Adagrasib for NSCLC (May 26, 2022)
142 Table 25: CAN-2409 for NSCLC (May 26, 2022)
143 Table 26: Multiple Drugs for NSCLC (May 11, 2022)
144 Table 27: Sintilimab for NSCLC (February 10, 2022)
145 Table 28: Bavencio for NSCLC (February 8, 2022)
146 Table 29: Ilaris for NSCLC (October 25, 2021)
148 Table 30: Libtayo for NSCLC (September 19, 2021)
150 Table 31: Rybrevant for NSCLC (September 19, 2021 and September 17, 2021)
151 Table 32: Enhertu for NSCLC (September 18, 2021)
153 Table 33: Ilaris for NSCLC (September 17, 2021)
154 Table 34: Imfinzi for NSCLC (September 17, 2021)
155 Table 35: Imfinzi for NSCLC (September 9, 2021)
157 Table 36: Libtayo for NSCLC (August 5, 2021)
158 Table 37: Plinabulin for NSCLC (August 4, 2021)
160 Table 38: LN-145 for NSCLC (June 29, 2021)
162 Table 39: Iressa for NSCLC (June 6, 2021)
163 Table 40: Tecentriq for NSCLC (June 6, 2021)
166 Table 41: CLN-081 for NSCLC (June 4, 2021)
168 Table 42: DZD9008 for NSCLC (June 4, 2021)
169 Table 43: Imfinzi for NSCLC (June 4, 2021)
171 Table 44: Keytruda for NSCLC (June 4, 2021)
172 Table 45: Lumakras for NSCLC (June 4, 2021)
173 Table 46: Patritumab Deruxtecan for NSCLC (June 4, 2021)
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